1. 1 CBS Journal Club CBS Journal Club Christopher Sharpe MD, FRCPC R6 Transfusion Medicine March 1, 2011

2. 2 Objectives to discuss the impact of deferring female plasma and platelet apheresis donors on blood component availability in the US to discuss TRALI-mitigation strategies (including the current CBS policy)

3. Focus of Journal Club “ Blood donations from previously transfused or pregnant donors: a multicenter study to determine the frequency of alloexposure ” “ Blood donations from previously transfused or pregnant donors: a multicenter study to determine the frequency of alloexposure ” Rios JA, Schlumpf KS, Kakaiya RM, et al. Transfusion 2011

4. 4 Introduction transfusion-related acute lung injury (TRALI) is a leading cause of death due to blood transfusion US FDA data: - 35% of deaths due to transfusion (2008) - 30% of deaths due to transfusion (2009)

5. 5 Introduction November 2006: - TRALI mitigation strategies implemented widely to minimize the preparation of high- plasma volume components from donors immunized (or at risk for immunization) against white blood cell antigens

6. 6 Introduction UK data (Chapman, Transfusion 2009) - risk for highly likely or probable TRALI cases was 15.5 cases per 1 million units of FFP issued in 1999-2004 (when both male and female plasma was transfused) - risk for highly likely or probable TRALI cases was 3.2 cases per 1 million units of FFP issued in 2005-2006 (when male plasma was transfused)

7. 7 Introduction UK Data: SHOT Steering Committee 2010 - plasma for transfusion is manufactured from males since late 2003 2002: 32 cases of TRALI 2009: 14 cases of TRALI

8. 8 Introduction Remaining question: - do other TRALI-mitigation steps need to be considered aside from the complete exclusion of all female donors from the donor pool?

9. 9 Introduction CBS policy: - defer female donors from donating transfusable plasma (unless AB plasma is required) - use female plateletpheresis donors only if they do not have a history of pregnancy - female donor plasma used for fractionation

10. 10 Specificities of leukocyte alloantibodies in transfusion- related acute lung injury and results of leukocyte antibody screening of blood donors Reil et al., Vox Sang 2008 Purpose: - to determine the specificities of leukocyte antibodies implicated in previous severe TRALI reactions Results: - 36 TRALI cases reviewed - anti-HLA class II (17 cases) - anti-HNA (12 cases; 10 with anti-HNA-3a) - anti-HLA class I (4 cases) - anti-HLA class I/II (3 cases)

11. 11 Specificities of leukocyte alloantibodies in transfusion- related acute lung injury and results of leukocyte antibody screening of blood donors Reil et al., Vox Sang 2008 Results: - investigated 5332 parous female donors - 473 had leukocyte antibodies (8.9% alloimmunization rate) - 61% had anti-HLA class I - 19% had anti-HLA class II - 12% had both anti-HLA class I and class II - 5% had anti-HNA

12. 12 Specificities of leukocyte alloantibodies in transfusion- related acute lung injury and results of leukocyte antibody screening of blood donors Reil et al., Vox Sang 2008 Results: - no antibody-mediated TRALI cases were observed following introduction of a policy of accepting transfusable plasma only from male donors, nulliparous female donors, or tested multiparous female donors without HLA antibodies - no shortage of plasma or platelet products was encountered as a result of the restrictive strategy

13. 13 Specificities of leukocyte alloantibodies in transfusion- related acute lung injury and results of leukocyte antibody screening of blood donors Reil et al., Vox Sang 2008 Conclusion: - isolated HLA-class I antibody screening is insufficient for leukocyte antibody screening

14. 14 Introduction the prevalence of human neutrophil antibodies (HNA) antibodies among US blood donors is small compared to the number with HLA antibodies (Triulzi, Transfusion, 2008)

15. 15 Prevalence of HLA antibodies in remotely transfused or alloexposed volunteer blood donors (LAPS-1) Kakaiya et al., Transfusion 2010 7920 donors (2086 males, 5834 females) were tested for antibodies against HLA class I and HLA class II the prevalence of HLA class I and/or class II antibodies was similar in nontransfused (1138; 1.0%) vs. transfused men (895; 1.7%)

