MASSIVE BLEEDING IN TRAUMA & SURGERY
Introduction Uncontrolled HaemorrhageSecond Leading Cause of Death  Associated Coagulopathy   “What to do next” ?
Introduction                                            (Cont)  Traumatic injury is the leading cause of death in age    ...
Physiology of Bleeding Injury: Definition and Consequence Classification of the bleeding/ haemorrhage  {American college...
Classification of the Bleeding   Class I Hemorrhage     up to 15%.   Class II Hemorrhage    15-30%.   Class III Hemorrh...
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 Pa...
Class III Hemorrhage involves loss of 30-40% of circulating blood    volume   Tachycardia, ↓ Blood pressure   ↓ periphe...
Class IV Hemorrhage Involves loss of >40% of circulating blood  volume The limit of the bodys compensation is  reached ...
Massive bleedingDefined as the loss of one bloodvolume within 24 hours or the loss ofhalf blood volume within three hours....
Classification of the Bleeding(UK)   As Described In The American Way, Except The   Cut Off Points At 5% Lesser. Viz.   10...
HaemostasisDefinition                 Stages Stage I      : - Vasoconstriction Stage II     :- Platelet plug formation ...
Stage I Vasoconstriction Mediators of Vasoconstriction are released     Noradrenaline, TBXS, mediators of RA system Vas...
Stage II Platelet plug formation 1. Platelet adhesion 2. Platelet release reaction     1. Platelets create extensions and ...
Stage III Coagulation cascade  Multifactorial process  Liquid blood gets converted in to a gel or   coagulum/ clot made ...
Stage IV           Fibrinolysis For checking excessive clot formation and  preventing its spread, factors like  plasminog...
Coagulation cascade Initiation phase Amplification phase Propagation phase    Hoffman M, Monroe DM: A cell-based model ...
Initiation phase Vessel wall injury takes place Tissue factor is exposed to the circulating  endogenous factor VII VII ...
Upon vessel wallinjury, tissuefactor is exposedto circulatingendogenousfactor VII/VIIa-leading to theTF/VIIa complexwhich ...
Amplification phase Factor XA/VA complex activates prothrombin Prothrombin                             Thrombin at sub e...
The factorXa/Va complexactivates smallamounts ofprothrombinto thrombin atthe surface ofsub-endothelialcellsThis limitedamo...
Propagation phase The thrombin activated platelets change their  shape Expose negatively charged phospholipids to  which...
Thrombin-activatedplatelets change shapeand expose negativelycharged phospholipidsto which the factorVllla/IXa complex bin...
“Thrombin burst” XA with VA forms complex leading to Activation of large amount of prothrombine  to thrombine          “...
Uncontrolled Haemorrhage in surgical settings! Second leading cause of death from trauma  (surgical or non surgical) Pro...
rFVIIa (NovoSeven®7)             (novo nordisk®) Recombinant Protein (50 kDa) Structurally similar to Factor VIIa Half-...
Mechanism of Action
• rFVIIa works locally at                                                                                    the site of v...
How does it help? By directly activating Factor X to Xa It bypasses the pathway dependence on VIIIa    &/or IXa mechanis...
FDA approved Indications Congenital hemophilia Acquired hemophilia   Especially secondary to formation antibodies    ag...
FDA approved Indications(Cont)  Rarer bleeding disorders    Inherited FVII deficiency    Congenital deficiencies of mul...
“Off the Label” IndicationsUse for Bleeding in Peri-operative period?  No Randomized Controlled Trials  No FDA approval ...
Gynaecological surgeries Post menopausal patients (age range 58-72    yrs, N=4)   Hysterectomies: fibroids, Ca Cx,      ...
Oncological surgeries Paediatric surgeries (N=8)     Resection of brain tumors     Promising results and better outcome...
Cardiac surgeries Infants and elderly patients (N=18). Cardiac surgery Either single bolus dose or divided doses Bleed...
Prostate surgeries Patients for Prostate surgeries (N=36) rFVIIa pre operatively Reduced blood loss and the need for bl...
Orthopedic surgeries THR, TKR, posterior spinal fusion Patients with various coagulation disorders rFVIIa prevented pos...
Post L.S.C.S. PPH 2 young females ( both, 29 yrs old) multipara Both essentially normal preoperatively developed uterin...
Ist open non-randomized study   Patients with post-partum Haemorrhage   26 patients with rFVIIa   22 women without rFVI...
Isreali MRTF Guidelines rFVIIA as an Adjunct to concomitant surgical  measures If packs to be removed, then, before rFVI...
Recommendations Replace lost/consumed haemostatic factors with:   FFP   Cryoprecipitate   Platelets   Red blood cells...
Recommendations             (Cont) The use of rFVIIa should be considered if bleeding  continues when:   Greater than on...
