Investigation of the Pathophysiological Mechanisms of Intracranial Hemorrhage and Miscarriage in alphaIIb Integrin Mediated Fetal and Neonatal Alloimmune Thrombocytopenia

Investigation of the Pathophysiological Mechanisms of Intracranial Hemorrhage and Miscarriage in anti-alphaIIb Integrin Mediated Fetal and Neonatal Alloimmune Thrombocytopenia Darko Zdravic Master of Science Department of Laboratory Medicine and Pathobiology University of Toronto 2017 Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life threatening bleeding disorder often leading to bleeding diatheses including intracranial hemorrhage (ICH). Miscarriages have also been reported; however the frequency of pregnancy loss has not been investigated. Approximately 85% of FNAIT cases are anti-beta3 mediated, whereas anti-alphaIIb mediated FNAIT makes up 3-5% of cases, although their polymorphic frequencies are similar. We hypothesized that anti-alphaIIb antibodies target trophoblasts during pregnancy, causing impaired placental perfusion and miscarriage in alphaIIb mediated FNAIT. Miscarriages were observed in the majority of immunized alphaIIb-/- mothers, and their placentae showed ischemic appearances with vascular and structural abnormalities, poor perfusion in the labyrinths, and decreased circulating fetal erythrocytes. Neonates developed severe thrombocytopenia and ICH. In vitro experiments demonstrated that anti-alphaIIb antisera significantly inhibited endothelial cell migration and invasion. The results of our studies suggest that a lower reported incidence of anti- alphaIIb mediated FNAIT may be due to miscarriage.M.Sc