An Evidence Based Approach to Transfusion

1. An Evidence Based Approach to Transfusion Terry Gernsheimer, MD U W School of Medicine Puget Sound Blood Center June 1, 2008

2. Transfusion Indications Relieve symptomatic anemia improve O2 delivery Replacement of rapid blood loss Correction of clotting abnormalities in a bleeding patient prophylaxis for a planned procedure

3. Hemoglobin Level and Symptoms

4. Effect of Hematocrit on Hemodynamics

7. Effect of Hematocrit on Mortality in Elderly Patients with Acute MI

8. Relationship Between Platelet Count and Hemorrhage

13. Duration of Aspirin - Platelet Effect Irreversible inhibition of COX1 causes decreased Thromboxane A2 production. Bleeding depends on procedure. No diffin prostatectomy. Many studies show increase chest tube drainage & tx w/ CABG. D/c 5-7 days preop. Platelet transfusion for emergent surgeryIrreversible inhibition of COX1 causes decreased Thromboxane A2 production. Bleeding depends on procedure. No diffin prostatectomy. Many studies show increase chest tube drainage & tx w/ CABG. D/c 5-7 days preop. Platelet transfusion for emergent surgery

14. Duration of Aspirin - Platelet Effect

15. Platelet Inhibitors Eptifibatide (Integrelin®) Tirofiban (Aggrastat®) Ticlopidine Clopidogrel NSAIDS Bind to GPIIb/Iia and inhibit aggregation. Continuous infusion renal clearnace T½ 2-3 hours but functional recovery ½ life at least 4 hours. Can cause thrombocytopenia. No excess bleeding seen with cardiac surgery in IMPACT Trial, No increased transfusion seen in PURSUIT trial. Therory – if inhibit GPIIb/IIIa, will have decreased fibrinogen interaction with circuit and possibly preserve function and number and therefore see less bleeding.Bind to GPIIb/Iia and inhibit aggregation. Continuous infusion renal clearnace T½ 2-3 hours but functional recovery ½ life at least 4 hours. Can cause thrombocytopenia. No excess bleeding seen with cardiac surgery in IMPACT Trial, No increased transfusion seen in PURSUIT trial. Therory – if inhibit GPIIb/IIIa, will have decreased fibrinogen interaction with circuit and possibly preserve function and number and therefore see less bleeding.

16. Mechanisms of the Uremic Hemostatic Defect Defects in platelet function and metabolism Defects of vascular endothelial/ smooth muscle cell metabolism Abnormal platelet – vessel wall interactions Anemia of renal failure Rbc may enhance ADP and TXA2 release. Anemia causes vasodilatation Epo may have some vasoconstrictive effect. May affect platelet cytoskeleton demonstrated that treatment with rHuEPO enhances the response of uremic platelets to thrombin, by improving the assembly of contractile proteins and the signaling through phosphotyrosine proteins.6 Rbc may enhance ADP and TXA2 release. Anemia causes vasodilatation Epo may have some vasoconstrictive effect. May affect platelet cytoskeleton demonstrated that treatment with rHuEPO enhances the response of uremic platelets to thrombin, by improving the assembly of contractile proteins and the signaling through phosphotyrosine proteins.6

17. The Importance of Hematocrit for Platelet Function The importance of not allowing a thrombocytopenic patient’s hematocrit to fall too low is shown in this study of normal volunteers who underwent a red cell and also a platelet apheresis procedure. Although the plateletpheresis reduced their platelet count significantly, as shown in the right-hand set of bars, their bleeding time did not change. However, a red cell apheresis procedure that reduced their hematocrit from 41 to 35% (with only a minor change in their platelet count) caused almost a doubling of their bleeding time. It is thought that red cells occupy the axial portion of blood flow and push platelets toward the periphery of the flow, thereby making better use of their capabilities.The importance of not allowing a thrombocytopenic patient’s hematocrit to fall too low is shown in this study of normal volunteers who underwent a red cell and also a platelet apheresis procedure. Although the plateletpheresis reduced their platelet count significantly, as shown in the right-hand set of bars, their bleeding time did not change. However, a red cell apheresis procedure that reduced their hematocrit from 41 to 35% (with only a minor change in their platelet count) caused almost a doubling of their bleeding time. It is thought that red cells occupy the axial portion of blood flow and push platelets toward the periphery of the flow, thereby making better use of their capabilities.

19. Effective Therapeutic Regimens for Uremic Bleeding Dialysis Red Blood Cell transfusion Erythropoietin Desmopressin (DDAVP) Cryoprecipitate Conjugated estrogens Transdermal low dose estrogens

22. Available Platelet Components Pooled Whole Blood (2 – 8 U) Apheresis Family Donor HLA Selected Donor

24. Expected Platelet Increment

25. Blood Component Modification Leukocyte Depletion CMV Screening Gamma Irradiation Volume Depletion Cell “Washing”

26. HLA Antigens on Transfused Cells

27. Tried to do a study here about 10 years ago and our control arm had such a low incidence of alloimmunization that we gave up. We don’t leukoreduce post transplant for that reason.Tried to do a study here about 10 years ago and our control arm had such a low incidence of alloimmunization that we gave up. We don’t leukoreduce post transplant for that reason.