Recommendations               (Cont) If it is felt that rFVIIa may be of benefit Normally only be requested by a consult...
Recommendations          (Cont) One 4.8 mg vial should be given (50-100ug/kg  for a 50-100 kg patient). Bleeding does no...
PrecautionsThrombotic risk associated with the use of rFVIIa Patients with   A history of Coronary Artery Disease.   A ...
Summary Safe and effective in haemophilia patients    with inhibitors.   Also effective in a variety of bleeding    cond...
Conclusions Use of rFVIIA as a life saving measure in some  patients experiencing life-threatening  hemorrhage seems warr...
Massive bleeding in trauma and surgery role of factor r VII a (rFVIIa) by prof.mridul m. panditrao
Massive bleeding in trauma and surgery role of factor r VII a (rFVIIa) by prof.mridul m. panditrao
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Massive bleeding in trauma and surgery role of factor r VII a (rFVIIa) by prof.mridul m. panditrao

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Prof.Mridul Panditrao dwells upon the peri-operative and emergency problem of massive bleeding, the physiology of coagulation, anf the role of recombinanat activated factor VII.
KUWAIT MEDICAL JOURNAL
December 2011
176
Review Article
Kuwait Medical Journal 2011; 43 (3): 176-188
Massive Bleeding in Trauma and Surgery: Role of rFVIIa
ABSTRACT
KEY WORDS: recombinant activated factor VII, recommendations
Mridul Panditrao1, 2, Minnu Panditrao1, Mohammed Shamsah2
1Department of Anesthesiology and Critical Care, Dr. D Y Patil Medical College (Deemed University), Pune, India
2Department of Anesthesia and Intensive Care, Al-Adan Hospital, Kuwait
Address correspondence to:
Prof. Dr. Mridul M. Panditrao, MD, DA, Senior Specialist, Department of Anesthesia and Intensive Care, Al-Adan Hospital, Kuwait.
Tel: 65 88 90 25, E-mail: drmmprao1@ gmail.com
INTRODUCTION
Traumatic injury is the leading cause of death worldwide among persons between one and 44 years of age[1,2], fourth leading cause of death over all age groups[3] and accounts for 10% of all deaths[4]. In fact, Global Burden Diseases (GBD) Study has classifiedtheinjuriesasGroup-3,alongwithothertwo broader categories of diseases; communicable, and non-communicable[5]. Despite improvement in care, uncontrolled bleeding contributes to 30 to 40% of trauma related deaths and is a leading cause of potentially preventable early in-hospital deaths[6 – 9].
PHYSIOLOGY OF BLEEDING AND HEMOSTASIS[10,11]
As a physiological response to an injury, whether, traumatic or planned (surgical), especially, if there is an integumental (skin or mucus membrane) breach then logically hemorrhage is the result. American College of Surgeons[12] (Advanced Trauma Life Support (ATLS) Team) has classifiedbleeding/hemorrhage intofourclasses (Table1, Annexure1 ). This has further been modifiedrecentlytoincludesomemoreparameters[11] (Table 2, Annexure1), Class I being, non-shock state, such as occurs when donating a unit of blood, whereas class IV being pre-terminal event requiring immediate therapy[13]. Massive hemorrhage may be definedasloss of total EBV within a 24-hour period, or loss of half of the EBV in a 3-hour period. Bleeding secondary to surgical / traumatic cause is usually as a result of combination of vascular injury and coagulopathy[14].
STAGE I: VASOCONSTRICTION
As a response to hemorrhage, all the mediators of vasoconstriction: noradrenaline, thromboxanes (TBXs) and mediators of RA system are released, causing intense vasoconstriction.
Effects: The firstaidsystemcanlastfromminutesto hours.
1. Vasoconstriction minimizes vessel diameter and slows bleeding
2. TBXA2 leads to smooth muscle relaxation
3. The tamponade effect by the extravasated blood adds to vasoconstriction
STAGE II: PLATELET PLUG FORMATION
A complex phase formed by three sub-phases
1. Platelet adhesion
2. Platelet release reaction
Platelets create extensions and come in contact with each other. They release their contents i.e.,

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Massive bleeding in trauma and surgery role of factor r VII a (rFVIIa) by prof.mridul m. panditrao

  1. 1. MASSIVE BLEEDING IN TRAUMA & SURGERY
  2. 2. Introduction Uncontrolled HaemorrhageSecond Leading Cause of Death Associated Coagulopathy “What to do next” ?
  3. 3. Introduction (Cont)  Traumatic injury is the leading cause of death in age group - 5 to 44 years Krug EG, Sharma GK, Lozano R: The global burden of injuries. Am J Public Health 2000, 90:523-526  Accounts for 10% of all deaths in spite of improved careMurray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997, 349:1269-1276.  Uncontrolled bleeding contributes to 30% to 40% of trauma related early deaths  Especially in the hospital setting 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.
