Regular Article THROMBOSIS AND HEMOSTASIS Heparin rescues factor V Leiden–associated placental failure independent of anticoagulation in a murine high-risk pregnancy model

Placental abnormalities have serious consequences for mothers and babies. Consequences include fetal growth restriction, early and late fetal death, and maternal hypertensive disorders, such as preeclampsia. These are disorders of multifactorial origin that affect more than 5% of all pregnancies, and they are a major cause of preterm deliveries, small birth weight, and maternal/neonatal morbidity and mortality. Babies born small for gestation age are also at an increased risk of developmental problems and adult onset cardiovascular and metabolic disorders. Maternal inherited thrombophilia is a risk factor for placentamediated pregnancy complications. The extent of the risk varies with ethnicity, the type of pregnancy complication, and the thrombophilia mutation under investigation. The mechanism that connects maternal thrombophilia with adverse pregnancy outcomes is unknown and suspected to involve thrombotic occlusion of the uteroplacental circulation. It is hypothesized that the low-pressure placental flow is susceptible to thrombotic complications, much like the maternal venous circulation. Accordingly, interventions aimed at limiting placental thrombosis, such as treatment with low molecular weight heparin (LMWH), are being tested to prevent placental dysfunction and the related sequelae in at-risk pregnancies. While these studies suggest that LMWH may be beneficial for a subset of women with heritable thrombophilia and recurrent pregnancy loss (RPL), the risk-to-benefit balance of antithrombotic prophylaxis during pregnancy is a subject of intense ongoing debate. Study limitations and related methodological concerns contribute to the debate, but it is largely due to the uncertain role of thrombotic processes in placental disease and a lack of established criteria for identifying high-risk pregnancies that may benefit from the use of LMWH. Given the multifactorial and heterogeneous nature of thrombophilia-associated pregnancy disorders, these issues have proven to be complex and difficult to resolve based on epidemiological and clinical data alone. In the last few years, new nonanticoagulant roles of LMWH have emerged, some of which are directly related to trophoblast function. Thus, any beneficial effects of LMWH treatment may not necessarily reflect a causal thrombotic link between thrombophilia mutations and pregnancy loss. The mouse is a well-studied experimental model system that shares chorioallantoic placentation with humans; this occurs around the end of first trimester in humans and corresponds to 9 days post coitum (dpc) in mice. Both species form a hemochorial placenta where maternal cells are eroded and zygote-derived trophoblast cells