28. Transfusion Transmitted CMV in the Immunocompromised Patient Disseminated disease more common Pneumonitis Retinitis Hepatitis Graft loss

29. Prevention of CMV Infection

30. Leukocyte Reduction: Indications Direct Evidence Febrile transfusion reactions Prevention of CMV transmission Prevention of alloimmunization to platelets

31. Gamma Irradiation - Indications Prevention of TR Graft vs Host Disease Immunocompromised patients Premature infants HSCT patients Leukemia Lymphoproliferative disease Intensive chemotherapy Recipients & donors who share HLA antigens

33. Indices Predictive of Microvascular Bleeding

34. Fresh Frozen Plasma: Task Force Recommendations

35. Fresh Frozen Plasma - Dosage

36. Cryoprecipitate:Task Force Recommendations Fibrinogen <80-100mg/dl No available factor concentrates or DDAVP Pre-procedure/trauma Bleeding patient massive transfusion and microvascular bleeding peripartum and DIC platelet dysfunction

37. Laboratory Tools

38. The procoagulant system is a series of enzymatic reactions leading to fibrin formation. The players are the serine protease proenzymes, cofactors (VIII, V, Ca++) and Phospholipid. The liver is the site of synthesis of almost all of the coagulation factors except vWF and VIII. Patients with liver disease can have a range of bleeding abnormalities.   Activated forms of the serine proteases in complexes with cofactors lead to activation of other serine proteases. Tissue factor is an important activator of the extrinsic pathway. It’s external to the blood, being released by adventitia and damaged endothelial cells – hence the name extrinsic pathway.   These activated enzymes eventually activate a common proenzyme, Factor X and eventually prothrombin (II) and fibrinogen. This is the common pathway that precedes clot formation.   You should note several important things. The procoagulant system is a series of enzymatic reactions leading to fibrin formation. The players are the serine protease proenzymes, cofactors (VIII, V, Ca++) and Phospholipid. The liver is the site of synthesis of almost all of the coagulation factors except vWF and VIII. Patients with liver disease can have a range of bleeding abnormalities.   Activated forms of the serine proteases in complexes with cofactors lead to activation of other serine proteases. Tissue factor is an important activator of the extrinsic pathway. It’s external to the blood, being released by adventitia and damaged endothelial cells – hence the name extrinsic pathway.   These activated enzymes eventually activate a common proenzyme, Factor X and eventually prothrombin (II) and fibrinogen. This is the common pathway that precedes clot formation.   You should note several important things.

39. Recombinant VIIa (Novo-Seven®) Severe Hemophilia A Inhibitor patients Warfarin overdose Cerebral bleeding Thrombocytopenia Liver disease and transplantation Massive trauma Vascular surgery 80kg patient at 60ug/kg =$4500/dose Up to 120ug/kg q 2 hours 80kg patient at 60ug/kg =$4500/dose Up to 120ug/kg q 2 hours

40. Adverse Effects of Transfusion Transmission of infections Transfusion reactions Graft vs Host disease Immunomodulation Post-transfusion purpura

41. Infections that can be Transmitted by Transfusion HIV 1:1,900,000 units Hepatitis C 1:1,000,000 units Hepatitis B 1:1,000,000 units HTLV I & II 1:640,000 units CMV 50-95% of units West Nile Virus

42. Other Transfusion Transmitted Infections Bacterial contamination Chagas Disease Yersinia, Syphilis Babesiosis Transfusion transmitted prions: Fact or fantasy?

43. Transfusion Reactions Febrile non-hemolytic Txn Rxn 1: 20 – 100 Urticarial 1 : 50-100 Bacterial Contamination < 1: 2,000 Transfusion Related Acute 1: 500 -10,000 Lung injury (TRALI) Anaphylaxis 1 : 20,000 Acute Hemolytic Transfusion Rxn 1: 30,000 Delayed Hemolytic Transfusion Rxn 1: 35,000 (?)

45. Transfusion Related Acute Lung Injury (TRALI) 10 – 14% of reported transfusion fatalities Non-fatal incidence increasing 1997 - 3, 1998 - 12, 1999 - 17 90% anti HLA; anti PMN As little as 50cc Plasma

46. Intravascular Hemolytic Transfusion ReactionsSymptoms Chest or back pain Chills Flushing Dyspnea Nausea Sense of “doom”

47. Intravascular Hemolytic Transfusion Reaction - Signs Fever Hypotension Tachycardia 10% Mortality Hemoglobinemia Hemoglobinuria Anuria & Renal Failure Bleeding DIC

48. Management of Transfusion Reactions Stop transfusion; Keep line open Clerical check Examine plasma for free hemoglobin

49. Management of Transfusion Reactions Stop transfusion; Keep line open Clerical check Examine plasma for free hemoglobin Serologic examination Test for hemolysis LDH, bilirubin, haptoglobin