  4. 4. Physiology of Bleeding Injury: Definition and Consequence Classification of the bleeding/ haemorrhage {American college of Surgeons [Advanced Trauma Life Support (ATLS) Team]} 4 classes
  5. 5. Classification of the Bleeding  Class I Hemorrhage up to 15%.  Class II Hemorrhage 15-30%.  Class III Hemorrhage 30-40%.  Class IV Hemorrhage >40%.
  6. 6. Class I Hemorrhage Up to 15% of blood volume No change in vital signs Fluid resuscitation is not necessary
  7. 7. 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
  8. 8. 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
  9. 9. Class IV Hemorrhage Involves loss of >40% of circulating blood volume The limit of the bodys compensation is reached Aggressive resuscitation is required to prevent death
  10. 10. Massive bleedingDefined as the loss of one bloodvolume within 24 hours or the loss ofhalf blood volume within three hours.Spahn DR, Rossaint R: Coagulopathy and blood component transfusion in trauma. Br J Anaesth 2005, 95:130-139
  11. 11. 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%
  12. 12. HaemostasisDefinition Stages Stage I : - Vasoconstriction Stage II :- Platelet plug formation Stage III : - Coagulation cascade Stage IV : - Fibrinolysis
  13. 13. 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
  14. 14. Stage II Platelet plug formation 1. Platelet adhesion 2. 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 aggregation ADP increases platelet stickiness and they go on adhering with each other to create a platelet plug
  15. 15. 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
  16. 16. Stage IV Fibrinolysis For checking excessive clot formation and preventing its spread, factors like plasminogen, antithrombin III, protein C etc influence this
  17. 17. 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.
  18. 18. 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 surface Hoffman 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.
  19. 19. Upon vessel wallinjury, tissuefactor is exposedto circulatingendogenousfactor VII/VIIa-leading to theTF/VIIa complexwhich initiatescoagulationAt the surface ofTF-bearing cellsthe TF/VIIacomplexactivates.•Factor IX to IXa•Factor X to XaFactor Xa binds tofactor Va on thecell surface
  20. 20. 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.
  21. 21. The factorXa/Va complexactivates smallamounts ofprothrombinto thrombin atthe surface ofsub-endothelialcellsThis limitedamount ofthrombinactivatesfactors V, VIIIand plateletsThe activatedplatelet bindsfactors Va,VIlla and IXa
  22. 22. 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.
  23. 23. Thrombin-activatedplatelets change shapeand expose negativelycharged phospholipidsto which the factorVllla/IXa complex binds• This results in factor Xactivation on thesurface of activatedplateletsThe factor Xa/Vacomplex activates largeamounts ofprothrombin resultingin a "thrombin burst"which:•Converts fibrinogen tofibrin•Activates fibrin-stabilising factor- XIIIThe amount and rateof thrombingenerationdetermines thestrength of thehaemostatic plug
  24. 24. “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”
  25. 25. 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’
  26. 26. 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.
  27. 27. Mechanism of Action
  28. 28. • 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 whichRecombinant factor Vila (rFVIIa) controls bleeding at the site of vascular injury only controls the bleeding6
  29. 29. 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”
  30. 30. 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.
  31. 31. 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
  32. 32. “Off the Label” IndicationsUse for Bleeding in Peri-operative period?  No Randomized Controlled Trials  No FDA approval  But some anecdotal/ case reports evidence  Sketchy, yet tempting!
  33. 33. 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 resolution Ciacma A et al. rFVIIa effectively controls bleed in gynecological surgery: J of Gyne Surg 2005: 21(1) 13-20
  34. 34. Oncological surgeries Paediatric surgeries (N=8)  Resection of brain tumors  Promising results and better outcome 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 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. 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.
  35. 35. 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 pump Midhathada MV, Mehta P, Milton W: Recombinant factor VIIa in the treatment of bleeding. Am.j. Clinical pathology: 2004; 12(1); 124-137
  36. 36. Prostate surgeries Patients for Prostate surgeries (N=36) rFVIIa pre operatively Reduced blood loss and the need for blood transfusion
  37. 37. Orthopedic surgeries THR, TKR, posterior spinal fusion Patients with various coagulation disorders rFVIIa prevented postoperative bleeding
  38. 38. 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); 200-2Heilmann 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.
  39. 39. 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
  40. 40. 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 consideredMartino witz U. Michaelson M. Guidelines for use of rFVIIa . Journal of thrombosis and hemostasis 2005, 3: 1-9.
  41. 41. 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.
  42. 42. 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.
  43. 43. 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.
  44. 44. 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.
  45. 45. PrecautionsThrombotic 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.
  46. 46. 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.
  47. 47. 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.

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