1. Female Donor Plasma: Have we made a terrible mistake? Shuen Tan TMR Journal Club March 2, 2010

2. Background  TRALI not fully understood  2 forms exist: Immune-mediated: anti-HLA, anti-HNA Nonimmune-mediated: neutrophil priming  #1 cause of transfusion-related mortality  All blood products but especially high plasma-volume components  Them pesky multiparous women!

3. Where did all the women go?  UK SHOT (AABB 2006) Strong association between TRALI and plasma/platelet transfusion Frequently associated with leukocyte ab’s No TRALI associated with male donors Anti-HLA in 1/7 of females, increasing with parity Female plt/plasma donors excluded 2003 “Highly likely” TRALI cases: 16 in 2003, 3 in 2005

4. Meanwhile, across the Pond…  Canadian Consensus Conference gives us a common definition (2004)  AABB recommends TRALI risk reduction measures in 2006  October 2007: CBS starts preferentially using male plasma for transfusion Buffy coat begins  July 2009: We wave good-bye to multiparous plt pheresis donors

6. Welsby IJ et al. The relationship of plasma transfusion from female and male donors with outcome after cardiac surgery. J Thorac Cardiovasc Surg 2010: epub.

7. Methods  Study Type Retrospective cohort  Place Duke University Medical Center (single centre)  Patients Adult, primary, non-emergency, CABG surgery  Time June 1, 1995 - June 30, 2002 “preceding concerns regarding donor gender”

8. Methods  Extracted paired subsets of patients receiving exclusively male or female plasma Matched for number of plasma units and nearest surgery date Other plasma products not matched  Plasma units cross-matched with ARC to find donor characteristics

9. Outcomes  Primary outcome Pulmonary dysfunction: composite of pulmonary edema, pneumonia, and ARDS Not specifically TRALI  Secondary outcomes Death within 30 days Prolonged hospital stay Long-term survival Other post-op complications (STS criteria)

10. Results

11. Primary Outcome  Less common in recipients of female plasma 5.9% vs. 10.8%, p=0.01

12. Secondary Outcomes  Death/prolonged hospital stay less common in recipients of female plasma 9% vs. 16.4%, p=0.002  Long-term survival no different when adjusted for differences, p=0.47  Fewer infectious complications 1% vs. 4%, p=0.01

13. Secondary analyses  All plasma recipients (n=2157) Complications vs. likelihood of receiving male donor plasma Pulmonary dysfunction associated with male donor plasma (60.9% vs. 54.8%, p=0.03) Prolonged hospital stay or death within 30 days associated with male donor plasma (59.1% vs. 54.6%, p=0.02) Infectious complications not associated with male or female plasma (p=0.46)

14. Conclusions  “… neither support nor refute blood systems decisions to limit the use of female plasma to reduce TRALI”  “… data that expose potentially concerning effects that suggest that such a change may have an impact on outcomes other than TRALI in patients undergoing cardiac surgery.”

15. Assessing the study quality  Is this evidence about harm valid?

16. 1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?  No difference in Hannan mortality risk index or Charlson comorbidity index  No difference in amount of transfusion of other products  Platelets  Red cells  Cryo  Matched by computer algorithm for units of plasma and date of surgery

17. 1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?  NO! Groups were not similar  NOT matched for platelets, cryo, and other high plasma volume products  Table 1: Male donor plasma patients are more likely to be: Female (37% vs. 26%, p=0.002) Lighter (78kg vs. 83kg, p=0.001) Non-Caucasian (14% vs. 18%, p=0.03) Previous stroke (16% vs. 11%, p=0.02) Preop IV heparin (49% vs. 42%, p=0.03)

18. 2. Were exposures and clinical outcomes measured in the same ways in both groups?  Maybe?  Prospectively collected cardiac surgery database Complications recorded as defined by STS Recorded as presence or absence during hospital stay Timing not reported  No reports of TRALI Was TRALI recognized/defined?

19. 3. Was the follow-up of the study patients sufficiently long and complete?  Yes  TRALI, by definition, has onset within 6 hours  In-hospital complications recorded in database  Long-term follow-up to 1500 days Complete?

20. 4. Do the results of the study fulfill some of the diagnostic tests for causation? A) Is it clear that the exposure preceded the onset of the outcome?  Yes, BUT patients were also exposed to Sternotomy and major surgery Intubation and ventilation Cardiopulmonary bypass  Any of these can contribute to lung injury, postop complications, and mortality  Timing of complications not recorded Correlation between plasma transfusion and onset of symptoms not shown

21. 4. Do the results of the study fulfill some of the diagnostic tests for causation? B) Is there a dose-response gradient?  Mortality associated with number of plasma units transfused (OR 1.52 per unit)  Primary analysis shows “dose effect” which could be attributed to a sicker population

22. Dose-response  Grey = male plasma  White= female plasma  Relatively few received >2 units  Almost no difference between 1 or 2 units  Dose effect would have to include: All high plasma products Donor pregnancy and transfusion history

23. The Secondary Analysis  “Male donor ratio” calculated for each patient and averaged for each complication  Patients with outcomes exposed to more male plasma  Given our understanding of TRALI, the math doesn’t make sense

24. 4. Do the results of the study fulfill some of the diagnostic tests for causation? C) Is the association consistent from study to study?  No studies in cardiac surgery population  3 studies in ICU All showed no difference or decreased morbidity in the male donor plasma groups

25. 4. Do the results of the study fulfill some of the diagnostic tests for causation? D) Does the association make biological sense?  No  Not in keeping with our current understanding of TRALI  Authors suggest non-immune TRALI may be more important in cardiac surgery BUT gender-specific differences in mediators of inflammation in plasma not shown No explanation postulated for non-respiratory complications

26.  Significant threats to validity preclude conclusions about importance and application of study

27. Should we be worried?  I think not  More likely that results are due to unequal groups and flawed study design than to an unidentified difference between male and female donor plasma

28. Things that would lend a study like this more credence  Retrospective  Patient population with less obvious risk factors for TRALI  Equal recipient groups Include more information on recipients Include pregnancy and transfusion history of donors Include all high plasma volume products  Outcomes Should make biologic sense -- respiratory Should make temporal sense

29. Where to go from here  No prospective trials possible  Epidemiologic evidence TRALI reporting and education  Developments in our understanding of pathophysiology

30. Definite & Possible TRALI TRALI cases 20012002200320042005200620072008 2009 Total1534325545515734 Definite and Possible 666161421361912 TRALI CCC (Apr) BC Edmonton (Oct) Male plasma (Oct) BC BC&Y (Mar) BC Toronto (Jan)

31. Questions and Comments?