Serologic changes and transfusion requirements after ABO incompatible stem cell transplant

1. Serologic changes and transfusion requirements after ABO incompatible stem cell transplant Kimberly W. Sanford, M. D. Associate Medical Director of Transfusion Medicine Virginia Commonwealth University Health System

2. Objectives • Review basic ABO serology • Define the types of incompatible ABO transplants • Serologic changes in recipient • Discuss transfusion strategies

3. RBC Antigen Substance capable of inducing immune response • Protein, carbohydrate, lipid • Can be cell bound or free floating ANTIGEN

4. Antibody A protein synthesized by B lymphocyte in response to antigen and resides in the plasma • Expected antibody – • Naturally occurring • Example • Anti A, Anti-B antibodies • Unexpected antibody • Exposure to donor blood through transfusion • Exposure during pregnancy • Example: • Anti-D, Anti-Kell antibodies

5. RBC ABO System • The antigens present on the surface of RBC are numerous • Several hundred antigens present on surface • ABO system • A antigen • B antigen • AB antigen • O lacks both A and B antigen • Rh system • 49 antigens make up the Rh system • 5 antigens most important: • D, C,E,c,e

6. ABO system Group B Group A Group AB Group O

7. ABO antibodies RULES: WE FORM ANTIBODIES TO THE ANTIGENS WE LACK WE DO NOT FORM ANTIBODIES TO OUR OWN ANTIGENS

8. Blood Group A • Patient has A antigen on RBC • Patient lacks B antigen • Therefore patient will form Anti-B antibodies, but NOT Anti-A antibodies.

9. Blood Group B • Patient has B antigen on RBC • Patient lacks A antigen • Therefore patient forms Anti-A antibodies but NOT Anti-B antibodies

10. AB group • Patient have both A and B antigen on RBC • Therefore patient does NOT form any AB antibodies.

11. O Blood Group • Patient lacks both A and B antigen • Patient forms both: • Anti-A antibody • Anti-B antibody

12. HLA & ABO inherited separately • HLA: Chromosome 6 (6p21.3) contains 200 genes, expressed on WBC • ABO: located on Chromosome 9, expressed on RBC • Patient & donor may be 6/6 HLA match but disparate ABO groups

13. HLA system • Human Leukocyte Antigen system expressed on all nucleated cells • Mature circulating RBCs do not have nuclei, do not express HLA antigens • Look at HLA antigens to determine if donor is a match • Class I: HLA A, B, C • Class II: HLA DP, DQ, DR • HLA-A, B, DRB1 (Cw) are most important for matching

14. HLA and ABO Antigens • HLA compatibility • Strongest predictor for occurrence of severe GVHD • Single most important factor to consider in selecting donor

15. ABO mismatch transplant • ABO mismatch does not: • Affect engraftment since stem cells do not have ABO antigens • The lack of the ABO antigens allow for homing and engraftment of stem cells regardless of ABO incompatibility • Does NOT affect neutrophil, platelet engraftment, graft failure or rejection.

16. ABO mismatched transplants • Complications • Require more transfusion • Delayed RBC engraftment or RBC aplasia • Acute RBC hemolysis • Acute hemolysis of RBC with infusion of HPC product • Delayed RBC hemolysis • After engraftment, marrow produces donor RBC incompatible with recipient antibodies. • After engraftment, ABO antibodies produced against recipient RBC • Patient develops a positive DAT and hemolysis • Can be life threatening • Complex transfusion requirements

17. Intravascular hemolysis • Antibody binds intravascular to RBC activating complement • Complement causes pores in RBC membrane • Free hgb escapes, hgb drops, LDH increases, haptoglobin decreases • Binds NO2 • Renal vasoconstriction, ischemia, tubal necrosis, renal failure • Complement activation generates • Anaphylatoxins, C3a & C5a • Proinflammatory cytokines activated • IL-1, IL-6, IL-8, TNF • Fever, Hypotension, Activate WBC and clotting cascade • Disseminated Intravascular coagulation • Death

18. Intravascular Hemolysis

19. ABO incompatibilities in transplant • Major • Recipient has ABO antibodies directed against donor RBC • Minor • Donorhas ABO antibodies directed against recipient RBC • Bidirectional: Major and Minor ABO Incompatibility: • Recipient has ABO antibodies directed against donor red cells AND • Donor has ABO antibodies directed against recipient red cells.

