1A.2 Hemostasis in normal pregnancy

Abstract

Human coagulation consists of a highly regulated system of proand anticoagulant forces that insure maintenance of blood fluidity and localize thrombus formation to the site of vascular injury. Normal pregnancy is associated with various alterations of the hemostatic system, tipping the balance between proand anticoagulants towards a hypercoagulable state [1]. Most clotting factors increase throughout pregnancy (fibrinogen, thrombin, factors V, VII, VIII, IX, X, and XII, von Willebrand factor antigen), and a decrease of anticoagulant factors (protein S) as well as alterations in the fibrinolytic system (low tissue plasminogen activator levels, high plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor levels) are seen. Notably, platelets tend to decrease at the end of the third trimester and factor XI levels gradually fall throughout pregnancy. At the time of delivery, clotting activity is at its maximum most likely due to expulsion of the placenta and subsequent release of thromboplastins, e.g. tissue factor. Changes in system coagulation are presumably important to reduce blood loss during delivery, but at the same time increase the thrombotic risk in a pregnant woman. Indeed, the risk of venous thromboembolic events is increased during pregnancy (0.7 per 1000 women) and is threeto fourfold higher in the postpartum period as compared to nonpregnant women at comparable age. In addition, several pregnancy-related complications, including miscarriage, stillbirth, or fetal growth retardation, have been related to thrombotic complications in the uteroplacental circulation. The hemostatic changes during normal pregnancy are reflected by a shortened prothrombin and partial thromboplastin time. These assays are not sensitive enough to detect subtle alterations in the hemostatic system and are thus not useful to detect clinically relevant hypercoagulable conditions (i.e. thrombosis). Consequently, more sensitive and specific coagulation markers and assays with the potential to detect and monitor hypercoagulable states already at a preclinical level have been evaluated in normal pregnancy. We and others investigated levels of prothrombin fragment F1+2, thrombin-antithrombin complexes and D-Dimer in healthy pregnant women at fixed time points during their pregnancy and found a substantial increase of these coagulation and fibrinolytic markers [2]. The endpoint of routine laboratory tests is clot formation which occurs already after formation of small amounts of thrombin. The amount of thrombin that may potentially be generated upon stimulation of the clotting system can be measured by continuous registration of cleavage of a chromogenic or fluorogenic substrate in plasma. Thus far available data indicate that the endogenous thrombin potential (= the area under the thrombin generation curve) remains almost unchanged throughout pregnancy [2]. Future studies will show if the changes in hemostatic system during pregnancy may be better explored by use of other thrombin generation assays or by use of other parameters which may be deferred from the thrombin generation curve. Activated protein C (APC) resistance is a risk factor of venous thrombosis and in most patients is genetically determined by mutant factor V Leiden. In pregnant women, however, an acquired form of APC resistance has been described [3]. In one study, the response to APC during pregnancy correlated with changes in levels of factor VIII, factor V and protein S [4]. We found a significant decrease during pregnancy among pregnant women who received low molecular weight heparin during pregnancy as well as among healthy pregnant women without any treatment [5]. More recently, an increase in levels of plateletand endothelial-derived microparticles during normal pregnancy has been described [6]. Microparticles are membrane vesicles formed after cell activation or apoptosis and have been associated with thrombotic and inflammatory complications. Their role in physiologic and pathophysiologic mechanisms during pregnancy needs further exploration. Several weeks after delivery blood coagulation and fibrinolysis have generally normalised [7].