Angiogenesis and bleeding disorders in FNAIT

Angiogenesis is a physiological process essential for embryo/fetal growth, wound healing, and repair of the myocardium after myocardial infarction. Angiogenesis is also implicated in pathological processes such as retinopathy and tumor growth. Anti-angiogenic agents have been demonstrated to have promising therapeutic potential for inhibiting tumour growth. Earlier studies suggested that β3 integrin (i.e. αVβ3 that is formed by β3 subunit and αV subunit) expressed on angiogenic endothelial cells (ECs), is required for angiogenesis [1]; however, subsequent studies demonstrated that β3 integrin deficiency (β3-/-) did not prevent embryo/fetal growth and interestingly, enhanced pathological angiogenesis was observed in β3-/-mice [2]. It is therefore important to further study the roles of β3 integrin in angiogenesis, fetal development and related diseases. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder that occurs when maternal alloantibodies cross the placenta and target paternally derived antigens, especially GPIIbIIIa (integrin αIIbβ3) and GPIbα, on fetal/neonatal platelets. In contrast to αVβ3, integrin αIIbβ3 is composed of a β3 subunit and αIIb subunit, which are almost exclusively expressed on platelets and megakaryocytes. Half of the polymorphisms known to cause FNAIT are located on the β3 subunit. Approximately 80-90% of reported FNAIT cases are caused by antibodies targeting Human-Platelet-Antigen-1a (HPA-1a) on β3 subunit. Antibodies targeting the HPA-2a on GPIbα have also been reported. Intracranial hemorrhage (ICH), which occurs in 10-20% of affected fetuses/neonates, is a major clinical complication of FNAIT, leading to neurological impairment and death. Unfortunately, the mechanism responsible for ICH, has only been inferred but not adequately explored. Thrombocytopenia was considered to be the cause of bleeding in FNAIT. Interestingly, mice deficient in transcription factor NF-E2, which lack circulating platelets, did not develop significant bleeding disorders in utero. More strikingly, the murine fetuses with combined deficiencies in NF-E2 and fibrinogen genes exhibited normal embryonic development and were morphologically indistinguishable from their wild-type control counterparts at 18.5 days postcoitum [3]. Therefore, it is likely that neither thrombocytopenia nor blood coagulation are crucial for the development of ICH in FNAIT. Furthermore, several animal models have demonstrated that impairment of angiogenesis may contribute to bleeding in fetuses, particularly in their brains, since the brain is one of the major sites of angiogenesis during fetal development. However, whether ICH in FNAIT is caused by impairment of angiogenesis induced by maternal anti-platelet antibodies, is unclear. This is particularly interesting since the roles of β3 integrin in angiogenesis are still controversial. In a …