Human Factor Va1 and Factor Va2: Properties in the Procoagulant and Anticoagulant Pathways

Abstract

Human plasma factor V is heterogeneous and yields two forms of activated factor V that bind with low (factor Va₁) and high affinity (factor Va₂) to phospholipids. The properties of factor Va₁ and factor Va₂ 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 Va₁ was inactivated by APC at 15-fold lower rates than factor Va₂, both in the absence and in the presence of protein S. At high phospholipid concentrations and on membranes with more than 15 mol % PS, factor Va₁ and factor Va₂ were inactivated with equal efficiency. Differences between cofactor activities of factor Va₁ and factor Va₂ in prothrombin activation were only observed on membranes with less than 7.5 mol % 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 V₁ was 7-fold higher than that of factor V₂ 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 V₁ can considerably exceed that of factor V₂.