c protein concentrates in paediatric septic patients giacomo monti, md university vita – salute s....
TRANSCRIPT
C protein concentrates in paediatric septic
patientsGiacomo Monti MD
University Vita ndash Salute S Raffaele MilanoDepartment of
Anesthesia and Intensive Care
2
montigiacomohsrit
3
C- protein concentrate
C proteinbull Virtually side ndash effect free drugbull No bleeding riskbull Few papers but very often used in clinical
practice expecially in Italybull Active in a disease that causes severe
mortality and morbidity
4
Protein C
bull CEPROTIN(Human)BAXTER
bull PC
bull Zymogen
bull (human) protein C concentrate(s)
bull Protein C zymogen (concentrate)
bull XIGRIS(Recombinant)LILLY
bull APC rhAPC
bull Enzyme
bull Activated protein C
bull Drotrecogin alfa activated
4
55
6
PC in literature
bull Extensive literature scan by PubMed Embase Google Scholar
bull Contact with expertbull Update to January 2009
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
2
montigiacomohsrit
3
C- protein concentrate
C proteinbull Virtually side ndash effect free drugbull No bleeding riskbull Few papers but very often used in clinical
practice expecially in Italybull Active in a disease that causes severe
mortality and morbidity
4
Protein C
bull CEPROTIN(Human)BAXTER
bull PC
bull Zymogen
bull (human) protein C concentrate(s)
bull Protein C zymogen (concentrate)
bull XIGRIS(Recombinant)LILLY
bull APC rhAPC
bull Enzyme
bull Activated protein C
bull Drotrecogin alfa activated
4
55
6
PC in literature
bull Extensive literature scan by PubMed Embase Google Scholar
bull Contact with expertbull Update to January 2009
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
3
C- protein concentrate
C proteinbull Virtually side ndash effect free drugbull No bleeding riskbull Few papers but very often used in clinical
practice expecially in Italybull Active in a disease that causes severe
mortality and morbidity
4
Protein C
bull CEPROTIN(Human)BAXTER
bull PC
bull Zymogen
bull (human) protein C concentrate(s)
bull Protein C zymogen (concentrate)
bull XIGRIS(Recombinant)LILLY
bull APC rhAPC
bull Enzyme
bull Activated protein C
bull Drotrecogin alfa activated
4
55
6
PC in literature
bull Extensive literature scan by PubMed Embase Google Scholar
bull Contact with expertbull Update to January 2009
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
4
Protein C
bull CEPROTIN(Human)BAXTER
bull PC
bull Zymogen
bull (human) protein C concentrate(s)
bull Protein C zymogen (concentrate)
bull XIGRIS(Recombinant)LILLY
bull APC rhAPC
bull Enzyme
bull Activated protein C
bull Drotrecogin alfa activated
4
55
6
PC in literature
bull Extensive literature scan by PubMed Embase Google Scholar
bull Contact with expertbull Update to January 2009
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
55
6
PC in literature
bull Extensive literature scan by PubMed Embase Google Scholar
bull Contact with expertbull Update to January 2009
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
6
PC in literature
bull Extensive literature scan by PubMed Embase Google Scholar
bull Contact with expertbull Update to January 2009
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
7
Sepsis in children US
bull In the United States there were 42000 cases of severe sepsis in children in 1995 in 1997 the total number of cases increased to 47700
bull Hospital mortality among US children with severe sepsis was 103
7
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
8
Sepsis in children US - 2
bull Sepsis is the 2nd cause of death among children 4th among infants
bull Children who develop severe sepsis consume substantial healthcare resources with an average length of stay of 31 days and cost of $40600
8
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
9
Sepsis in children Italy
bull In 2004-2005 lower overall incidence of sepsis severe sepsis and septic shock (79 16 and 21 of PICU admission)
bull Severe sepsis and septic shock had a mortality rate of 177 and 508 respectively
Incidence of and mortality due to sepsis severe sepsis and septic shock in Italian Pediatric Intensive Care Units a prospective national survey Wolfler A et al Intensive Care Med 2008 341690-7
9
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
1010
ldquoProtein C concentrations in children reach adult values at the age of 3 yrs Thismight indicate that the importance of protein C supplementation either as proteinC concentrate or as rhAPC is greater in young children than in adultsrdquo
