1. Transfusions in Surgery Dr. Carolyn Faught November 28, 2006

2. FACT Approximately 60% of all red cell transfusions are administered to surgical patients Therefore need to understand indications and risks of transfusion

3. Main Objectives Be aware of the adverse effects of transfusion Discuss “transfusion triggers” in surgical patients Treatment of massive transfusion Indications for recombinant FVIIa in surgical patients

4. Blood Components Blood components made by physical separation from whole blood: –Packed red blood cells (PRBCs) –Platelets –Plasma ( FFP, cryoprecipitate) –Granulocytes Blood derivatives: –Fractioned, virally inactivated product (ie. albumin, IVIG) –Recombinant products (VIII, IX, VIIa)

5. Universal donor/ Universal recipient Group O RBCs: universal donor, can be given to patients of all blood groups, because no A or B antigens on surface of RBCs Group AB person is the universal recipient for RBCs, because has no anti-A or anti-B antibodies in plasma Group AB plasma can be given to all recipients, as it has no anti-A or anti-B antibodies Emergency (uncrossed) products = O neg RBCs and AB plasma Still best to give Group specific blood

6. Blood Products: Universal leukoreduction of all blood products in Canada ‘third generation’ filters to remove WBCs from blood (leukoreduction) to less than 5x10 6 WBC/bag of RBCs Leukoreduction reduces CMV transmission, HLA alloimmunization, febrile non-hemolytic transfusion reactions

7. Adverse Effects of Transfusion Transfusion Reactions –Infectious –Non-infectious Immunologically mediated Non-immunologic –Immediate –Delayed

8. Infectious risks of transfusion Bacterial contamination of platelets 1:40,000* HBV - 1/250,000 HIV - 1/1,900,000 HCV - 1/1,800,000 HTLV1 - 1/1,000,000 Less clear CJD (Creutzfeldt-Jakob disease) West Nile 1/4,000

9. Non-infectious risks Febrile reactions Allergic/anaphylactoid reactions Hemolytic reactions – 1/20,000 Volume overload Acute lung injury (TRALI) Serologic sensitization –Alloimmunization to red cell antigens (delayed hemolytic transfusion reaction) –Graft-versus host disease –Platelet refractoriness, post-transfusion purpura Immunomodulation - ? Increased risk of infection, cancer recurrence

10. TRALI Transfusion-Related Acute Lung Injury Non-cardiogenic pulmonary edema after transfusion Incidence up to 1:5000 transfusions Antibodies in donor plasma against HLA or neutrophils react with recipient leukocytes Leukoagglutination in lungs, increase in vascular permeability, fluid enters alveolar spaces Need to identify, to remove donor from donor pool

11. TOH Blood Conservation Program 800 patients a year assessed at Civic Best candidates are hips, backs, prostate, some gynecologic surgery Patients assessed 4 wks prior to surgery so they can benefit Liberal use of Epo and iron Autologous or 2 unit collection with TRIMA If Hb > 130 g/L, no Epo If Hb < 125-130 g/L, no autologous donation

12. Transfusion Rates Across Canada Locally, transfusion rates are ~ 45% in hips, 35% in prostate, 25% in knee Across Canada: –Cardiac: 43.8% female 65% vs male 37% –Hip: 34.4% –ICU (post-op and trauma): 36.9% Can J Anesth 2005: 52(6); 581-590

13. Transfusion Practices in Surgery Little evidence to support age-old practice of keeping Hb > 100g/L General trend towards conservative RBC transfusion practices in elective circumstance TRICC Trial largest RCT showed RBC transfusion threshold of 70 g/L was as safe as 100 g/L in terms of morbidity and mortality in the critical care setting Hebert, P.C., NEJM 340(6), 1999;409-418

