Fetal and neonatal alloimmune thrombocytopenia: Current pathophysiological insights and perspectives for future diagnostics and treatment

FNAIT is a pregnancy-associated condition caused by maternal alloantibodies against paternally-inherited platelet antigens, most frequently HPA-1a on integrin ß3. The clinical effects range from no symptoms to fatal intracranial hemorrhage, but underlying pathophysiological determinants are poorly understood. Accumulating evidence suggests that differential antibody-Fc-glycosylation, activation of complement/effector cells, and integrin function-blocking effects contribute to clinical outcome. Furthermore, some antibodies preferentially bind platelet integrin ¿IIbß3, but others bind ¿vß3 on endothelial cells and trophoblasts. Defects in endothelial cells and angiogenesis may therefore contribute to severe anti-HPA-1a associated FNAIT. Moreover, anti-HPA-1a antibodies may cause placental damage, leading to intrauterine growth restriction. We discuss current insights into diversity and actions of HPA-1a antibodies, gathered from clinical studies, in vitro studies, and mouse models. Assessment of all factors determining severity and progression of anti-HPA-1a-associated FNAIT may importantly improve risk stratification and potentially reveal novel treatment strategies, both for FNAIT and other immunohematological disorders.The authors gratefully acknowledge financial support from Sanquin (PPOD grant # 17-29) and the Landsteiner Foundation for Blood Transfusion Research (LSBR; grant # 2019)