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HGD Hendriks MD, PhD
University Medical Center Groningen
Balanced Transfusion Resuscitation
Transparency in Transfusion Medicine 2013Transparency in Transfusion Medicine 2013
“Balancing”
Preoperative Peroperative Postoperative
1
2
3
BalancedCoagulation management is an understanding of
this balance
Perfect Haemostasis:
No bleedingNo thrombotic events
- Balance the benefits of haemostatic actions against the risks- Haemostasis: platelets, coagulation proteins, fibrinolysis & endothelium- Haemostasis: monitoring
- Balance in Trauma and Obstetrics
Benefit of Prohemostatic Actions balanced with the risk of Adverse Events
Renal insufficiency, Cardiovascular complications, AnaphylaxisAprotinin
AnaphylaxisProtamine sulfate
Anaphylactoid Reaction (IV administration)Vitamin K
Arterial thrombotic eventsrFVIIa
Urinary tract obstruction (Hematuria)Epileptic insult
Lysine Analogs (Tranexamic Acid)
Acute Coronary SyndromeHyponatremia
DDAVP (Desmopressin)
Thrombotic complications4FC
TRALI, fever, allergic reactions, Platelets
TACO,TRALI, Fever,hemolysisRBC
TRALI, TACO, Allergic/anaphylactic reactionsFFP
Adverse EventProcoagulant Action
Panday S, Vyas GN. Adverse effects of plasma transfusion. Transfusion 2012;52:65S-79S
Carson JL et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012;157:49-58
Refaai et al. Platelet transfusions: impact on haemostasis, thrombosis, inflammation and clinical outcomes. Thromb Res. 2011127: 287-91
M.Levi. Safety of Prohemostatic Interventions. Semin Thromb Hemost 2012;38:292-298
PlateletsNormal range: 150.000 – 350.000 x 109/L
average life span Platelet ~ 10 days each day 15 each day 15 –– 35 x 1035 x 1099/L new platelets/L new platelets
Consensus:Consensus:
Invasive procedures: 50 x 109/L Neurosurgery: 100 x 109/L Neuraxis Blockade: 50 x 109/L
Assumption: all other components of coagulation system are intact
Function of PlateletsNo clinical Test for Platelet Function
Thromboelastography/metry is often used to treat andguide platelet administration
but does not reflect the effect of aspirin/clopidogrel
or a deficient von Willebrand factor function.
Trentalange MJ. Walts LF. A comparision of thromboelastogram and template bleeding time in the evaluation of platelet function after aspirin ingestion. J Clin Anesth 1991;3(5);377-81Mousa et al. Comparison of the effect of different platelet GPIIb/IIIa antagonists on the dynamics of platelet/fibrin-mediated clot strength induced using thromboelastography. Thromb Res 2001;104:49-56
Coagulation Proteins
TF+VIIa
Xa + Va
IIa
Fibrine
XIa
IXa
VIIIa
PlateletPlateletactivationactivation
Concentration
Rea
ctio
nra
te
0 9 20 30 40 0 9 20 30 40 50 60 70 50 60 70 80 90 10080 90 100
INR: 3 1.8 1.2 1.0
Coagulation activity
A level of 1.5 times the upper limit of the PT and aPTT A level of 1.5 times the upper limit of the PT and aPTT is generally considered a risk for bleeding during surgery is generally considered a risk for bleeding during surgery
Assumption: all other components of coagulation system are intact
Classical Coagulation Tests
PT & aPTTProvide
Important, but limited information
Ungoing blood loss: retrospective analysis
These test don’t predict blood lossThese test don’t predict blood lossThey only measure the initial stages of fibrin formationThey only measure the initial stages of fibrin formation
Haemostasis in end-stage Liver Disease
Mannucci. Abnormal hemostasis test and bleeding in chronic liver disease: are they related? No. J Thromb Haem 2006;4:721-723
FibrinolysisPlasminogen
FibrinolysistPA TAFI
Coagulation ProteinsFVIIIProteïne C/S, AT
Coagulation ProteinsFactor II, V, VII, IX, X, XI
PlateletsVon WillebrandADAMTS-13
PlateletsThrombopenie/pathie
Liver transplant patients are in balanceLiver transplant patients are in balance
They fly low
Haemostasis in end-stage Liver Disease
FibrinolysisPlasminogen
FibrinolysistPA TAFI
