PHYSIOLOGIC CHANGES IN COAGULATION AND FIBRINOLYSIS DURING NORMAL PREGNANCY

The human hemostatic system consists of multiple independent, yet integrally related, cellular and protein components that function to maintain blood fluidity under normal conditions and promote localized, temporary thrombus formation at sites of vascular injury. A normal hemostatic system is the human physiologic defense against exanguination. An abnormal hemostatic system can result in pathologic bleeding, vascular thrombosis, or both. The hemostatic system comprises of six major components: platelets, vascular endothelium, procoagulant plasma protein factors, natural anticoagulant proteins, fibrinolytic proteins, and antifibrinolytic proteins. Each of these six hemostatic components must be present in a fully functional form and in an adequate quantity to prevent excessive blood loss following vascular trauma and at the same time prevent pathologic thrombosis. The hemostatic system is highly regulated and maintains a delicate balance between a prohemorrhagic state and a prothrombotic state. Any significant acquired or congenital imbalance in the hemostatic scales can lead to a pathologic outcome. Alterations in the quantitative and qualatative status of any hemostatic cellular or protein element can have significant biologic effect. Platelet deficiency (thrombocytopenia), platelet adhesion defects, and platelet aggregation disorders are associated with an inability to form an adequate primary hemostatic platelet plug and can lead to significant mucocutaneous bleeding and post-traumatic, life-threatening hemorrhage. In contrast, a marked increase in platelet count (thrombocytosis) and accentuated platelet aggregation (sticky platelet syndrome) are associated with thromboembolic events. 32 Deficiency of a procoagulant factor integral to the intrinsic (factors XI, IX, and VIII), extrinsic (factor VII), or common (factors X, V, II and fibrinogen) pathway of coagulation is associated typically with a variable degree of bleeding tendency. Elevated levels of procoagulant factors, such as factor VIII, fibrinogen, and factor VII, however, are recognized risk factors for vascular disease. 28,47 Deficiency of natural anticoagulant proteins, such as protein C, protein S, antithrombin III (AT-III), and heparin cofactor II (HC-II), is associated with venous thromboembolic disease; a natural anticoagulant protein excess state associated with bleeding has not been described to date. 13 Deficiency of a fibrinolytic cascade component, such as tissue-type plasminogen activator (t-PA) or plasminogen; and excess plasma levels of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1), have been linked to hypercoagulability and thrombosis. 24,29,53 Deficiency of fibrinolytic inhibitors, such as α-2 antiplasmin and PAI-1, may precipitate a hyperfibrinolytic bleeding state. 30,52 Deficiency of endothelial cell-derived von Willebrand factor is associated with altered primary and secondary hemostasis caused by deficient platelet anchoring at sites of vascular injury and shortened factor VIII survival characteristic of von Willebrand's disease. 20 Deficient endothelial cell production of thrombomodulin or release of t-PA may be associated with a thrombotic tendency. 19 The balance between these opposing groups of proteins and not the level of any individual factor seems most critical to hemostatic regulation. Pregnant women differ from nonpregnant adults in many physiologic and biochemical aspects. Normal pregnancy is associated with major changes in the coagulation and fibrinolytic systems. The many hemostatic derrangements detected during pregnancy must be considered to represent physiologic, adaptive, and preparatory mechanisms for the hemostatic challenges of delivery rather than pathologic processes. Most pregnant women do not manifest overt bleeding nor thrombotic problems. The hemostatic changes observed in each trimester of normal pregnancy and the puerperium reflect diverse changes in coagulation factor, fibrinolytic protein, regulatory protein, and cellular component activation, release, consumption, and synthesis. The fact that most hemostatic factors and proteins are liver derived, makes a review of coagulation alterations in pregnancy an appropriate component of an article on the liver and pregnancy. This article focuses on all hemostatic components involved in primary hemostasis (platelet plug formation) and secondary hemostasis (fibrin mesh formation) as well as the mechanisms responsible for thrombus localization (natural anticoagulants) and ultimate removal (fibrinolytic cascade proteins). The effects of each trimester of normal pregnancy and the puerperium on each of the major components of the hemostatic system are examined. Particular attention is paid to the balance between procoagulant and anticoagulant mechanisms and the net effect of the hemostatic changes at different periods during pregnancy.