Comment on Li et al, page 2716
The study by Li and colleagues in this issue of Blood demonstrates the critical role that fetal trophoblast cells play in the control of the coagulation reaction in the mother's blood in the placenta, and for preventing fetal loss as a consequence of placental thrombosis.
Mice and humans exhibit a hemochorial type of placentation, in which the integrity of maternal blood vessels transporting blood into the placenta is lost. As a result, the vascular space containing maternal blood in the placenta is lined by 2 genetically distinct cell types (ie, by endothelial cells lining the mother's blood vessels and by fetal trophoblast cells covering the surface of placental villi exposed to the mother's blood).
The current report follows the earlier observations that knockout mice lacking endothelial cell protein C receptor (EPCR) are lost early in gestation. EPCR is the receptor for the circulating protein C and augments the activation of protein C by the thrombin-thrombomodulin complex. In mice and humans, EPCR is expressed by trophoblast cells in the placenta and by endothelial cells throughout the vasculature. Here, Li and colleagues demonstrate that the aborted development of EPCR-deficient embryos is caused by the inability of fetal trophoblast cells to prevent tissue factor–initiated thrombosis in the vascular bed of the placenta. The findings in EPCR-deficient mice are consistent with those in mice lacking other components of the protein C anticoagulant pathway (ie, thrombomodulin1 or protein C2 ), and show that thrombomodulin and EPCR on trophoblast cells of the fetus must activate protein C present in the mother's blood to prevent fibrin deposition and thrombosis in the placenta. Severe deficiency of any of these pathway components causes fetal loss in mice.
Epidemiological evidence indicates that pre-existing thrombophilia of the mother not only exacerbates the mother's thrombosis risk, but may also cause loss of the fetus.3 The mouse studies corroborate such a cause-effect relation between placental thrombosis and fetal loss, and in addition suggest that genetic or epigenetic alterations in fetal trophoblast function are risk modifiers of fetal loss.
Of note, Li and colleagues also show that the absence of EPCR from endothelial cells in the vasculature of adult mice causes only minimal derangements of the hemostatic balance. One explanation why the placenta may be particularly prone to thrombosis is that trophoblast cells, in contrast with endothelium of normal blood vessels, constitutively express the initiator of blood coagulation, tissue factor; probably because the latter is necessary for normal placental development.4 The striking vascular bed–specific manifestation of thrombosis in these mouse models also raises the question of whether the absence of a thrombosis history or thrombosis risk factors in the mother is an adequate indicator for the potential benefit of anticoagulation therapy for thrombophilic women whohaveexperienced fetalloss.5
In summary, the present work highlights the endothelial cell–like anticoagulant function fetal trophoblast cells must exert in the vascular bed of the placenta, and the role of blood coagulation as a critical aspect of the interplay between fetus and mother that determines the successful outcome of pregnancy. ▪
