Download - Massive bleeding in trauma and surgery role of factor r VII a (rFVIIa) by prof.mridul m. panditrao
MASSIVE BLEEDING IN TRAUMA &
SURGERYRole of rFVIIa
CONSULTANTDEPARTMENT OF ANESTHESIOLOGY
&INTENSIVE CARE
PUBLIC HOSPITAL AUTHORITY’S RAND MEMEORIAL HOSPITAL
FREEPORT, BAHAMAS
Dr. MRIDUL. M. PANDITRAO
Uncontrolled Haemorrhage
Second Leading Cause of Death
Associated Coagulopathy
“What to do next” ?
Introduction
Introduction (Cont)
Traumatic injury is the leading cause of death in age group - 5 to 44 years
Accounts for 10% of all deaths in spite of improved care
Uncontrolled bleeding contributes to 30% to 40% of trauma related early deaths
Especially in the hospital setting
Krug EG, Sharma GK, Lozano R: The global burden of injuries. Am J Public Health 2000, 90:523-526
Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997, 349:1269-1276.
Sauaia A, Moore FA, Moore EE, Moser KS, et al’ Epidemiology of trauma deaths: a reassessment. J Trauma 1995, 38:185-193.Holcomb JB: Methods for improved hemorrhage control. Crit Care 2004, 8(Suppl 2):S57-60.Kauvar DS, Wade CE: The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care 2005, 9(Suppl 5):S1-9.
Physiology of Bleeding
Injury: Definition and Consequence
Classification of the bleeding/ haemorrhage {American college of Surgeons [Advanced Trauma Life Support (ATLS) Team]}
4 classes
Classification of the Bleeding
Class I Hemorrhage up to
15%.
Class II Hemorrhage 15-30%.
Class III Hemorrhage 30-40%.
Class IV Hemorrhage >40%.
Class I Hemorrhage Up to 15% of blood volume
No change in vital signs
Fluid resuscitation is not necessary
Class II Hemorrhage
Involves 15-30% of total blood volume
Tachycardia, ↓ Pulse pressure Peripheral vasoconstriction Pallor, Cold Acute volume resuscitation with
crystalloids Blood transfusion is not required
Class III Hemorrhage involves loss of 30-40% of circulating
blood volume Tachycardia, ↓ Blood pressure ↓ peripheral perfusion, such as
capillary refill Mental status worsens Fluid resuscitation with crystalloid Blood transfusion
Class IV Hemorrhage Involves loss of >40% of circulating
blood volume The limit of the body's compensation
is reached Aggressive resuscitation is required
to prevent death
Massive bleeding
Defined as the loss of one
blood volume within 24 hours
or the loss of half blood volume
within three hours.
Spahn DR, Rossaint R: Coagulopathy and blood component transfusion in trauma. Br J Anaesth 2005, 95:130-139
Classification of the Bleeding (UK)As Described In The American Way,
Except The Cut Off Points At 5% Lesser. Viz. 10% 10-25%25-35%> 35%
Haemostasis
Definition
Stages
Stage I : - Vasoconstriction Stage II :- Platelet plug
formation Stage III : - Coagulation
cascade Stage IV : - Fibrinolysis
Stage I Vasoconstriction Mediators of Vasoconstriction are
released Noradrenaline, TBXS, mediators of RA
system
Vasoconstriction minimizes vessel diameter & slows bleeding
TBXA2 leads to smooth muscle relaxation
The tamponade effect by the extravasated blood adds to vasoconstriction
Stage II Platelet plug formation
1. Platelet adhesion2. Platelet release reaction
1. Platelets create extensions and come in contact with each other
2. Release their contents i.e. α granules & dense granules
3. 5HT & TBXs: - Potentiate vasoconstriction
3. Platelet aggregationADP increases platelet stickiness and they go on adhering with each other to create a platelet plug
Stage III Coagulation cascade
Multifactorial process Liquid blood gets converted in to a
gel or coagulum/ clot made up from proteinous fibers – fibrin
Various elements of blood are trapped in this network
Stage IV Fibrinolysis
For checking excessive clot formation and preventing its spread, factors like plasminogen, antithrombin III, protein C etc influence this
Coagulation cascade
Initiation phase
Amplification phase
Propagation phase
Hoffman M, Monroe DM: A cell-based model of hemostasis. Thromb Haemost 2001; 85(6):958-965.
Initiation phase Vessel wall injury takes place Tissue factor is exposed to the
circulating endogenous factor VII VII gets activated to VII A Formation of TF/ VII A complex This complex activates the cells bearing
TF to produce Factor IX to IX A Factor X to X A
The XA binds to VA on the cell surfaceHoffman M, Monroe DM: A cell-based model of hemostasis. Thromb Haemost 2001; 85(6):958-965.Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol. 2006 Jan; 26(1):41-8.
