Human factor Va(1) and factor Va(2): Properties in the procoagulant and anticoagulant pathways

Human plasma factor V is heterogeneous and yields two forms of activated factor V that bind with low (factor Va(1)) and high affinity (factor Va(2)) to phospholipids. The properties of factor Var and factor Vat in the anticoagulant and procoagulant pathways were evaluated by comparing their sensitivity for inactivation by APC and their ability to act as cofactor in prothrombin activation. At low phospholipid concentrations and on membranes containing low amounts of phosphatidylserine (PS), factor Va(1) was inactivated by APC at 15-fold lower rates than factor Va(2), both in the absence and in the presence of protein S. At high phospholipid concentrations and on membranes with more than 15 mel % PS, factor Va(1) and factor Va(2) were inactivated with equal efficiency. Differences between cofactor activities of factor Var and factor Vat in prothrombin activation were only observed on membranes with less than 7.5 mel % PS. Due to the different phospholipid requirements of APC-catalyzed factor Va inactivation and of expression of factor Va cofactor activity in prothrombin activation, the thrombin-forming capacity of factor V-1 was 7-fold higher than that of factor V-2 in a reaction system containing factor Xa, prothrombin, APC, protein S, vesicles with a phospholipid composition resembling that of activated platelets, and traces of thrombin to initiate prothrombin activation. This shows that in the process of generation, expression, and down-regulation of factor Va cofactor activity on physiological membranes, the overall procoagulant activity of factor V-1 can considerably exceed that of factor V-2.