FcγRIII blockade prevents anti-HLA-mediated platelet clearance in a humanized murine model of platelet transfusion refractoriness.

Immune platelet transfusion refractoriness (iPTR) is a major complication in transfusion medicine. Although anti-HLA antibodies are recognized contributors, the mechanisms by which they drive platelet clearance remain incompletely defined. We examined sera from 18 patients with iPTR and found that anti-HLA antibodies induced uptake of human platelets expressing the cognate HLA-A2 target antigen and platelet particles derived from these platelets. These sera also mediated clearance of transgenic mouse platelets expressing human HLA-A2. Using THP-1-CD16A macrophages, uptake of both platelets and platelet particles was mediated predominantly through FcγRIIIa, with a partial contribution from FcγRI and little to no role for FcγRII. To test this pathway in vivo, we used a reductionist humanized murine model of iPTR in which HLA-A2 transgenic mouse platelets sensitized with human iPTR sera were transfused into FcγR-humanized mice. In this model, FcγRIII blockade with 17C02-albumin prevented platelet clearance under the conditions tested. These findings extend previous FcγR studies in antibody-mediated platelet clearance to the alloimmune setting of iPTR and support further investigation of FcγRIII-dependent pathways in antibody-mediated PTR.