https://orcid.org/0000-0002-9059-0344
In this issue of Blood, Magid-Bernstein et al examine the question of the significance of ABO-incompatible platelet transfusion.1
Like red blood cells, platelets express ABO antigens, and the general practice is to provide ABO-compatible platelets whenever possible. The rationale for this has primarily been concern over the infusion of ABO-incompatible plasma with the platelets and the associated risk of hemolysis in the recipient. Because of the pressure on platelet availability and/or lack of knowledge of the blood group of the recipient, platelets are not infrequently transfused across the ABO blood group as an incompatible transfusion. Historically, less attention has been paid to the fate of platelets transfused into an ABO-incompatible recipient. The PATCH trial reported that the use of platelet transfusion in intracranial hemorrhage (ICH) patients receiving antiplatelet drugs is associated with an increase in mortality and disability.2,3
Magid-Bernstein et al have now investigated the role of ABO-incompatible platelet transfusion in the treatment of patients with ICH, a factor that was not examined in the original PATCH trial. Their analysis shows that patients who received ABO-incompatible transfusions had significantly lower platelet recovery, increased odds of in-hospital mortality, and poorer neurological outcomes. Although the study is somewhat limited by its size, nearly 40% of patients received ABO-incompatible platelet transfusions. Interestingly, there was no significant change in the progression of ICH between ABO-compatible and -incompatible platelet transfusions. Although the mechanisms contributing to these clinical outcomes remain to be determined, the observation is important for the management of ICH patients.
There have been other reports of suboptimal transfusion outcomes from ABO-incompatible platelet transfusion; however, the literature is inconsistent. ABO-incompatible transfusions may result in lower platelet count increments than ABO-compatible transfusions, although at least for prophylactic transfusions, these are not associated with detrimental clinical effects.4 Literature on bleeding patients contains reports of ABO-incompatible transfusions where patients did worse as well as reports of no discernable effect of incompatible transfusion, sometimes in the same patient population.5,6 As a result, we are left with a lack of clarity on appropriate use, and day-to-day practice may require pragmatism based on which platelets are available.7 It is clear that additional clinical trials are needed to understand which patient populations are at risk for adverse outcomes from ABO-incompatible platelet transfusions. The new information in the Magrid-Bernstein et al study is an important contribution to move toward improving transfusion practice.
Some issues require further exploration. The platelets in the Magid-Bernstein et al study were exclusively apheresis platelets, meaning that each dose came from a single donor, reflecting >90% of the platelet inventory in the United States. The expression of ABH antigens on platelets is complex. The amount of A antigen on platelets varies widely in donors whose red cell type is A1, ranging from 0% to 87%, whereas donors with A2 red cells express no A antigen on their platelets.8 However, the amount of A antigen on the platelets of a given donor is quite consistent over time.8 The expression of B antigen is less variable, but both A and B are influenced by the Lewis and secretor statuses of the donor, because some fraction of the antigen is adsorbed to the platelet surface from the plasma.9
The recognition that the ABO compatibility of platelets matters to outcomes for at least some patients argues for a more sophisticated understanding of the characteristics of platelet donors and an appreciation that not all doses of platelets are equivalent. This is complicated by the ongoing pressure on the platelet supply in the United States, as plateletpheresis donors become more difficult to retain in the donor pool, and platelet demand continues to increase. Approximately 30% of platelet transfusions in the United States may be major incompatible, which may shorten the intertransfusion interval, particularly for prophylactic platelet use, resulting in increased platelet demand.10 For ICH patients and others for whom incompatible platelet transfusions may matter, consideration must be given to alternative strategies that maintain the best platelet inventory to ensure platelet transfusions are not performed that fail to improve patient outcomes because of issues of compatibility.
Conflict-of-interest disclosure: D.V.D. is a member of the scientific advisory board of Macopharma and has received research support from TerumoBCT, Hemanext, and Macopharma.