16. 16 Identification of specificities of antibodies against human leukocyte antigens in blood donors (LAPS-1) Endres et al., Transfusion 2010 antibody frequencies against HLA class I and HLA class II were determined for 7920 donors (2086 males, 5834 females) with a positive antibody screen positive rate increased among women with 0 to 4 or more pregnancies (0.3-15.6% for anti-HLA class I and 0.4-18% for anti-HLA class II; p<0.00001)

17. 17 The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy Triulzi et al., Transfusion 2009 Purpose: to determine the prevalence of HLA antibodies in blood donors and and their relationship to previous transfusion or pregnancy Methods: - 8171 volunteer blood donors were prospectively recruited by six US blood centers from December 2006 to May 2007 - donors provided a detailed history of prior pregnancies and transfusion events - donors were tested for HLA Class I and II antibodies

18. 18 The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy Triulzi et al., Transfusion 2009 Results: - HLA antibodies were detected in 17.3% of all female donors (n = 5834) and in 24.4% of those with a history of previous pregnancy (n = 3992) - the prevalence of HLA antibodies increased in women with more pregnancies: - 1.7% (no pregnancies) - 11.2% (one pregnancy) - 22.5% (two pregnancies) - 27.5% (three pregnancies) - 32.2% (four or more pregnancies; p < 0.0001)

19. 19 Introduction Retrovirus Epidemiology Donor Study-II (REDS-II) - funded by NIH - investigated the presence of antibodies to human leukocyte antigens (HLA) and/or human neutrophil antigens (HNA) among six US blood centers

20. 20 Blood donations from previously transfused or pregnant donors: a multicenter study to determine the frequency of alloexposure Rios JA, Schlumpf KS, Kakaiya RM, et al. Transfusion 2011 Purpose: - to estimate the prevalence of WBC alloimmunization according to the pregnancy and transfusion history of allogeneic blood donors at each of the REDS-II blood centers - to compare the impact of the implementation of the aaBB TRALI mitigation strategies among six different blood centers in the US (only using male plasma for transfusion and deferring female plateletpheresis donations)

21. 21 Methods data used was from Retrovirus Epidemiology Donor Study-II (REDS-II) Six participating blood centers in study: - Blood Centers of the Pacific (San Francisco) - American Red Cross Blood Services Southern Region (Atlanta, GA) - New England (Massachusetts) - Hoxworth Blood Center (Cincinnati) - Institute for Transfusion Medicine (Pittsburgh) - BloodCenter of Wisconsin (Milwaukee)

22. 22 Methods donation data was sent to the REDS-II central coordinating center for compilation data collected from Jan 2006 – Dec 2008 - age - sex - first-time or repeat donor status - transfusion history - pregnancy history - donation procedure (whole blood vs apheresis component) - blood donation type (allogeneic vs. autologous donation) - blood type

23. 23 Methods the percentages of donations from donors with risk factors for HLA and/or HNA alloimmunization were calculated the number of donations of apheresis platelets from female donors that could have HLA antibodies was calculated (according to prior pregnancy history from this study AND the proportion of female donors with positive screening test results for HLA antibodies from the LAPS-I Study)

24. 24 Methods the percentages of donations resulting in 1, 2, or 3 units of apheresis PLTs at two REDS-II blood centers were used to calculate the numbers of apheresis PLTs products that could be lost if the following groups were deferred from future apheresis PLT donations: - all female donors - all ever-pregnant female donors - all ever-pregnant female donors with anti-HLA

25. 25 Methods the percentages of donations from donors with AB blood type were calculated from: - all male donors - all female donors - all ever-pregnant female donors - all ever-pregnant female donors with positive screening tests for HLA antibodies chi-square test was performed to assess the association between the percentage of female apheresis PLT donors in 2006 compared to 2008

