The Immunobiology of Fetal/Neonatal Alloimmune Thrombocytopenia

ABSTRACT/SUMMARY Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT), is a non-malignant hematologic bleeding disorder that arises when maternal antibodies specific for fetal platelet alloantigens cross the placenta and remove a baby's platelets from circulation in the fetal and/or neonatal period. Cases of mild thrombocytopenia often resolve without incident, but 10-20% of severely thrombocytopenic cases are unpredictably associated with major organ bleeds such as intracranial hemorrhage (ICH), which can cause irreversible brain damage and death. More than 35 polymorphic Human Platelet Alloantigens (HPAs) on seven membrane glycoproteins have thus far been iden- tified. Among these, HPA-1a (formerly known as PlA1) is the most clinically significant cause of FNAIT in the US, being responsible for the vast majority of FNAIT cases, and is most frequently associated with ICH and other adverse pregnancy complications. Interestingly, studies in a number of laboratories, including ours, have re- vealed remarkable heterogeneity in maternally-derived HPA-1a-specific alloantibodies, and have reported an association of specific subpopulations with the severity of FNAIT. Whether such subpopulations actually contrib- ute mechanistically to the severity of FNAIT by binding to and inhibiting the function of platelets and other vascular cells, however, is not known. Studies proposed in Project 1 will take advantage of a preclinical animal model of FNAIT that we recently developed, and a newly assembled battery of epitope-specific human and mouse alloantibodies. Specific Aim 1 will utilize expertise and technologies available in shared Core B and in the laboratories of the Leaders of Projects 2 and 3 to characterize in vitro the functional and structural properties of HPA-1a-specific antibodies that differentially recognize platelet and endothelial cell alloantigenic epitopes, and test the hypothesis that the presence of specific alloantibody subsets contributes to the severity of FNAIT in vivo. A second topic to be addressed in this proposal will confront the unexplained discrepancy between FNAIT and its red cell counterpart, Hemolytic Disease of the Fetus and Newborn (HDFN), that has puzzled the field for more than four decades: whereas red cell alloimmunization primarily occurs as a result of fetal maternal hemorrhage that occurs at the time of delivery, affecting subsequent pregnancies, >25% of FNAIT cases occur without warning during gestation of what is experienced as a first pregnancy. Specific Aim 2, therefore will examine various modes of alloantigen exposure that might lead to maternal alloimmunization to test the hypothesis that pregnancy complications that give rise to FNAIT are similar to those that cause HDFN, and that undetected, unnoticed, and unobserved routes of platelet alloimmunization are likely taking place that induce undetected alloantibody production, even in first gestations. Taken together, these studies will improve our understanding of the etiology of this alloimmune disorder, and enable more accurate prediction of the severity of FNAIT - all with the ultimate goal of preventing development of the maternal alloimmune response that causes FNAIT, even in first at-risk pregnancies.