Comments
ABO and platelet transfusion
In a recent review of our institutional experience, implementation of universal leukoreduction in 2000 reduced the needs for HLA matched platelets by half compared with selective leukoreduction for patients with hematologic maligancies (3). The opponents of universal leukoreduction in the USA were tragically mistaken in this regard (4). We still do not have universal leukoreduction in the USA, despite extensive randomized trial evidence of reductions of morbidity and mortality, and the recommendations of three separate FDA advisory panels. When our institution standardized on ABO identical blood transfusions for all patients in 2005, the use of HLA matched platelets dropped by another 70%, demonstrating that many patients who become refractory are missed by conventional criteria for patients at risk.
As demonstrated in the study by Roh and colleagues (5), ABO major incompatible platelets do not provide hemostatic benefit, and they likely increase bleeding and mortality. This effect is also observed in surgical patients (6) and may influence mortality in repeatedly transfused patients with hematologic malignancies. (7) The mechanism of increased bleeding is likely due to the formation of very large immune complexes of soluble ABO antigen and antibody that create a hostile environment which impairs recovery of subsequent ABO identical transfusions. (8) These ABO immune complexes impair platelet function, clot formation, endothelial monolayer integrity and increase inflammatory cytokine secretion. (9,10)
Several studies often cited as proof that ABO makes no difference in platelet transfusion are observational and contain few or no patients who received only ABO identical platelet transfusions. These studies characterized patients by the ABO identicality of only their first transfusion (11,12) and ignored subsequent ABO mismatched platelet transfusions to the same patient. This is scientifically invalid. Would anyone classify patients receiving treatment of pneumoccal pneumonia as being in the antibiotic group if they received one dose of antibiotic and then 9 doses of chicken soup? Likewise, would anyone classify patients who receive a first dose of chicken soup and 9 doses of antibiotics in the chicken soup group? No attempt was made in these studies to group patients by whether they only received ABO identical transfusions, or one or more ABO mismatched transfusions.
The only scientifically valid data demonstrate that ABO identical transfusions, by avoiding infusion of ABO incompatible antigen and antibody, prevent platelet transfusion refractoriness, reduce bleeding and mortality. It’s overdue to implement universal leukoreduction in the USA, and to make greater efforts to administer ABO identical platelets and red cells. Alternatives to ABO identical platelet transfusions are removing the incompatible supernatant of ABO non-identical red cells and platelets. This could include washed or volume reduced group O platelets for non-O patients when ABO identical are not available. The practice of considering AB plasma as universal donor despite the presence of large amounts of soluble antigen incompatible with 95% of recipients should likewise be reconsidered, given that it is associated with increased lung injury, sepsis and mortality in observational studies (13,14).
Never underestimate the importance of the ABO blood group.
1. Carr R, Hutton JL, Jenkins JA, Lucas GF, Amphlett NW. Transfusion of ABO-mismatched platelets leads to early platelet refractoriness. Br J Haematol. 1990 Jul;75(3):408-13. doi: 10.1111/j.1365-2141.1990.tb04356.x. PMID: 2201403.
2. Heal JM, Rowe JM, McMican A, Masel D, Finke C, Blumberg N. The role of ABO matching in platelet transfusion. Eur J Haematol. 1993 Feb;50(2):110-7. doi: 10.1111/j.1600-0609.1993.tb00150.x. PMID: 8440356.
3. Cardillo A, Heal JM, Henrichs K, Masel D, Fountaine T, Liesveld J, Noronha S, Cahill C, Ngo A, Gupta GK, Refaai MA, Blumberg N. Reducing the Need for HLA-Matched Platelet Transfusion. N Engl J Med. 2021 Jun 24;384(25):2451-2452. doi: 10.1056/NEJMc2034764. PMID: 34161713.
4. Thurer RL, Luban NL, AuBuchon JP, Silver H, McCarthy LJ, Dzik S, Stowell CP, Moore SB, Vamvakas EC, Armstrong W, Kanter MH, Jeter E, Becker J, Higgins M, Galel S, Kleinman S, Marshall CS, Newman R, Ocaríz JA, Blackall D, Petz LD, Toy P, Oberman H, Siegel DL, Price TH, Slichter SJ. Universal WBC reduction. Transfusion. 2000 Jun;40(6):751-2. doi: 10.1046/j.1537-2995.2000.40060751.x. PMID: 10864999.