Coagulation ProteinsFVIIIProteïne C/S, AT
Coagulation ProteinsFactor II, V, VII, IX, X, XI
PlateletsVon WillebrandADAMTS-13
PlateletsTrombopenie/pathiePlatelet count
PT, aPTT
Fibrinogen
Fibrinolysis
Anti-Coagulants
Interactions
Liver Transplantation
Hepatitis Cirrhosis Primary Biliary Cirrhosis
PT = 21 sec aPTT 42 sec
Platelet count 78
Fibrinolysis
Plasminogen Plasmin
FIBRIN
Hyperfibrinolysis:CPBOLTTraumaObstetricsOrthopaedic surgery
ADP-ase b b b b
Intact vessel wall
NO
FVIIa
FVIIa
PGI2
Collagen (subendothelial)
Endothelial cell
Platelet Activated platelet
Breached vessel wall
Vasoconstriction
Von Willebrand Factor (Intermediary between collagen & platelet)
Tissue factor
FVIIa
Thrombin
FVIIa
FVIIa = activated FVII
GPIIb/IIIa – fibrinogen - GPIIb/IIIa
ADP-aseNO PGI2
PlateletPlatelet activationactivation
Thrombomodulin
TFPI
AT
Heparan sulfate
AT = antithrombin
TFPI = tissue factor pathway inhibitor
APC = activated protein C
tPA = tissue Plasminogen activator
Thrombomodulin
Blood flow
Intact vessel wall
TFPI
APC APC
ATAT
APC tPA
tPA
ADP-ase b b b b
Intact vessel wall
NO
FVIIa
FVIIa
PGI2
Collagen (subendothelial)
Endothelial cell
Platelet Activated platelet
Breached vessel wall
Vasoconstriction
Von Willebrand Factor (Intermediary between collagen & platelet)
Tissue factor
FVIIa
Thrombin
FVIIa
FVIIa = activated FVII
GPIIb/IIIa – fibrinogen - GPIIb/IIIa
ADP-aseNO PGI2
PlateletPlatelet activationactivation
Thrombomodulin
TFPI
AT
Heparan sulfate
AT = antithrombin
TFPI = tissue factor pathway inhibitor
APC = activated protein C
tPA = tissue Plasminogen activator
Thrombomodulin
Blood flow
Intact vessel wall
TFPI
APC APC
ATAT
APC tPA
tPA
ADP-ase b b b b
Intact vessel wall
NO
FVIIa
FVIIa
PGI2
Collagen (subendothelial)
Endothelial cell
Platelet Activated platelet
Breached vessel wall
Vasoconstriction
Von Willebrand Factor (Intermediary between collagen & platelet)
Tissue factor
FVIIa
Thrombin
FVIIa
FVIIa = activated FVII
GPIIb/IIIa – fibrinogen - GPIIb/IIIa
ADP-aseNO PGI2
PlateletPlatelet activationactivation
Thrombomodulin
TFPI
AT
Heparan sulfate
AT = antithrombin
TFPI = tissue factor pathway inhibitor
APC = activated protein C
tPA = tissue Plasminogen activator
Thrombomodulin
Blood flow
Intact vessel wall
TFPI
APC APC
ATAT
APC tPA
tPA
ADP-ase b b b b
Intact vessel wall
NO
FVIIa
FVIIa
PGI2
Collagen (subendothelial)
Endothelial cell
Platelet Activated platelet
Breached vessel wall
Vasoconstriction
Von Willebrand Factor (Intermediary between collagen & platelet)
Tissue factor
FVIIa
Thrombin
FVIIa
FVIIa = activated FVII
GPIIb/IIIa – fibrinogen - GPIIb/IIIa
ADP-aseNO PGI2
Platelet activationPlatelet activation
Thrombomodulin
TFPI
AT
Heparan sulfate
AT = antithrombin
TFPI = tissue factor pathway inhibitor
APC = activated protein C
tPA = tissue Plasminogen activator
Thrombomodulin
Blood flow
Intact vessel wall
TFPI
APC APC
ATAT
APC tPA
tPA
Endothelium
Role Endothelium is Crucial
There are no (clinical) tests to evaluate the function of the Endothelium
“Is a promising and necessary target for affecting haemostasis”
Jerrold H Levy et al: Multidisciplinary approach to the challenge of hemostasis. A&A 2010;110:354-364
Haemostasis
• Platelets • Coagulation Proteins• Fibrinolysis• Endothelium
Preconditions:Preconditions:
Preconditions of HaemostasisCalcium Ca++ : ≥ 0.9 mmol/LpH: 7.4 (Activity 50% at pH7.1)Anemia: Ht ≥ 30%Temperature: 37°C
- Coagulation Protein Activity 10%/ 1°C)- Platelet function *
Lier et al: Preconditions of hemostasis in trauma: a review. J Trauma 2008;65:951-960
* Kermode et al: Marked temperature dependence of the platelet calcium signal induced by human vWF. Blood 1999;94:199-207
TemperatureMJ Rohrer. Crit Care Med 1992;20:1402-1405
PT & aPTT
at
37 0C
Platelets, Coagulation Proteins, Endothelium
Fibrinolysis, pH, Temperature
Temperature
37°C vs 32° C
pH7.4 vs 7.1
Ramaker et al. Blood Coagul Fibrinolysis. 2009 Sep;20(6):436-9.Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser.