Upon vessel wall injury, tissue factor is exposed to circulating endogenous factor VII/VIIa-leading to the TF/VIIa complex which initiates coagulation
At the surface of TF-bearing cells the TF/VIIa complex activates.•Factor IX to IXa•Factor X to XaFactor Xa binds to factor Va on the cell surface
Amplification phase Factor XA/VA complex activates
prothrombin Prothrombin Thrombin at sub
endothelial surface Thrombin amplifies the process by
activating V,VII and platelets Activated platelets bind to factors
VA, VIIA, IX A Monroe DM , Hoffman M. Transmission of a procoagulant signal from tissue factor-bearing cell to platelets. Blood Coagul Fibrinolysis. 1996 Jun;7(4):459-64.
The factor Xa/Va complex activates small amounts of prothrombin to thrombin at the surface of sub-endothelial cellsThis limited amount of thrombin activates factors V, VIII and platelets
The activated platelet binds factors Va, VIlla and IXa
Propagation phase The thrombin activated platelets
change their shape Expose negatively charged
phospholipids to which, factor VIIIA/ IXA complex binds
→ factor X activation (XA) on the surface of activated platelets.
Thrombin-activated platelets change shape and expose negatively charged phospholipids to which the factor Vllla/IXa complex binds• This results in factor X activation on the surface of activated platelets The factor Xa/Va complex activates large amounts of prothrombin resulting in a "thrombin burst" which:•Converts fibrinogen to fibrin•Activates fibrin-stabilising factor- XIIIThe amount and rate of thrombin generation determines the strength of the haemostatic plug
“Thrombin burst”
XA with VA forms complex leading to Activation of large amount of
prothrombine to thrombine “Thrombin burst”
Fibrinogen → Fibrin XIII → XIIIA (fibrin stabilizing factor)
“Plugged in”
Uncontrolled Haemorrhage in
surgical settings! Second leading cause of death from trauma (surgical or non surgical)
Profound bleeding with coagulopathy Mortality and / or Morbidity:
Severity of injury Degree of systemic coagulopathy Co-existing acidosis
can rFVIIA help!!!! ? A ‘novel concept’
rFVIIa (NovoSeven®7)(novo nordisk®)
Recombinant Protein (50 kDa) Structurally similar to Factor VIIa Half-life 2 – 3 h Recommended Doses
Factor VIII and IX deficiencies 90 μg/kg Haemophilia 300
μg/kg Plasma rVIIa level > 10
U/ml
Delonhery TG. Management of bleeding emergencies: when to use recombinant activated factor VII. Expert opinion Pharmaco Therapeutics: 2006; 7(1) 25-34.
Mechanism of Action
Recombinant factor Vila (rFVIIa) controls bleeding at the site of vascular injury only
• rFVIIa works locally at the site of vascular injury, where tissue factor (TF) is exposed and activated platelets are found
• Binding of factor Vila or rFVIIa to TF initiates the coagulation generating small amounts of thrombin
• At pharmacological doses rFVIIa directly activates factor X on the surface of activated platelets resulting in a "thrombin burst”
• The thrombin burst leads to the formation of a stable haemostatic plug which controls the bleeding6
How does it help?
By directly activating Factor X to Xa It bypasses the pathway dependence on
VIIIa &/or IXa mechanism Overcomes any deficiency/decreased
levels of Factors VIII and IX Directly leads to initiation of “Thrombin
Burst” Shortens the time required for Clot
formation Improves the quality of the ‘Final Clot”
FDA approved Indications
Congenital hemophilia
Acquired hemophilia Especially secondary to formation
antibodies against inherent factor VIII. Drug induced e.g. penicillin,
chloramphenicol, phenitoin. Autoimmune conditions like rheumatoid
arthritis, SLE, malignancies: solid or haematologic, lympho-proliferative.
Pregnancy related and post partum.
FDA approved Indications(Cont)
Rarer bleeding disorders Inherited FVII deficiency Congenital deficiencies of multiple
coagulation factors Glanzmann’s thrombasthenia Patients with Factor VII and XI deficiency Bernard - Soulier syndrome Giant platelet syndrome
Pre-procedural management in patients with end-stage liver disease
“Off the Label” Indications Use for Bleeding in Peri-operative period?
No Randomized Controlled Trials
No FDA approval
But some anecdotal/ case reports evidence
Sketchy, yet tempting!
Gynaecological surgeries
Post menopausal patients (age range 58-72 yrs, N=4)
Hysterectomies: fibroids, Ca Cx, Ca endometrium, body or metastatic
Ca.. Dose range of rFVIIa 17-70 µg/kg Bleeding resolved after 1st dose in 3 pts
(12 hrs.) 2nd dose was needed in 1 pt. for complete
resolutionCiacma A et al. rFVIIa effectively controls bleed in gynecological surgery: J of Gyne Surg 2005: 21(1) 13-20
Oncological surgeries Paediatric surgeries (N=8)
Resection of brain tumors Promising results and better outcome
lung cancer patient for thoracotomies (N=3) rFVIIa to control massive postoperative hemorrhage A bolus of 90µg/kg was given, while in 2 of them it
had to be repeated after 2 hrs at 60µg/kg . Absolutely effective without hypercoagulability or
thrombo embolic phenomena.
