Inhibition of human FcγRIII prevents platelet destruction in a dual-humanized murine model of FNAIT.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs when maternal anti-fetal platelet antibodies, most frequently against human platelet antigen 1a (HPA-1a), cause fetal platelet destruction. The precise pathogenic mechanisms remain incompletely understood. Here, we examined potential mechanisms underlying anti-HPA-1a-mediated platelet clearance, focusing on phagocytosis, complement fixation, platelet activation, and desialylation. Anti-HPA-1a antibodies in pooled plasma and in individual samples of 9 of 10 patients with FNAIT induced Fc gamma receptor (FcγR)-dependent platelet phagocytosis in vitro, indicating this as the major contributor to platelet destruction. In contrast, complement fixation, platelet activation (CD62P expression), and desialylation (Ricinus communis agglutinin I binding) were observed in only a minority of patients. To model anti-HPA-1a-mediated platelet clearance in vivo, we developed a dual-humanized mouse model combining HPA-1a-expressing platelets (from APLDQ transgenic mice [C57BL/6 mice expressing A30P32L33D39Q470 on a murine GPIIIa backbone]) with mice engineered to express human FcγRs in place of murine FcγRs. Platelets from APLDQ mice sensitized with anti-HPA-1a sera underwent rapid clearance in these FcγR-humanized recipients. Pretreatment with an FcγRIII-blocking monovalent antibody significantly reduced clearance, confirming FcγRIII's central role in mediating platelet destruction. These results demonstrate that FcγRIII-dependent phagocytosis is a dominant mechanism in anti-HPA-1a-driven platelet clearance in this model. Although complement activation and platelet desialylation were observed in a minority of samples, their contribution to platelet destruction remains speculative. Together, these findings highlight the complexity of FNAIT pathophysiology yet identify FcγRIII blockade as a promising strategy to prevent platelet clearance in this disease.