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 anti-FcRn is a more effective and economical therapy for FNAIT requires further clinical studies.Aside from its expression on platelets and ECs, β3 integrin is also expressed on highly invasive trophoblasts, which are essential for normal placental vascular remodeling and development.Therefore, further studies on the effects of anti-β3 antibodies on trophoblast proliferation, differentiation, migration, and invasion, may provide insights into the mechanism of IUGR and miscarriage in FNAIT, as well as aid in the development of new therapies to manage these disorders.

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