rs6025 — F5 Leiden

Factor V Leiden - The Clotting Mutation

Factor V Leiden is the most common inherited thrombophilia¹¹ Thrombophilia: an inherited tendency to form blood clots more easily than normal in people of European descent. Named after the Dutch city of Leiden where it was discovered in 1994 by Bertina et al.²² Bertina et al.
Bertina RM et al. Mutation in Blood Coagulation Factor V Associated with Resistance to Activated Protein C. Nature, 1994, this variant affects the Factor V clotting protein, making it resistant to inactivation by activated protein C (APC), a natural anticoagulant.

The Mechanism

The rs6025 variant causes an arginine-to-glutamine substitution at position 534³³ Amino acid change: arginine to glutamine at position 534 (R534Q), historically reported as R506Q of the Factor V protein. Position 534 is one of the APC cleavage sites - the exact spot where activated protein C normally cuts and inactivates Factor V to prevent excessive clotting. The glutamine substitution prevents APC from cleaving at this site, leaving Factor V active for longer and promoting a hypercoagulable state⁴⁴ Hypercoagulable state: a condition where the blood clots more readily than normal. This variant is classified as pathogenic by ClinVar⁵⁵ ClinVar
VCV000000642 and is found almost exclusively in populations of European ancestry (about 2.4% allele frequency).

The Risk Spectrum

Heterozygous carriers (CT) have a 5-10 fold increased risk⁶⁶ 5-10 fold increased risk
Ridker PM et al. Factor V Leiden and risks of venous thrombosis among men. Lancet, 1995 of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Homozygous carriers (TT) have a 50-100 fold increased risk. These are lifetime risks that compound with other risk factors like oral contraceptives, pregnancy, surgery, immobility, and long-haul flights.

The Estrogen Interaction

The most critical clinical interaction is with estrogen-containing medications. Estrogen increases several clotting factors and reduces protein S (another natural anticoagulant). For Factor V Leiden carriers, estrogen-containing oral contraceptives multiply the already elevated clotting risk by an additional 30-50 fold⁷⁷ 30-50 fold
Vandenbroucke JP et al. Factor V Leiden and oral contraceptive interaction on VTE risk. Thromb Haemost, 1999. This is why Factor V Leiden testing is recommended before prescribing estrogen-containing contraceptives in women with a personal or family history of blood clots.

Practical Implications

If you are a carrier, the most important actions are: avoid estrogen-containing contraceptives, inform surgeons before any procedure (prophylactic anticoagulation may be needed), stay hydrated and mobile during long flights, and be aware of DVT symptoms (unilateral leg swelling, pain, warmth). Pregnancy requires consultation with a hematologist. Despite the frightening-sounding risk ratios, the absolute annual risk of VTE in heterozygous carriers is still relatively low (about 0.5-1% per year), making this a risk to manage rather than fear.