Thrombophilia and placenta-mediated pregnancy complications: from the bench to bedside to policy

Abstract

While it is well known that thrombin plays a central role in the coagulation component of hemostasis [1] a developing story is emerging that demonstrates thrombin’s central role in placental development. Tissue Factor (TF), the most important initiator of coagulation, is constitutively expressed on almost all cells other than endothelial cells [2]. Endothelial cells line the inner layer of blood vessels and provide a physical barrier between TF laden sub-endothelial tissues and coagulation ready blood. When the endothelial barrier is disrupted (e.g. vascular injury) coagulation ensues. FVIIa circulates in minute quantities in normal plasma at the ready to encounter TF. Coagulation activation is initiated through interaction of Tissue Factor, calcium and circulating FVIIa which then convert factor X to Xa and factor IX to IXa. Xa then complexes with Va and calcium on a phospholipids surface to form the Tenase complex. The Tenase complex then converts prothrombin to thrombin. Next, coagulation activation is maintained by thrombin activating factors XI, V and VIII to generate a positive feedback cycle that leads to a thrombin burst which then cleaves sufficient fibrinogen to form adequate fibrin for a hemostatic plug. Thrombin also activates platelets via binding to the PAR-4 receptor on platelets. Without an adequate anticoagulant mechanism unchecked thrombin generation would lead to disseminated coagulation throughout the vascular system. The