20. Major mismatch: O recipient & A donor • O recipient: Anti-A, Anti-B antibodies and O RBCs • Donor RBCs: A antigen RBC • Complications • Immediate hemolysis of donor RBC at transplant R R R R R R R D R D R

21. Delayed complications • Delayed hemolysis after RBC engraftment • Persistent recipient anti-A abs • 120-605 days post transplant • Hemolyze donor A RBC produced from marrow. • Delay RBC engraftment • 20% of patients experience • RBC aplasia (severe) • Reticulocytopenia persists > 60 days • RBC precursors not present in marrow aspirate

22. Minimize Risk • Apheresis collections can minimize RBC contamination of product to hematocrit < 2-3%. • Remove RBCs from the graft below 10-20 ML during processing of stem cell product

23. Minor Mismatch: A recipient & O donor • Recipient A : A RBC and Anti-B abs • O donor: infusion of Anti-A abs into recipient • Complication • Delayed hemolysis (1-2 wks) after donor lymphocyte engraftment D R D D D R R R R R

24. Minimize Risk • Remove donor plasma and antibody from graft to prevent hemolysis at transplant • Biggest risk is 5-14 days after transplant, the donor lymphocytes create antibodies against recipient RBC cells. • Positive DAT and hemolysis of RBC • Severe hemolysis can lead to multisystem organ failure • Death

25. R Passenger donor lymphocytes • “Passenger” donor lymphocytes proliferate within the marrow and produce ABO antibodies.

26. Bidirectional Mismatch: A recipient & B donor • Recipient: A RBC’s with Anti-B antibodies • Donor: B RBC’s with Anti-A antibodies • Complication: immediate hemolysis of donor cells, delayed hemolysis after lymphocyte engraftment of recipient RBC and RBC aplasia R D R D D R D R

27. Minimize Risk • Deplete the donor graft of RBC and plasma. • Biggest risk is 5-14 days after transplant, the donor lymphocytes create antibodies against recipient RBC cells. • Delayed RBC engraftment, pure RBC aplasia • Positive DAT and hemolysis of RBC • Can lead to multisystem organ failure • Death • Bidirectional ABO incompatibility have significantly increased risk of mortality over major and minor incompatibilities

28. Transfusion support • Difficult to select components • Recipient antibodies can persist for weeks or months after transplant and engraftment • Donor lymphocytes produce antibodies against recipient RBC • Patients are chimeras • Patient has 2 distinct blood group RBC populations • Donor RBC production increases after engraftment, incompatible with persistent recipient antibody • Concerns • Intravascular hemolysis in major and bidirectional mismatches • Delayed hemolysis in minor mismatches • Select product that will not exacerbate hemolysis • Transfusion support can affect overall survival

29. ABO/Rh incompatible transplant transfusion • Phase I: Prior to transplant • Phase II: Transplant until engraftment • Recipient antibodies are still detectable • Chimera: recipient and donor type RBC detectable • Front and back types don’t match • Interpret as undetermined type • Phase III: Complete engraftment • Patient RBC type like donor RBCs • Patient ABO antibodies are same as donor. • Requires confirmed new blood type on 2 separate occasions to switch blood products to donor type

30. ABO selection of products • Major Incompatibility: O recipient receives A donor • PRBC • Transfuse with recipient type RBC until recipient antibodies are no longer detectable. • Then switch to donor type RBC • Plasma • Continue with donor type plasma

31. ABO Selection of PRBC • Major incompatibility: O recipient & A donor • Recipient has Anti-A or Anti B antibody against donor A RBC • Transfuse with recipient type, O RBC R D

32. ABO Selection of Plasma products • Major incompatibility: O recipient & A donor • Recipient has Anti-A or Anti-B antibody against donor A RBC • Transfuse with donor type A plasma R R D

33. Transfusion for Major Incompatiblity

34. ABO selection of products • Minor Incompatibility: A recipient receives O donor • PRBC • Transfuse with donor type RBC until engraftment • Plasma • Continue with recipient type plasma until recipient RBCs are no longer detectable, then switch to donor type

35. Minor Mismatch: A recipient & O donor • RBC: provide donor type O RBC start immediately after transplant and continue after engraftment.

