Transfusing HPA-mismatched platelets to mimic fetomaternal hemorrhage elicits fetal/neonatal alloimmune thrombocytopenia

Abstract

Abstract Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder in which maternal antibodies target fetal and neonatal platelet alloantigens, most commonly human platelet alloantigen-1a (HPA-1a), resulting in fetal and neonatal thrombocytopenia severe enough to cause life-threatening organ bleeds, such as intracranial hemorrhage. Hemolytic disease of the fetus and newborn (HDFN) is an analogous disease caused by maternal exposure to fetal red blood cell (RBC) alloantigens, most commonly because of postpartum fetomaternal hemorrhage (FMH), which can be prevented by prophylactic administration of fetal RBC-specific antibodies. Unlike HDFN, the events that trigger FNAIT are unknown and can occur during first pregnancies, making FNAIT difficult to predict and prevent. Herein, we investigated the ability of in utero FMH to induce maternal alloimmunization to HPA-1a and cause FNAIT in a preclinical model. Transfusion of HPA-1a+ platelets into wild-type (WT) mice in numbers representing moderate and severe FMH in humans induced production of equivalent levels of HPA-1a–specific antibodies in nonpregnant mice and mice pregnant with WT or HPA-1a+ fetuses, causing FNAIT in the latter. Administration to pregnant females of the HPA-1a–specific monoclonal antibody (mAb) RLYB212/mAb 26.4 prevented FMH-induced maternal alloimmunization to HPA-1a and FNAIT in genetically susceptible pups. In mice pregnant with HPA-1a+ fetuses but not exposed to FMH, administration of RLYB212/mAb 26.4 did not cause FNAIT. Together, these findings identify in utero FMH as a potential trigger for maternal alloimmunization to fetal HPA-1a, and provide proof of concept that prophylactic administration of HPA-1a–specific antibodies may safely and effectively prevent FMH-induced FNAIT in at-risk pregnancies.