26. 26 Table 1

27. 27 Figure 1

28. 28 Table 2

29. 29 Figure 2

30. 30 Table 3A

31. 31 Table 3B

32. 32 Table 4A

33. 33 Table 4B

34. 34 Table 5

35. 35 Table 6

36. 3 3 Discussion study provided data on the frequency of risk factors for alloimmunization to WBC antigens among US blood donors (transfusion and pregnancy history) study data allowed for an estimation of the loss of available blood components using various TRALI mitigation strategies: - deferring all female donors would incur a 50% reduction in the number of units of whole blood available for transfusable plasma manufacturing - deferring all female donors would incur a loss of 37% of apheresis platelet donations 4

37. 3 3 Discussion only 3-4% of blood donors between 2006 and 2008 reported a history of prior transfusion the prevalence of HLA antibodies among blood donors appears independent of prior transfusions - deferring donors with a transfusion history is not an effective TRALI mitigation strategy 4

38. 3 3 Discussion 66.7% of 95000 donations of apheresis platelets from female donors were donated by women reporting a history of one or more pregnancies TRALI mitigation strategies for female apheresis platelet donors: - defer all female donors (lose 37.1% of donors) - defer female donors who have had at least one prior pregnancy (lose 22.5% of donors) - defer previously-pregnant females who have HLA antibodies (lose 5.4% of donors) 4

39. 3 3 Discussion Strategies to make up for the deferred units from previously-pregnant female apheresis platelet donors who have HLA antibodies (5.4%): - increase the production of platelet concentrates from whole blood - replace with male donors - replace with nulliparous female donors - replace with ever-pregnant female donors without HLA antibodies the institution of HLA antibody measurement in this setting is problematic 4

40. 3 3 Critical Appraisal Are the results valid ? yes: - information on what impact various TRALI mitigation strategies would have on the availability of blood components is needed - the volume of donor data available for analysis in this study is large (but it represents only ~8% of total donations made in the United States) 4

41. 3 3 Critical Appraisal Are the results valid? - the methodology used to measure HLA and HNA antibodies in the REDS-II study was not stated in the current study - bias in information collection is likely not an issue in this study since donors volunteered relatively simple demographic information (gender, pregnancy and transfusion history) - missing data on previous pregnancies was an issue in only a small number of donors (~ 3%) 4

42. 3 3 Critical Appraisal Are the results valid? - it appears safe to assume that females that have not been previously-pregnant will not have HLA antibodies - is it safe to accept that prior transfusion is not a significant risk factor for WBC alloimmunization? 4

43. 3 3 Critical Appraisal Are the results valid? - not every country or jurisdiction may possess the capacity to measure HLA or HNA antibodies in their donor population - plateletpheresis units are not usually split into multiple units in Canada - double-RBC collections are not usual in Canada (yet) 4

44. 3 3 Critical Appraisal What are the results? In the Unites States : - deferral of all female apheresis PLT donors: 37.1% loss of total donations - deferral of all female apheresis PLT donors with a prior pregnancy history: 22.5% loss of total donations - deferral of all female apheresis PLT donors with a prior pregnancy history and positive screening results for HLA antibodies: 5.4% loss of total donations 4

45. 45 How Can I Apply The Results To Patient Care? Current CBS policy: - defer female donors from donating transfusable plasma (unless AB plasma is required) - female donor plasma used for fractionation - use female plateletpheresis donors only if they do not have a history of pregnancy

46. 46 TRALI Cases Reported to CBS 2001-2009 PMP (predominantly male plasma) used for transfusion October 2007 46 Year200120022003200420052006200720082009 Definite/ Possible TRALI 666161421361912

47. 47 TRALI Cases Reported to CBS 2001-2009 component breakdown for definite/possible TRALI cases 47 YearTotalRBCPLTPlasmaMixed 20073618378 20081911323 2009127113

48. 48 CBS Data

49. 49 CBS Data

50. 50 CBS Data

51. 51 CBS Data

52. 52 CBS Data

53. 53 CBS Data

54. 54 CBS Data

55. 1616 Questions or Questions or comments? comments?