5. Magid-Bernstein J, Beaman CB, Carvalho-Poyraz F, Boehme A, Hod EA, Francis RO, Elkind MSV, Agarwal S, Park S, Claassen J, Connolly ES, Roh D. Impacts of ABO-incompatible platelet transfusions on platelet recovery and outcomes after intracerebral hemorrhage. Blood. 2021 May 13;137(19):2699-2703. doi: 10.1182/blood.2020008381. PMID: 33649761.
6. Refaai MA, Fialkow LB, Heal JM, Henrichs KF, Spinelli SL, Phipps RP, Masel E, Smith BH, Corsetti JP, Francis CW, Bankey PE, Blumberg N. An association of ABO non-identical platelet and cryoprecipitate transfusions with altered red cell transfusion needs in surgical patients. Vox Sang. 2011 Jul;101(1):55-60. doi: 10.1111/j.1423-0410.2010.01464.x. Epub 2011 Mar 18. PMID: 21414009; PMCID: PMC3115402.
7. Heal JM, Kenmotsu N, Rowe JM, Blumberg N. A possible survival advantage in adults with acute leukemia receiving ABO-identical platelet transfusions. Am J Hematol. 1994 Feb;45(2):189-90. doi: 10.1002/ajh.2830450219. PMID: 8141126.
8. Heal JM, Masel D, Rowe JM, Blumberg N. Circulating immune complexes involving the ABO system after platelet transfusion. Br J Haematol. 1993 Nov;85(3):566-72. doi: 10.1111/j.1365-2141.1993.tb03349.x. PMID: 8136280.
9. Zaffuto BJ, Conley GW, Connolly GC, Henrichs KF, Francis CW, Heal JM, Blumberg N, Refaai MA. ABO-immune complex formation and impact on platelet function, red cell structural integrity and haemostasis: an in vitro model of ABO non-identical transfusion. Vox Sang. 2016 Apr;110(3):219-26. doi: 10.1111/vox.12354. Epub 2015 Nov 3. PMID: 26528766.
10. Hannah L McRae, Spencer Slavin, Arshad Rahman, Neil Blumberg, Majed A Refaai,
The Effect of ABO Immune Complexes on Endothelial Cell Integrity As Measured By Electric Cell-Substrate Impedance Sensing (ECIS) and Confocal Microscopy,
Blood, Volume 130, Supplement 1,2017, Page 2306.
11. Lin Y, Callum JL, Coovadia AS, Murphy PM. Transfusion of ABO-nonidentical platelets is not associated with adverse clinical outcomes in cardiovascular surgery patients. Transfusion. 2002 Feb;42(2):166-72. doi: 10.1046/j.1537-2995.2002.00037.x. PMID: 11896330.
12. Triulzi DJ, Assmann SF, Strauss RG, Ness PM, Hess JR, Kaufman RM, Granger S, Slichter SJ. The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia. Blood. 2012 Jun 7;119(23):5553-62. doi: 10.1182/blood-2011-11-393165. Epub 2012 Apr 10. PMID: 22496156; PMCID: PMC3369689.
13. Inaba K, Branco BC, Rhee P, Holcomb JB, Blackbourne LH, Shulman I, Nelson J, Demetriades D. Impact of ABO-identical vs ABO-compatible nonidentical plasma transfusion in trauma patients. Arch Surg. 2010 Sep;145(9):899-906. doi: 10.1001/archsurg.2010.175. PMID: 20855762.
14. Shanwell A, Andersson TM, Rostgaard K, Edgren G, Hjalgrim H, Norda R, Melbye M, Nyrén O, Reilly M. Post-transfusion mortality among recipients of ABO-compatible but non-identical plasma. Vox Sang. 2009 May;96(4):316-23. doi: 10.1111/j.1423-0410.2009.01167.x. Epub 2009 Feb 24. PMID: 19254234.