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
11
The ldquoRESOLVErdquo study
Drotrecogin alfa (activated) in children with severe sepsis a multicentre phase III randomised controlled trial Nadel S et al Lancet 2007 369 836ndash43
Our results showed no significantdifference between groups in CTCOFR score
(p=0middot72) or in 28-day mortality (placebo 17middot5 DrotAA 17middot2 p=0middot93)
11
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
12
Author Year Journal NGerson 1993 Pediatrics 1Rivard 1995 J Pediatr 4Smith 1997 Lancet 12Rintala 1998 Crit Care Med 3Ettingshausen 1999 Semin Thromb Hemost 8Clarke 2000 Intensive Care Med 1Leclerc 2000 Crit Care Med 2White 2000 Blood 36De Kleijn 2003 Crit Care Med 30Fourrier 2003 Intensive Care Med 15Pettenazzo 2004 Minerva Anestesiol 8Silvani 2005 Minerva Anestesiol 11De Carolis 2008 Turk J Pediatr 1TOTAL 131
Summary of all published papers reporting on children patients
receiving protein C concentrates
12
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
13
Author N Setting SurvivalGerson 1 Meningococcal purpura fulminans 1Rivard 4 Meningococcal septic shock 4Smith 12 Meningococcal septic shock 12Rintala 3 Meningococcal septic shock 2Ettingshausen 8 Meningococcal septic shock 6Clarke 1 Meningoccal severe sepsis 1Leclerc 2 Meningococcal septic shock 2White 35 Septic shock and presumptive
meningococcemia33
De Kleijn 30 Severe sepsis or meningococcal disease 23
Fourrier 15 Meningococcal purpura fulminans 6Pettenazzo 8 Septic shock 6Silvani 11 Severe sepsis or septic shock 8De Carolis 1 Severe sepsis 1TOTAL 131 103
(79)
13
Summary of all published papers reporting on children patients
receiving protein C concentrates
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
14
bull Few papers account for more than half of published ndash treated patients
bull 3 ldquomajorrdquo papers 78 children (59)
14
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
15
Smith Lancet 1997
bull 12 patientsbull Meningoccemia and
septic shockbull GMSPS score predicted
mortality 80bull PRISM predicted
mortality 57bull Dose titrate to
concentration of 08-12 IUml (normal)
bull 100 survivalbull 2 (17) lower limb
amputation
bull No drug ndash related adverse event
15
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
16
Mean time to PC infusion begin in non amputated 12 (31) hMean time to PC infusion begin in amputated 60 (170) h
plt001
Use of protein-C concentrate heparin and haemodiafiltration in meningococcus-induced purpura fulminans Smith OP et al Lancet 1997 350 1590ndash93 16
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
17
White Blood 2000
bull 36 patients (some adults mean age 12)
bull Meningococcemia and septic shock
bull GMSPS score predicted mortality 50
bull Dose bolus 100 IUkg and infusion 10 IUkgh
bull 92 survivalbull 4 (12) amputation
bull No drug ndash related adverse event
17
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
18
Four amputation 2 patients received PC after 24 hours to admission
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia White B et al Blood 2000 96 3719-3724 18
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
19
De Kleijn Crit Care Med 2003
bull Only RCT double blinde PC vs placebo
bull 40 patients (10 placebo 30 treatment)
bull Meningoccemia and septic shock
bull Fase two study (dose findings safety)
bull 1 placebo groupbull 3 treatment groups
incremental doses (50 100 150 IUkg6h
19
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
20
Main findings
MortalityNot powered to achieve a
significant result
No linear trend comparing predicted versus observed mortality
Fascinating result compared to predicted mortality
Group PRISM predicted mortality
Actual mortality
placebo 67 20
50 IUkg 35 9
100 IUkg 26 11
150 IUkg 60 50
Overall (drug)
40 23
Adapted from De Kleijn et al Crit Care Med 2003 311839-47
20
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
21
Main findings - 2
bull Supplementation of PC is effective
bull Concentration is dose ndash dependant
21
bull 50 IUkg6 h restore normal PC value (08-12 IUml)bull 100 ndash 150 IUkg6h obtain 2-25 folds normal value
bull Effect on concentration is stable in the 6 hours beetwen doses
Dose response - PC
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
22
Main findings - 3
Dose response ndash aPCbull PC is activated by patientsbull Activation is dose ndash
dependant
bull With a 100 - 150 IUkg6 h schedule peak aPC is significantly higher
