Resistance to activated protein C caused by the R⁵⁰⁶Q mutation in the gene for factor V is a common risk factor for venous thrombosis

Abstract

The protein C system is an important natural anticoagulant pathway. Protein C is the key component of the system and it is activated by thrombin bound to thrombomodulin on the surface of endothelial cells. Activated protein C (APC) inhibits coagulation by cleaving and inactivating coagulation factors factor Va and factor Villa. Until recently, the major genetic causes of familial venous thrombophilia were inherited deficiencies of protein C, protein S or antithrombin, but together they were found in less than 5‐10% of patients with thrombosis. In 1993, the situation changed drastically with the description of inherited APC‐resistance as a novel risk factor for venous thrombosis. APC‐resistance is characterized by a poor anticoagulant response to APC. Inherited APC‐resistance is the most common genetic risk factor for this disease and it is found in 20‐60% of patients. The condition is caused by a single point mutation in the gene for factor V which predicts substitution of arginine (R) at position 506 with a glutamine (Q). Mutated factor V (FVR506Q, FV:Q506 or FV Leiden) expresses normal procoagulant properties but is partially resistant to APC. The resulting hypercoagulable state confers a life‐long increased risk of venous but not arterial thrombosis. The FVR506Q mutation is common in Caucasians with a prevalence of 1‐15%, whereas it is not found in other human races. The FVR506Q mutation may, due to its high prevalence, be an additional risk factor in individuals carrying other inherited defects such as deficiency of protein S, protein C or antithrombin. Such individuals have a high incidence of thrombosis and severe thrombophilia is a multigenetic disease. The high prevalence of inherited APC‐resistance and the availability of easy functional and genetic tests will stimulate the development of prophylactic regimens and hopefully result in a decreased incidence of thrombosis.

Long-term clinical and ultrasonographic evaluation of thrombophilic patients with deep venous thrombosis

“…Genotyping for genetic thrombophilias employed PCR and restriction protocols -digestion, as described elsewhere. 12,14 The Sapporo Criteria 24 were used for APS determination.…”

“…6,10,11 The most common of these is the factor V R306Q mutation (FV Leiden) which causes resistance to the action of PC, appearing in 1 to 15% of the general population and in 10 to 50% of patients with VTE. 12,13 The G20210A polymorphism of the prothrombin gene is associated with increased plasma prothrombin levels and is present in 1 to 3% of individuals in the general population and 6 to 18% of patients with VTE. 14 While the methylenetetrahydrofolatereductase mutation (MTHFR) does not itself appear to be a risk factor for DVT, 15 it may be associated with hyperhomocysteinemia.…”

The International HapMap Project

“…Examples include type 1 diabetes (human leukocyte antigen (HLA 5 ), insulin 6 and CTLA4 (ref. 7)), Alzheimer's disease (APOE) 8 , deep vein thrombosis (factor V) 9 , inflammatory bowel disease (NOD2 (refs 10, 11) and also 5q31 (ref. 12)), hypertriglyceridaemia (APOAV) 13 , type 2 diabetes (PPARG) 14,15 , schizophrenia (neuregulin 1) 16 , asthma (ADAM33) 17 , stroke (PDE4D) 18 and myocardial infarction (LTA) 19 .…”

Genotipos frecuentemente asociados a trombofilias

“…La proteína S es una glucoproteína dependiente de la vitamina K que actúa como cofactor no enzimático y hace que los factores Va y VIIIa sean más accesibles a la escisión mediada por la APC; durante la hemostasia normal, la APC hidroliza el factor V activado (FVa) y el factor VIII activado (FVIIIa) produciendo su inactivación (4). El factor V activado (FVa) participa en la activación de la protrombina, haciendo parte del complejo protrombinasa (34,35). Si esto no ocurre, se considera que hay resistencia a la proteína C activada.…”