Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Abstract

Inherited resistance to activated protein C (APC) is the most common genetic risk factor of venous thrombosis. It is caused by a single point mutation in the factor (F)V gene which predicts replacement of Arg506 with a Gln (FVR506Q, FV: Q506 or FV Leiden). This mutation affects the function of the protein C system, a physiologically important natural anticoagulant pathway. APC inhibits coagulation by cleaving a limited number of peptide bonds in both intact and activated forms of factor V (FV/FVa) and factor VIII (FVIII/FVIIIa). Degradation of FVa by APC is stimulated by protein S, whereas inactivation of FVIIIa requires the synergistic cofactor function of protein S and FV proteolytically modified by APC. Thus, FV has the potential to express opposing functions, as a procoagulant after cleavage by thrombin or FXa and as an anticoagulant after cleavage by APC. The FVR506Q mutation not only confers partial resistance of FVa to APC but also impairs the degradation of FVIIIa because APC-mediated cleavage of FV at Arg506 is required for expression of the anticoagulant activity of FV. The impaired degradation of both FVIIIa and FVa yield a hypercoagulable state conferring a lifelong increased risk of thrombosis. The FV mutation is common in Caucasians, whereas it is rarely found among other groups worldwide. In patients with severe thrombophilia having other inherited defects such as deficiencies of protein S, protein C, or antithrombin, APC resistance is often found as a contributing genetic risk factor. Individuals with combined genetic defects have a high risk of thrombosis, and it is now generally accepted that thrombophilia is a multigenetic disease.

Functional characterization of recombinant FV Hong Kong and FV Cambridge

“…11,12 In 90% of patients, it is caused by a point mutation in FV that results in the replacement of Arg506 with Gln (FV Leiden). 12,13 This inhibits the efficiency by which APC degrades FVa; in addition, it impairs the APC cofactor function of FV in the degradation of FVIIIa because 506-cleavage is needed for the generation of full anticoagulant FV function. 10,14 These dual functions of the FV Leiden mutation result in the generation of a hypercoagulable state, which constitutes a lifelong risk factor for thrombosis.…”

“…10,14 These dual functions of the FV Leiden mutation result in the generation of a hypercoagulable state, which constitutes a lifelong risk factor for thrombosis. 12 In 1998, 2 new mutations in FV, FV Hong Kong and FV Cambridge, were reported among patients with thrombosis. 15,16 Both mutations result in the replacement of Arg306, in FV Hong Kong with a Gly and in FV Cambridge with a Thr.…”

Procoagulants and anticoagulants in fetal blood. A literature survey.

“…APCr is in 90% caused by V Leiden factor -a genetic defect affecting approximately 5% of the general population [17]. There is also APCr associated with the use of contraceptives and pregnancy (elevated levels of factor VIII, fibrinogen and von Willebrand factor in a pregnant woman being nongenetic causes of APCr) [18].…”

The Factor V Leiden mutation is associated with a higher blood haemoglobin concentration in women below 50 of the Malmö Thrombophilia Study (MATS)

“…More recently it has been reported that the prevalence of FVL-mutation in European populations is approximately 3% to 7% with rare occurrence in black and Asian populations [8].…”