Interactions: Crucial
“Hypothermia is synergistic with acidosis and dilution
resulting in greater clinical coagulopathy than can be
explained by in vitro experimentation”
Howard et al: Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions. Siminars in Thrombosis and Hemostasis 2012;38:250-258
Finding the Balance in a bleeding patient:difficult
• Haemostasis: not entirely understood
• Coagulation Tests: limited value
• Preconditions of Haemostasis: important
• Influence of Interactions: crucial
Evidence from Trials?
Trials• Difficult to do research in bleeding patients• Evidence from Trials are often not suitable on patients in our Clinic• Lack of Standardized guidelines for administration:
- Blood Products - Pharmacological Agents
• The balance in a patient is strongly influenced by the clinical situation::
Not all massive haemorrhage is the same
Balance in Trauma and Obstetrics
Haemorrhage
Trauma: haemorrhage is the most common cause of death
Obstetrics: haemorrhage is the most important cause of maternal death
Balance in Trauma
Prior to trauma normal coagulation profile
Blood loss: Haemodilution, Hypothermia, Acidosis (lethal triad)
(fibrinolysis, Inflammation, infections)
Trauma-Induced CoagulopathyLarge amounts of crystalloids (and RBC’s):
iatrogenic coagulopathy, resuscitation-associated coagulopathy
Trauma-Induced CoagulopathyDilution: strong correlation between fluid volume and
coagulopathy
25 – 33% of severely trauma patients are coagulopathic upon arrival in hospital*
50% who received > 3 L prehospital fluid were coagulopathic10% who received 500 ml showed also coagulopathy**
InteractionsInteractions with hypothermia and acidosis are crucial
*Frith et al. The acute coagulopathy of trauma shock: clinical relevance. Surgeon2010;8:159-163
**Maegele et al. AG Polytrauma of the German Trauma Society (DGU). Injury 2007;38:298-304
20th century: FFP administration was guided by PT and aPTT, PLT < 50
Trauma-Induced CoagulopathyRBC : FFP = 4 : <1 65% mortalityRBC : FFP = 3 : >2 19% mortality
Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J of Trauma 2007;63:805-813
RBC : Platelet = 2 : >1 30-d survival compared to low ratios
Holcomb et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients Ann. Of Surgery 2008;248:447-458
Trauma-Induced Coagulopathy
Shift toward balanced ratio of blood components
RBC : FFP : PLT = 1 : 1 : 1
Mortality :correction coagulation?
All data retrospective. Randomized and Prospective data are lacking
Survivorship bias: survivors live longer to receive the treatment
Magnotti et al: improved survival after hemostatic resuscitation: does the emperor have no clothes? J trauma 2011;70:97-102
MTB protocol
RBC FFP PLT Fibrinogen (g)
3 3 1 1 : 1: 0.3
6 3 < 70 2 : 1 : 1
3 3 1 1 : 1: 0.3 <1.5 g/l
3 3 1 1 : 1: 0.3
4 2 1 2 : 1 : 0.5
5 5 1 1 : 1 : 0.2 2-4
3 3 1 1 : 1: 0.3 <1.5 g/l
3 3 1 1 : 1: 0.3
4 2 1 2 : 1: 0.5
3 3 1 1 : 1 : 0.3
5 3 1 2 : 0.6 : 0.2 2
Trauma-Induced CoagulopathyTherapy
Transfusion Ratio: RBC : FFP : PTL = 3 : 3 : 1
• Fibrinogen: ? Critical value of 1 g/L* 1.5 – 2.0 g/L**Fibrinogen: first in line for depletion. Cause? Dilution and Consumption(impaired bioavailability, impaired production, enhanced breakdown, inadequate replacement)
• rFVIIa: wide variability in timing and dosing. Effect?*• Tranexamic acid (CRASH-2 Trial, decrease in mortality, but no difference in
bleeding). Early administration. Dose: 10 -15 mg/kg Guided by TEG/ROTEM**
• No routine use of Desmopressine**
Blood Pressure (MAP 60 mmHg) (Systolic 80-100mmHg)**Hb = 5 mmol/L
* Knudson et al.Trauma, transfusions, and use of rFVIIa. J Am Coll Surg2011;212:87-95
**Rossaint et al. Management of bleeding following major trauma: an updated European guideline. Critical Care 2010;14:R52
Trauma-Induced CoagulopathyTherapy
• Hypothermia: 0C“Hypothermia is a ominous clinical sign accompanied by high mortality”*
• Hypothermia: cold infusion, heat loss on the street (40% in trauma patients)• Mild (<36 °C) and moderate (32 – 36 °C) have already deleterious effect Smith et al: Avoiding hypothermia in the trauma patient. Curr Opin Aenesthesiol 2000;13:167-174
