7.3 HLA, Platelet-Specific & Granulocyte Antigens

HLA, Platelet-Specific & Granulocyte Antigens

Quick Answer: Beyond red cell antigens, the human leukocyte antigen (HLA) system, platelet-specific human platelet antigens (HPA), and human neutrophil antigens (HNA) drive a distinct set of transfusion complications: HLA alloimmunization causes platelet refractoriness and is a leading trigger of transfusion-related acute lung injury (TRALI); HPA antibodies (most often anti-HPA-1a) cause fetal/neonatal alloimmune thrombocytopenia and post-transfusion purpura; and HNA antibodies contribute to TRALI, febrile reactions, and neonatal alloimmune neutropenia. Leukoreduction of cellular blood products is the primary strategy for reducing new HLA alloimmunization, while donor-screening policies target implicated antibodies rather than antigens.

The HLA System in Transfusion Medicine

HLA Class I molecules (HLA-A, -B, -C) are expressed on essentially all nucleated cells and, importantly for transfusion, on platelets, while HLA Class II molecules (HLA-DR, -DQ, -DP) are restricted to antigen-presenting cells such as B lymphocytes, monocytes, dendritic cells, and activated T cells. Repeated exposure to allogeneic leukocytes — through pregnancy or prior transfusion of cellular blood products — can immunize a recipient against HLA Class I antigens. Once alloimmunized, a patient may develop platelet refractoriness: platelet transfusions fail to produce the expected rise in platelet count despite ABO-compatible, adequately dosed, fresh product. Refractoriness is quantified with the corrected count increment (CCI), which adjusts the post-transfusion platelet rise for the patient's body surface area and the number of platelets transfused; a persistently low CCI on two or more sequential transfusions, in the absence of a nonimmune cause such as sepsis, DIC, or splenomegaly, points toward HLA (or, less often, HPA) alloimmunization. Management options include HLA-matched apheresis platelets from a matched unrelated donor registry or platelet crossmatching to identify compatible units. Universal leukoreduction of red cell and platelet components substantially lowers the rate of primary HLA alloimmunization by removing the white cells that present HLA antigens, a strategy validated in large trials of leukoreduced versus non-leukoreduced components.

HLA Class I (and, less commonly, HNA) antibodies present in donor plasma are also central to the pathophysiology of TRALI. In the accepted two-hit model, a recipient's neutrophils become primed and sequestered in the pulmonary microvasculature by an underlying clinical condition (the first hit); when a plasma-containing component from a donor carrying anti-HLA or anti-HNA antibodies is transfused, those antibodies bind and fully activate the sequestered neutrophils (the second hit), triggering release of proteases and reactive oxygen species that damage the capillary endothelium and produce acute, noncardiogenic pulmonary edema, typically within six hours of transfusion. Donor antibodies of this kind are disproportionately found in multiparous female donors, who may have been alloimmunized by fetal antigens during pregnancy. Blood centers mitigate this risk by preferentially collecting plasma and whole-blood-derived platelets from male donors or from female donors without a pregnancy history, and by testing implicated donors for HLA/HNA antibodies once a TRALI case is reported.

Platelet-Specific (HPA) Antigens

Human platelet antigens are polymorphisms on platelet membrane glycoproteins, most importantly the fibrinogen receptor GPIIb/IIIa, which carries the HPA-1a/HPA-1b polymorphism (formerly named PlA1/PlA2). HPA-1a is the most clinically important platelet-specific antigen because it is highly immunogenic and present in roughly 98% of the population, leaving a small HPA-1a-negative minority at risk of alloimmunization. Other systems include HPA-2 (on GPIbα), HPA-3 (on GPIIb), HPA-4 (on GPIIIa), and HPA-5 (on GPIa). Two clinical syndromes dominate the SBB-relevant discussion of HPA antibodies. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs when an HPA-1a-negative mother is sensitized against paternally inherited HPA-1a on fetal platelets; maternal IgG anti-HPA-1a crosses the placenta and destroys fetal platelets, and the most severe cases can present with fetal or neonatal intracranial hemorrhage, sometimes in a first pregnancy since sensitization can occur early in gestation. Post-transfusion purpura (PTP) occurs in an HPA-1a-negative patient previously sensitized by pregnancy or transfusion; five to ten days after a subsequent transfusion of any HPA-1a-positive cellular product, a brisk secondary antibody response destroys both the transfused platelets and the patient's own HPA-1a-negative platelets, through immune-complex or bystander mechanisms, producing severe, potentially life-threatening thrombocytopenia. PTP is treated with intravenous immunoglobulin (IVIG) and, in urgent bleeding, HPA-1a-negative platelets or plasma exchange; platelet transfusion of antigen-positive units generally does not help and can worsen the reaction.

Granulocyte (HNA) Antigens

Human neutrophil antigens reside on neutrophil membrane glycoproteins, including HNA-1 on the Fc receptor FcγRIIIb (CD16b) and HNA-2 on CD177. Antibodies against HNA antigens, like anti-HLA antibodies, are implicated in TRALI when present in donor plasma, and they can also cause febrile nonhemolytic transfusion reactions and, in the neonatal setting, neonatal alloimmune neutropenia when maternal anti-HNA crosses the placenta and destroys fetal neutrophils, leaving the newborn susceptible to infection until the antibody clears. Because HNA and HLA antibody testing require specialized reference-laboratory assays rather than routine blood bank methods, most facilities send suspected TRALI or neonatal alloimmune neutropenia cases out for confirmatory antibody identification while managing the acute presentation supportively.

Putting It Together: CCI and Antibody Workups

The corrected count increment ties several of these concepts together and is worth committing to memory: CCI = (post-transfusion platelet count minus pre-transfusion platelet count, in platelets per microliter) multiplied by body surface area in square meters, divided by the number of platelets transfused (×10¹¹). A one-hour CCI below roughly 7,500–10,000 on repeated occasions, without a nonimmune explanation, is the threshold most laboratories use to trigger an HLA antibody screen and consideration of HLA-selected or crossmatch-compatible platelets. The same logic of testing for an antibody once expected outcomes fail applies across this chapter: a fetus with unexplained anemia despite reassuring bilirubin trends prompts a Kell antibody workup, a newborn with unexplained thrombocytopenia and a sensitized mother prompts an HPA-1a workup, and a recipient with acute respiratory distress shortly after transfusion prompts a donor HLA/HNA antibody investigation.

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