Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) is a disorder caused by a mismatch in human platelet antigens (HPAs), leading to maternal antibody formation and platelet destruction in the fetus or neonate. The clinically most relevant antigen is HPA-1a on the b3 subunit of integrins aIIbb3 and avb3, which are conformationally regulated cell adhesion receptors on platelets and endothelial cells, crucial for hemostasis and vascular integrity. The clinical effects of anti-HPA-1a alloimmunization are highly heterogeneous and range from no symptoms to intracranial hemorrhage, potentially causing perinatal death or lifelong complications. However, determinants of disease severity are largely unknown, which hampers implementation of screening programs to identify alloimmunized high-risk women who will benefit from treatment. Using recombinant anti-HPA-1a antibodies and a cohort of retrospective FNAIT samples associated with mild or severe disease, we report here that the tested anti-HPA-1a antibodies inhibit binding of integrins avb3/aIIbb3 to ligands (vitronectin, fibronectin, and fibrinogen) and cell adhesion. Inhibition is dependent on antibody concentration, is mediated by the antibody Fab and does not require the Fc-tail, and is abolished when integrins are forced into a constitutively extended conformation. Furthermore, the extent of integrin inhibition correlates with disease severity. Together, our data demonstrate that anti-HPA-1a antibodies can block integrin activation, which likely contributes strongly to disease severity in FNAIT. These results aid development of a prenatal diagnostic test to identify pregnancies at high risk of developing FNAIT and associated severe complications. In addition, these data reveal novel opportunities for allosteric inhibition of b3 integrin activation.
Stam et al. (Sat,) studied this question.