14. Red blood cell transfusion practices amongst Canadian anesthesiologists: a survey A threshold above 70 g/L chosen by 48% for general surgery, 56% for orthopedic surgery and 9% for vascular surgery History of coronary artery disease associated with threshold of 100 g/L Very young age associated with threshold of </= 60 g/L Conclusion: general adoption of TRICC trial even in surgical patients Can J Anesth 2006: 53(4); P 344-352

16. Platelet storage

18. Fresh Frozen Plasma (FFP) Fresh Frozen Plasma contains the clotting factors necessary for the hemostatic process Plasma also has volume expansion and oncotic properties Typical adult dose = 10-20 ml/kg, 4-6 units Unlikely to be beneficial if PT and/or aPTT <1.5x normal

19. Massive Transfusion (MT) and Coagulopathy Definition: replacement of one blood mass in a 24 hour period More practical definition: transfusion of four or more PRBCs within one hour or replacement of 50% blood volume in three hours Uncontrolled bleeding causes 40% of deaths in severe trauma

20. Hemorrhage Symptoms relate to amount lost Blood volume (adult) = 75 ml/kg = 5 liters 10% loss:few symptoms 20% loss:postural hypotension 40% loss:shock 50% loss:irreversible shock

21. Massive Transfusion and Coagulopathy Hypothermia – slows activity of coagulation cascade, increases fibrinolysis and alters platelet function Dilutional coagulopathy – exacerbated by initial volume contraction, fluid resuscitation and transfusion of factor and platelet-deficient PRBCs Fibrinogen < 1.0 g/L when blood loss 142% DIC

22. The contribution of red cells to hemostasis

23. Disseminated Intravascular Coagulation Hemostatic defects related to the exaggerated generation of thrombin and fibrin and the excessive consumption of platelets and coagulation factors Low incidence in elective surgery In trauma patients: Due to degree of tissue trauma and tissue anoxia 40% incidence in brain injury, 25% without head injury

24. Disseminated Intravascular Coagulation Incidence of coagulopathy 98% if all of the following:  pH less than 7.10  Temperature less than 34C  SPB less than 70 mm Hg  Injury severity score greater than 25 Ferrara A, J Trauma 1997;42:857-61

25. Management of Coagulopathy in MT PT/PTT increase when factors V, VIII and IX < 50% Both PT/PTT increased if fibrinogen is low PT or PTT ratio ≥1.8 means factors are < 30% and leads to high rate of bleeding No prophylactic regimen of FFP/platelets concentrates has been shown to be effective in MT

26. Management of Coagulopathy in MT Correct hypothermia Correct low Hb – optimum Hb in MT to maintain hemostasis unknown but probably higher than required for O 2 delivery Correct markedly prolonged INR/PTT with FFP ( ratio > 1.5) Typical use 4-6 units (800-1500 ml) in average adult or 10-20 ml/kg; –gross underestimate in severely depleted, actively bleeding, hypothermic patient and should be 1-1.5:1 ratio of FFP to PRBCs

28. Management of Coagulopathy in MT If fibrinogen < 1.0 g/L despite FFP administer cryoprecipitate: 10-20 units Platelets for decreased platelet count with clinical coagulopathy Consider rFVIIa if above not sufficient to control bleeding

30. J.F.Hardy,Can J Anesth 2004;51(4):293-310

31. Recombinant factor VIIa (Niastase) - Background Recombinant factor VIIa developed to treat hemophilia patients with inhibitors –By-passing agent in patients not responding to factor replacement Recombinant factor VIIa used for treatment and prophylaxis of hemophiliacs with inhibitors Use expanded to other bleeding patients

32. Factor VIIa in Normal Hemostasis Hoffman M, et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65. TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa X Xa IIIIa IX VVa II VIII/vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa Fibrin Clot

33. FVIIa – FVIII and FIX Independant Hoffman M, et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65. TF-Bearing Cell Activated Platelet Platelet TF Va Va TF VIIa Xa X II IIa VVa II X IIa Xa VIIa Fibrin Clot

34. High-Dose FVIIa Enhances IIa Generation Without TF 4 [FVIIa] (nM) Relative IIa generation 3 2 1 0 0110100 NormalHemophilic Monroe DM, et al. Br J Haematol 1997;99:542-547.

