Clinical Information

Protein C, a part of the natural anticoagulant system, is a vitamin K-dependent protein zymogen (molecular weight = 62,000 Da) that is synthesized in the liver and circulates at a plasma concentration of approximately 5 mcg/mL. Protein C is activated to activated protein C (APC) via proteolytic cleavage by thrombin bound to thrombomodulin, an endothelial cell surface membrane protein. APC downregulates the procoagulant system by proteolytically inactivating procoagulant factors Va and VIIIa. Protein S, another vitamin K-dependent coagulation protein, catalyzes APC inactivation of factors Va and VIIIa. APC interacts with and proteolyzes factors V/Va and VIII/VIIIa at specific APC binding and cleavage sites, respectively. Resistance to activated protein C (APC resistance) is a term used to describe abnormal resistance of human plasma to the anticoagulant effects of human APC. APC resistance is characterized by a reduced anticoagulant response of patient plasma after adding a standard amount of APC. For this assay, the activated partial thromboplastin time fails to prolong significantly after the addition of APC.

The vast majority of individuals with familial APC resistance have a specific alteration in the procoagulant factor V gene (F5) encoding for a p.Arg534Gln substitution in the heavy chain of factor V (formerly R506Q). This glutamine to arginine amino acid change alters an APC cleavage site on factor V such that factor V/Va is partially resistant to inactivation by APC. The carrier frequency for the factor V Leiden variant varies depending on the population. Approximately 5% of asymptomatic White Americans of non-Hispanic ancestry are heterozygous carriers. In contrast, the carrier frequency among African Americans, Asian Americans, and Native Americans is less than 1%, and the carrier frequency for Hispanics is intermediate (2.5%). The carrier frequency can be especially high (up to 14%) among White individuals of Northern European or Scandinavian ancestry. Homozygosity for factor V Leiden is much less common but may confer a substantially increased risk for thrombosis. The degree of abnormality of the APC-resistance assay correlates with heterozygosity or homozygosity for the factor V Leiden variant; homozygous carriers have a very low APC-resistance ratio (eg, 1.1-1.4), while the ratio for heterozygous carriers is usually 1.5 to 1.8.