(Scanned from the applicant's description): APS is a disorder characterized by venous and arterial thrombosis, recurrent fetal loss, thrombocytopenia and by the presence of antiphospholipid antibodies. Recurrent pregnancy loss is produced also in APS patients due to thrombosis in the placental vasculature. Patients with APS also have higher risks of other obstetric and postnatal complications like preeclampsia, fetal distress, fetal growth impairment, premature delivery, maternal postpartum thrombosis and postpartum lung syndrome. In vitro, the annexins, a family of calcium dependent membrane binding proteins, are extremely potent inhibitors of blood coagulation. Annexin V has been proposed to regulate thrombosis and homeostasis on the villous trophoblast surface by shielding the anionic phospholipid membrane that may accelerate the coagulation cascade whereas the antiphospholipid antibodies have been proposed to displace the annexin V shield, causing exposure of phospholipid surfaces that produce activation in the coagulation cascade. Therefore, our initial hypothesis is that annexins could act in vivo as potent anticoagulants and could be beneficial in treating APS. In this study, we will evaluate therapeutic potential of wild type annexin V and mutants annexin V in vivo. Our prediction is that annexin mutants with higher affinity for phospholipid membranes may act as better anticoagulants. To test this hypothesis annexin V mutants will be created. The phospholipid binding affinity of wild type annexin and mutated annexin V will be compared with the antiphospholipid antibodies using three distinct approaches. Using a pregnant mice model, we will evaluate the therapeutic potential of these in vivo against the pathological effects of the antiphospholipid antibodies. Mice will be evaluated for fetal viability and size, fetal loss, placental thrombosis in the fetal and in the maternal side. We predict that annexin V may ameliorate the pathological consequences of the infusion of an antiphospholipid antibody. Transgenic mice will be used to evaluate the potential therapeutic of extracellular annexin V in the context of the whole animal. The results obtained with this work will provide useful treatment strategies to ameliorate the symptoms associated with the antiphospholipid syndrome.
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