bull Effect of activation is not mantained in the 6-hours ldquowindowrdquo
22
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
23
Main findings - 4
Safetybull 4 amputations (not
attributed to study drugs)
bull 1 not serious bleeding event in a patient with severe DIC
23
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
24
Lessons from literature - 1
bull Real efficacy ndashmortality reductionndash is not definitively established quality of evidence is poor
bull Safety is high
bull We need a RCT trial
24
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
25
Lessons from literature - 2
bull If you decide to use PC do use preferably within 24 hours from admission
bull A ldquosuggestedrdquo schedulendash Test dose of 10 IUkgndash From 100 to 150 UIkg first bolus dosendash Begin a perfusion that gives up a daily cumulative
dose of 400-600 IUkg or use bolus at least every 6 hours
25
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
26
Hot topics
bull From 131 patients published just 8 children were not affected by meningococcal disease
bull PC is always activated Should we really need activation
26
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
27
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS Faust el al NEJM 2001 345408-16 27
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
28
A-PC effect
282007
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
29
A-PC anticoagulative properties
bull The A-PC PS complex binds to VIIIa and Va and inactivate them
bull Decreased Thrombin Generationbull Decreased Fibrin Formation and
reduced amplification of inflammatory pathway
A-PC Side effects
29
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
3030
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
31
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
31
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
-
32
Protein C concentrations in severe sepsis an early directional change in plasma levels predicts outcome Shorr F et al Crit Care 2006 10 R92
Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newbornsldquoThe differences between survivors and non-survivors were statistically significant (respectively for ATIII P=0003 and for PC P=000002) A highly statistically significant correlation (P=00016) between plasma PC functional level and risk of death was found in patients with sepsisrdquoLauterbach R et al Eur J Pediatr 2006165585-9
Liaw PC et al Patients with severe sepsis vary markedly in their ability to generate activated protein C Blood 20041043958-3964
Lack of PC ndash EPCR interaction
32
33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
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33
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
33
34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
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34
APCs direct effects on cells include (i)alteration of gene expression profiles (ii)anti-inflammatory activities(iii)Antiapoptotic(iv)endothelial barrier stabilization
Mediated by a Gi protein intracellular pathway
EPCR binds to a-PC
34
35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
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35
PC and endothelium
Three possible pathwaysbull Lack of PC ndash EPCR interactionbull EPCR binds to
ndash Activated PCndash Not-activated PC
35
36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
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36
Bae JS et al Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand Thromb Haemost 2008 100 101ndash109
The ligand occupancy of EPCR couples PAR-1 to Gi proteinThe ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup et al Blood 2007 110 3909ndash3916
EPCR binds to PC (and thrombin)
36
37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
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37
wild type PC
Modified non anticoagulant PC
Unfortunately up to now just in mice 37
38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
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38
montigiacomohsrit
Thanks
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
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-
3939
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
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-
For these and further slides on these topics please feel free to visit the
metcardioorg website
httpwwwmetcardioorgslideshtml
- Slide 1
- Slide 2
- Slide 3
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