35. Niastase: Licensed Indications Treatment of bleeding in hemophilia patients with inhibitors Surgical management of hemophilia patients with inhibitors Congenital factor VII deficiency (USA) Glanzmann’s Thrombasthenia (UK)

36. Pharmacology of Recombinant Factor VIIa 50,000 MW molecule with t ½ of 2 hrs Normal concentration of factor VII: 10-20 nm 1% of factor VII circulates in activated form Standard dose in hemophilia 90 ug/kg –maximum concentration 50 nm –500 x normal concentration of VIIa Dosing q 2-3 h to maintain hemostatic levels

37. Expanded Use of VIIa Factor VII deficiency Other factor deficiencies (FXI, acquired FX) Von Willebrand’s disease Thrombocytopenia Platelet function defects Reversal of oral anticoagulation Coagulopathy of liver disease Surgical bleeding Surgical prophylaxis Intracranial hemorrhage Trauma

38. VIIa in Partial Hepatectomy: Placebo Controlled RCT Design: RCT comparing 20, 80 ug/kg or placebo in non- cirrhotic patients with 2 nd dose for OR > 6 hrs Monitored for bleeding for 7 days Results: 185 patients Lodge et al. Hepatology 2002;36:Abst177

39. VIIa in Partial Hepatectomy Placebo 20 ug/kg 80ug/kg Blood loss 1000 800 700 % transfused 37% 41% 25% Thrombosis 3 3 3 Trend but no significant difference

40. Effect of rVIIa on Perioperative Blood Loss During Prostatectomy Friederich. Lancet 2003 Design 36 pts randomized to placebo or rVIIa (20 ug/kg or 40 ug/kg) Followed for 10 days post-op Results Placebo20 ug/kg 40 ug/kg Blood loss (ml) 26881235 * 1089 * RBC units1.50.6 * 0*0* % transfused58%38%0% * OR time (min)180126120

41. RecombinantVIIa for Adjunctive Hemorrhage Control in Trauma Patients 7 patients with coagulopathic bleeding treated under compassionate use program Age 17-75 No atherosclerosis/thromboembolic disease Received 20-70 units RBCs + FFP and platelets Intervention 1-3 doses of 60-120 ug/kg of rVIIa Matinowitz et al. J Trauma 2001;51:431

42. Recombinant VIIa for Adjunctive Hemorrhage Control in Trauma Results Bleeding stopped/reduced in all patients Further transfusions limited to 1-2 units of RBCs Significant shortening of coagulation tests 4 of 7 patients survived No thrombotic events

43. Multicentre RCT of rVIIa in Trauma 280 pts with blunt or penetrating trauma All patients receive 3 doses –200 ug/kg followed by 100ug/kg 1h and 3h later Transfusion ICU/Hosp LOS Survival Adverse Events trauma Arrive at ER randomize 068 Units of RBCs rVIIa48h 30d placebo Boffard et al. J Trauma. 2005: 59: 8-15

44. Non significant reduction in RBC units transfused –Significant reduction in RBC units (2.6 units) and incidence of massive transfusion (14% vs 33%) in blunt trauma when early deaths excluded Similar overall survival - 25% vs 30% –Composite outcome incl organ dysfunction showed increased trend favouring rVIIa (29 vs. 43%) No difference in adverse events Multicentre RCT of rVIIa in Trauma Boffard et al. J Trauma. 2005: 59: 8-15

46. Complications Associated with Factor VIIa FDA report of adverse events from trials and voluntary reporting from 1999-2005 220 thromboembolic complications –193 in non-hemophiliac patients 129 arterial thrombosis 103 venous thrombosis Approx. 50% of reports within 24 hrs of infusion 43 of 67 deaths reported secondary to thrombosis