Annexin V is critical in the maintenance of murine placental integrity

OBJECTIVES: Recurrent fetal loss can be a consequence of placental thrombos is, frequently occurring in autoimmune disorders such as antiphospholipid s yndrome. A potent anticoagulant, annexin V, is abundant in placental tissue s. We investigated the role of annexin V in maintaining fetal viability. STUDY DESIGN: Sites of annexin V activity in placenta were found and neutra lized, and the physiologic consequences on fetal development were evaluated . To find extracellular binding sites for annexin V on placental membrane, 2 approaches were taken. An epitope-tagged recombinant annexin V was infuse d into pregnant BALB/c mice. Endogenous annexin V was evaluated by immunohi stochemical techniques. To define a role for annexin V during pregnancy, an nexin V was neutralized by tail-vein infusion of affinity-purified anti-ann exin V antibodies immediately before mating, 16 hours before the vaginal pl ugs were observed. Fetal viability, number, and size were evaluated at days 11 or 15 after conception. RESULTS: Endogenous annexin V is enriched along the apical surfaces of trop hoblasts. Animals infused with epitope-tagged annexin V had confirmed prese nce of extracellular binding sites for annexin V exclusively along these su rfaces. In mice infused with anti-annexin V antibodies, various degrees of fetal absorption were observed. Thrombosis and necrosis were present in the fetal component of placentas from partially absorbed embryos. Focal necros is and fibrosis were present in the decidua of placentas from embryos that were significantly smaller than the normal embryos in the same uterus. CONCLUSIONS: Apical surfaces of syncytiotrophoblasts in the placenta posses s annexin V binding sites. The binding of annexin V to these coagulation-pr omoting surfaces is crucial for the maintenance of blood flow through the p lacenta and consequently for fetal viability, infusion of anti-annexin V an tibodies decreased the availability of annexin V to bind to the trophoblast surfaces and caused placental thrombosis, necrosis, and fetal loss. Our st udy suggests that anti-annexin V autoantibodies may contribute to recurrent pregnancy failure resulting from placental thrombosis, as found in patient s with certain autoimmune diseases.