Clinical aspects of the relationship between oral contraceptives and abnormalities of the hemostatic system: relation to the development of cardiovascular disease

Abstract

Epidemiologic evidence has established that oral contraceptives increase the risk of both arterial and venous thromboembolic disease. This is dose related in the case of the estrogen component for both arterial and venous events and in the case of progestogens for arterial events. It is probable that the increased rate of thromboembolic events caused by estrogen is related to hypercoagulability. Plasma levels of several clotting factors have been shown to be elevated in oral contraceptive users, and this increase is graduated according to the dose of estrogen. In pregnancy, factor VIIc is increased after cold activation of plasma at 4 degrees C overnight. Likewise, in users of oral contraceptives, both factors VIIc and XIIc are increased, which suggests a direct effect of factor XIIc on the extrinsic system. In men, the risk of ischemic heart disease is strongly and independently related to factor VIIc and fibrinogen levels; thus it is possible that in women taking oral contraceptives, the mechanism of risk is similarly mediated. There is a good case for factor VIIc as the index of flux in the coagulation system and hence of a hypercoagulable state, and indeed it may directly contribute to the generation of thrombin. This article examines the available evidence on clotting factor activity in the risk of cardiovascular disease in oral contraceptive users.

PIP: There is a solid epidemiologic evidence that oral contraceptive (OC) use increases the risk of arterial and venous thromboembolic disease. Although the risk is dose-dependent for both the estrogen and progestogen components of OCs, estrogen appears to exert its main effect on the coagulation system while the progestogen acts on lipid metabolism and blood pressure. Both fibrinogen and factor VII--which leads to the activation of factor x and the formation of thrombin--are increased by estrogen and are important predictors of the risk of thrombosis. OC users (and nonusers, to a lesser extent) exhibit increased factor VII and XII activity after exposure to cold--a finding that confirms appreciable increases in clotting activity after endogenous hormonal variation and a direct effect of factor VIIc on the extrinsic system. Since factor VIIc and fibrinogen levels have been strongly predictive of ischemic events in men there are grounds for speculating that abnormalities in the coagulation system of female OC users also constitute a thrombotic risk.