Identification of two distinct heparin cofactors in human plasma: II. Inhibition of thrombin and activated factor X

Abstract

Heparin alone has two direct effects on the thrombin clotting time. First, there is an immediate prolongation of the clotting time, which can be fully reversed upon neutralization of the heparin by polybrene or protamine. Second, there is a slow, time-dependent increase in the clotting time, representing an irreversible decrease in the concentration of active thrombin. Increasing the heparin concentration above 10 −2 Units/ml leads to an increase in the rate of thrombin inactivation in the presence of cofactor A. This lost thrombin cannot be recovered by neutralization of the heparin. In the absence of heparin, cofactor A has only slight progressive antithrombin activity. Cofactor B by itself has marked progressive antithrombin activity, the rate of which is further enhanced by the addition of increasing concentrations of heparin above 10 −2 Units/ml. However, heparin diminishes the ultimate thrombin capacity of cofactor B. Cofactor B also inactivated activated Factor X (Factor Xa). The effect is greatly accelerated in the presence of heparin. Cofactor A has no effect on Factor Xa, even in the presence of heparin.