Direct warming up the patient, warming up fluids
• Acidosis: serum lactate (& base deficit)Metabolic dysfunction secondary to hypoperfusion and administration NaCl 0.9%Reversal of Acidosis does not always result in return of clotting functionMechanism? Uncertain (activation Protein C by thrombomodulin?)**
*Rossaint et al. Management of bleeding following major trauma: an updated European guideline. Critical Care 2010;14:R52
** Cohen et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection an death in traumapatients. Ann Surg 2012;255:379-385
PostPartum Hemorrhage
Postpartum HemorrhagePostpartum hemorrhage (PPH) has been defined as:blood loss in excess of 500 ml after a vaginal birth,
1000 ml after a cesarean delivery
No factors predict PPH:every pregnancy is at risk
Fibrinogen: < 2g/L positive predictor of postpartum haemorrhage*
No clinical trials to guide management
*Charbit et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost2007;5:266-73
Balance in Obstetrics
40% increase in Plasma Volume25% increase ErythrocytesHt decrease, Platelet Count drop
FibrinolysisFibrinolysistPA,
Coagulation ProteinsFI, FVII, FVIII, Protein C/S
Coagulation ProteinsUnchanged: FV, FXIIIUnchanged: AT
PlateletsVWF
PlateletsThrombopenie
PT and aPTT:
Unchanged
Platelet Count
TEG/ROTEM:
Hypercoaguable*
Lange et al. Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67:426-35
Solomon et al. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaest 2012;109:851-63
*Sharma et al. Thromboelastographic changes in healthy parturients and postpartum woman. Anest & Analg 1997;85:94-98
Balance in Obstetrics
40% increase in Plasma Volume25% increase ErythrocytesHt decrease, Platelet Count drop
FibrinolysisFibrinolysistPA,
Coagulation ProteinsFI, FVII, FVIII, Protein C/S
Coagulation ProteinsUnchanged: FV, FXIIIUnchanged: AT
PlateletsVWF
PlateletsThrombopenie
PT and aPTT:
Unchanged
Platelet Count
TEG/ROTEM:
Hypercoaguable*
Lange et al. Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67:426-35
Solomon et al. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaest 2012;109:851-63
*Sharma et al. Thromboelastographic changes in healthy parturients and postpartum woman. Anest & Analg 1997;85:94-98
Bleeding & Medication History
Balance in ObstetricsCause of bleedig: uterine atony (oxytocin, ergometrine)
Damage control: balloon tamponade, embolization, hysterectomyDilutionalDilutional CoagulopathyCoagulopathy (and consumptive)
“Recommended in 20th century”:
PT and aPTT ≤ 1.5 normal valuePlasma Fibrinogen ≥ 1 g/L
Platelets ≥ 50 x 109/L
Balance in ObstetricsTherapy
Transfusion Ratio: If If uterotonicsuterotonics and sutures failand sutures failRBC : FFP = 4 : 1 or 1: 1 (extrapolating)James et al. Postpartum Hemorrhage: when uterotonics and sutures fail. Am J Hematol. 2012;87:S16-22
Have a Protocol, EvaluateHave a Protocol, EvaluateTemperature, Ph, CalciumBlood Pressure (MAP 60 mmHg?)• rFVIIa: wide variability in timing and dosing. Effect?• Fibrinogen: Critical value of 1 g/L 1.5 – 2.0 g/L• Tranexamic acid: 1 gr iv *• Desmopressin: (0.3 µg/kg) Small trials**
Peitsidis et al. Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. Expert Opin Pharmacother 2011;12:503-16
* Novikova et al. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2010:CD007872
**Trigg et al. A systematic review: the use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy. Haemophilia 2012;18:25-33
CONCLUSIONS
Conclusions
• Haemostatic Balance is poorly understood
• Limited Evidence to guide therapy
• PT/aPTT limited value in a bleeding patient
• Not all massive haemorrhage is the same
Conclusions• Treatment is tailored:- Lab:
PT, aPTT, PC, Fibrinogen, lactate, TEG/ROTEM, last but not least: surgical field
• Have a Protocol, Evaluate• Tranexamic acid (recFVIIa)
• Fibrinogen administration (< 1 gr/L ? 4 gr/L?)• INERACTIONS: CRUCIAL• Influence on blood loss of the
surgeon/lab/anaesthetist/haematologist/
TEAM WORKTEAM WORK
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