The proposed mechanistic basis for the association between adverse fetal outcomes and heritable thrombophilias has focused on impaired placental development and function, secondary to venous and/or arterial thrombosis at the maternal–fetal interface. These findings have been noted in the placentas of women with adverse fetal outcomes and known inherited thrombophilias and have been demonstrated in patients with similar outcomes, but lacking inherited thrombophilic risk (40–44). Discussions of placental thrombosis as causal in early pregnancy losses (<10 weeks gestation) are particularly contentious, citing an elegant series of experiments demonstrating that maternal blood ﬂow into the intervillous spaces of the human placenta does not occur until approximately 10 weeks of gestation (45–48). Prior to establishment of intervillous circulation, nutrient transfer from maternal blood to fetal tissues appears to be dependent on transudation that, in turn, relies on ﬂow through the uterine vasculature. This suggests that maternal or fetal thrombotic episodes in the developing placental vasculature could be equally devastating prior to or after the establishment of intervillous circulation near 10 weeks of gestation. Very early pregnancy losses (biochemical, anembryonic) and known aneuploid fetal losses are unlikely to be altered by the presence of, or treatment for, an underlying thrombophilic state.
The coagulation system relies on a complex cascade of prothrombotic enzymatic activations (often via serine proteases) in delicate balance with antithrombotic pathways. Although pregnancy is most simply described as prothrombotic, the alterations in the coagulation system associated with pregnancy may be described as a state of compensated disseminated intravascular coagulation (DIC) (49). Human hemochorial placentation is unique and inherently unstable. Placental development involves invasion into the maternal decidua and its vasculature and requires precise control of hemostasis and fibrinolysis. Delicate control mechanisms exist locally within the placenta and globally within the pregnant woman (50). Hormonal and related physiologic changes characteristic of pregnancy affect important components of the clotting cascade, the fibrinolytic cascade, and platelet physiology.
Clot formation can be initiated through two pathways, called the extrinsic and intrinsic clotting cascades (Fig. 33.1). Both respond to blood vessel damage and the release of tissue factor (TF). Tissue factor is a glycoprotein expressed on the surface of cells surrounding blood vessels. It is not expressed on the endothelium of the blood vessel itself, so exposure of blood to TF is a sensitive indicator of vascular damage. The extrinsic clotting cascade begins with the interaction of newly released TF with factor VII of the clotting cascade. The complex formed by TF and factor VII can either activate factor X directly or activate factor X via the intrinsic pathway. In the intrinsic pathway, the TF/factor VII complex activates factor IX to factor IXa (activated factor IX). Factor IXa then complexes with factor VIIIa. In combination, factors
XIIIa Cross-linking of
Figure 33.1 The clotting cascade. Physiologic clotting is initiated by endothelial cell damage or abnormal exposure of negatively charged phospholipids to serum and blood components. Procoagulant pathways in black are part of the clotting cascade and are prothrombotic. Both lead to activation of cascades of proteolytic enzymes and cleavage of clotting factors. The extrinsic and intrinsic pathways are initiated by distinct mechanisms. They merge at the activation of factor X to form the common pathway. For all coagulation factors, the subscript letter “a” denotes the activated form of the factor.