The former includes pregnancy-associated elevations in factors VII, VIII, X, XII, von Willebrand’s factor, and fibrinogen levels (49,51,52). All rise throughout gestation. Factor II, factor V, and factor XIII levels also rise early in pregnancy, but return to normal levels after the first trimester (49,53). Normal pregnancy has been associated with the development of activated protein C resistance (acquired APCR, see below) via mechanisms that remain unclear (54). Changes in balancing antithrombotic control mechanisms during pregnancy also favor clot formation. The activities of protein C and antithrombin remain fairly constant during the course of pregnancy. Protein S activity significantly decreases in conjunction with pregnancy-induced increases in the production of C4b-binding protein, a complement factor-binding protein that complexes with protein S, making it unavailable for interaction with activated protein C. This increased binding does not fully explain the level of decrease in protein S activity during pregnancy (55).
Fibrinolysis is impaired during pregnancy, with decreases in fibrinolytic activity beginning at approximately 11 to 15 weeks of gestation (49). A significant factor in this impairment is a marked decrease in plasmin activity, resulting from placental production of the plasmin inhibitor PAI-2 (56,57). In conjunction with these changes, however, FDP levels are seen to rise in pregnancy, beginning at approximately 20 weeks of gestation, and continue their rise
VII VIIIa XIII XIIIa X Xa XII XIIa XI XIa TF TF/VII IX IXa VII TF Intrinsic Pathway Extrinsic Pathway IXa/VIIIa TF/VII Factor Va Va/Xa Prothrombin Factor II Thrombin Factor IIa fibrinogen fibrin Clot formation plasmin Fibrin degradation products (FDPs, FSPs) PAI-2 (placental) inactivates Protein S Protein S Changes in coagulation and fibrinolysis in pregnancy Cross-linking of fibrin monomers
Figure 33.3 Alterations coagulation and fibrinolysis during normal pregnancy. Pregnancy is a state of hypercoagulability. Levels of factors VII, VIII, X, and XII are elevated throughout pregnancy, levels of factors II, V, and XIII rise in the first trimester, then return to normal values. The antithrombotic activity mediated by protein S decreases in pregnancy. The placenta produces plasminogen activator inhibitor-2 (PAI-2). For all coagulation factors, the subscript letter “a” denotes the activated form of the factor. FSP, fibrin split products; FDP, fibrin degradation products.
throughout pregnancy (49,56). In normal pregnancy, platelet function and turnover is unchanged. In the third trimester, platelet number typically decreases as the result of increased platelet consumption. This benign gestational thrombocytopenia can reach levels less than 80 × 109/L (58). Taken together, pregnancy-associated alterations in the amounts and activities of pro-thrombotic clotting factors, anticoagulant control mechanisms, and fibrinolysis support the determination of human pregnancy as a state of compensated DIC. Although these changes reverse during the 4 to 6 weeks following delivery, the vascular damage associated with delivery is an additional significant risk factor for thrombosis, making the immediate postpartum period an important continuation of the prothrombotic state associated with pregnancy (49,58).