Heisel M, Nagib M, Madsen L. Use of recombinant factor VIIa ( rFVIIa) to control intraoperative bleeding in paediatric braintumor patients. Paediatr Blood Cancer: 2004; 43(6); 703-5
Koglera VM, Slobodnjakb Z. Successful use of activated recombinant factor VII in life threatening bleeding after thoracic surgery: Swiss med Wkly. 2007: 137; 407-410.
Cardiac surgeries Infants and elderly patients (N=18). Cardiac surgery Either single bolus dose or divided
doses Bleeding significantly reduced in 16
out of 18 Completely terminated in 9 out of 18
rFVIIa before removal of an intra-aortic balloon pumpMidhathada MV, Mehta P, Milton W: Recombinant factor VIIa in the treatment of bleeding. Am.j. Clinical
pathology: 2004; 12(1); 124-137
Prostate surgeries
Patients for Prostate surgeries (N=36)
rFVIIa pre operatively Reduced blood loss and the need for
blood transfusion
Orthopedic surgeries
THR, TKR, posterior spinal fusion Patients with various coagulation
disorders rFVIIa prevented postoperative
bleeding
Post L.S.C.S. PPH
2 young females ( both, 29 yrs old) multipara Both essentially normal preoperatively developed uterine atony , DIC and intra & post
partum hemorrhage Conventional treatment failed to control
bleeding 90µg/kg of rFVIIa as a final attempt within 15 – 20 minutes
Bleeding stopped Resolution of coagulopathy No side effectsUharcek P, Myneek M, Kellener M: Use of recombinant factor VIIa on the therapy of massive bleeding after caesarian section:
Ceska Gynekol: 2007: 72(3); 200-2 Heilmann L, Wild C, Honjnaeki B: Successful treatment of life threatening bleeding after caesarian section with recombinant activated
factorVIIa. Clin Appl Thromb Hemost. 2006: 12(2); 227-9.
Ist open non-randomized study Patients with post-partum Haemorrhage 26 patients with rFVIIa 22 women without rFVIIa Patients who had rFVIIa
Had significantly higher bleeding!! Longer (APTT) Longer (PT) Lower fibrinogen values
Hence as a “last resort” especially in obstetric hemorrhage.Ahonen J, Jokela R, Kortila K. An open non randomized study of recombinant activated factor VIIa in major
postmortem hemorrhage: Acta Anaesthesiol Scand: 2007: 1-7
Isreali MRTF Guidelines
rFVIIA as an Adjunct to concomitant surgical measures
If packs to be removed, then, before rFVIIA administration
If bleeding is encountered outside OR, then “second look” must be considered
Martino witz U. Michaelson M. Guidelines for use of rFVIIa . Journal of thrombosis and hemostasis 2005, 3: 1-9.
Recommendations
Replace lost/consumed haemostatic factors with: FFP Cryoprecipitate Platelets Red blood cells
Full blood count, PT, APTT and fibrinogen
should be checked regularly to guide
replacement.
Recommendations (Cont)
The use of rFVIIa should be considered if bleeding continues when: Greater than one blood volume has been
transfused Adequate replacement with FFP,
cryoprecipitate and platelets has been given. No identifiable surgical source of bleeding
has been found.
Recommendations (Cont)
If it is felt that rFVIIa may be of benefit
Normally only be requested by a consultant anaesthesiologist.
Normally only to be used following discussion with a consultant haematologist.
Recommendations (Cont)
One 4.8 mg vial should be given (50-100ug/kg for a 50-100 kg patient).
Bleeding does not diminish in 30-60 minutes? a further 4.8 mg vial
Bleeding continues after a second dose, NO THIRD DOSE
Surgical re-exploration should be considered.
Precautions
Thrombotic risk associated with the use of rFVIIa
Patients with
A history of Coronary Artery Disease.
A history of arterial or venous Thrombosis.
Cerebral Vascular Disease.
DIC.
Summary Safe and effective in haemophilia patients
with inhibitors. Also effective in a variety of bleeding
conditions in non-hemophilic patients. “Universal” or “General” Hemostatic
agent ?? But not always effective in all the
conditions Life saving in some patients experiencing
life-threatening hemorrhage.
Conclusions
Use of rFVIIA as a life saving measure in some patients experiencing life-threatening hemorrhage seems warranted as a ‘last resort’ modality, inclusive of peri-operative patients
However urgent, randomized controlled clinical trials are needed to define the appropriate role of this agent.
Thank you!