Fibrinogen gamma ' increases the sensitivity to activated protein C in normal and factor V Leiden plasma

Activated protein C (APC) resistance, often associated with the factor V (FV) Leiden mutation, is the most common risk factor for venous thrombosis. We observed increased APC resistance in carriers of fibrinogen gamma gene (FGG) haplotype 2, which is associated with reduced levels of the alternatively spliced fibrinogen gamma ' chain. This finding prompted us to study the effects of fibrinogen and its gamma ' chain on APC resistance. Fibrinogen, and particularly the gamma A/gamma ' isoform, improved the response of plasma to added APC in the thrombin generation-based assay. Similarly, a synthetic peptide mimicking the C-terminus of the fibrinogen gamma ' chain, which binds thrombin and inhibits its activities, greatly increased the APC sensitivity of normal and FV Leiden plasma, likely due to its ability to inhibit thrombin-mediated activation of FV and FVIII. Although the fibrinogen gamma ' peptide also inhibited protein C activation by the thrombin/thrombomodulin complex, it still increased the sensitivity of plasma to endogenously formed APC when thrombin generation was measured in the presence of soluble thrombomodulin. We conclude that fibrinogen, and particularly fibrinogen gamma ', increases plasma APC sensitivity. The fibrinogen gamma ' peptide might form the basis for pharmacologic interventions to counteract APC resistance.