36. Minor Mismatch: A recipient & O donor • Plasma: provide recipient type A or AB plasma until recipient red blood cells are no longer detected, then switch to donor type plasma.

37. Minor ABO Incompatibility

38. Bidirectional Mismatch: A recipient & B donor • Bidirectional Incompatibility • PRBC • Provide O PRBC • FFP • Provide AB plasma products R D R D D R D R

39. Bidirectional (Major and Minor) ABO Incompatibility Continue until offending RBC antigens and antibodies are no longer detected.

40. RBC Alloantibody incompatibility • Have major and minor incompatibilities of other antigens • Rh system: Anti- D, C, E • Anti – Kell or Kidd abs are particularly bad • Major: Recipient has antibodies to donor antigens • Ex: Kell antigen + donor, recipient with Anti-Kell abs • Minor: Donor has antibodies to recipient RBC antigen • Ex: donor with Anti-E abs, E antigen + recipient • HPC product • Keep low hct during collection • Remove plasma from HPC product • Provide antigen negative, crossmatch compatible RBC for transfusion.

41. Alloimmunization to RBC antigens • Despite immunosuppression, may still see immune response to foreign RBC antigens. • Complicates transfusion by now requiring antigen negative blood in addition to ABO transfusion requirements. • 2 studies have demonstrated red cell alloimmunization of 2-8% in patients undergoing stem cell transplant. • Perseghin P, Balduzzi A, Galimberti et al. Bone Marrow Transplant 2003;32:231-6. • Abou-Elella AA, Camarillo TA, Allen MB et al. Transfusion 1995;35:931-5.

42. Rh Negative Transplant patients • Minimize exposure to Rh positive products • Rh positive platelets contain about 2 ml of RBC/dose • Risk of forming Anti-D is low, 0-22% • 22 adult patients, none alloimmunized • Cid J, Ortin X, Elies E, et al. Transfusion 2002;42:173-6.patients • 35 pediatric patients, none alloimmunized • Molnar R, Johnson R, Sweat LT, Geiger TL. Transfusion 2002;42:177-82. • 98 adult patients, received 445 D+ RBC units • 22 formed anti-D, 22% • Yazer MH, Triulzi DJ. Transfusion 2007;47:2179-2201.

43. Rh Incompatible Transplants

44. Summary • Complex transfusion requirements • See acute and delayed hemolysis • Lower overall survival in minor and bidirectional mismatched grafts. • Delayed RBC engraftment or red blood cell aplasia. • ABO doesn’t affect engraftment of stem cell product, lymphocytes or granuloctyes • Studies have found ABO incompatibility bigger risk of mortality in certain cases: • based on disease condition • reduced intensity conditioning • receiving unrelated grafts.

45. References • Szczepiorkowski ZM. Transfusion Support for Heamotpoietic Transplant Recipients. In: Roback J. Ed. Technical manual 16th ed. Bethesda MD: American Association of Blood Banks, 2008. 679-96. • Tormey CA, Synder EL. Transfusion Support for the Oncology Patient. In: Toby L. Simon et al. Ed. Rossi’s Priniciples of Transfusion Medicine 4th ed. American Association of Blood Banks, 2008. 482-97. • Perseghin P, Balduzzi A, Galimberti et al.Red blood cell support and alloimmunization rate against erythrocyte antigens in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;32:231-6. • Abou-Elella AA, Camarillo TA, Allen MB et al. Low incidence of red cell and HLA antibody formation by bone marrow transplant patients. Transfusion 1995;35:931-5.