Annexin V is critical in the maintenance of murine placental integrity

OBJECTIVES: Recurrent fetal loss can be a consequence of placental thrombosis, frequently occurring in autoimmune disorders such as antiphospholipid syndrome. A potent anticoagulant, annexin V, is abundant in placental tissues. We investigated the role of annexin V in maintaining fetal viability. STUDY DESIGN: Sites of annexin V activity in placenta were found and neutralized, 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 infused into pregnant BALB/c mice. Endogenous annexin V was evaluated by immunohistochemical techniques. To define a role for annexin V during pregnancy, annexin V was neutralized by tail-vein infusion of affinity-purified anti-annexin V antibodies immediately before mating, 16 hours before the vaginal plugs 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 trophoblasts. Animals infused with epitope-tagged annexin V had confirmed presence of extracellular binding sites for annexin V exclusively along these surfaces. 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 necrosis 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 possess annexin V binding sites. The binding of annexin V to these coagulation-promoting surfaces is crucial for the maintenance of blood flow through the placenta and consequently for fetal viability, infusion of anti-annexin V antibodies decreased the availability of annexin V to bind to the trophoblast surfaces and caused placental thrombosis, necrosis, and fetal loss. Our study suggests that anti-annexin V autoantibodies may contribute to recurrent pregnancy failure resulting from placental thrombosis, as found in patients with certain autoimmune diseases.