Inherited point mutation in the Factor V gene (most commonly Arg506→Gln) that makes factor V resistant to inactivation by activated protein C, resulting in a hypercoagulable state with increased tendency for venous thrombosis.
It's the most common inherited thrombophilia (especially in individuals of European descent). Factor V Leiden is present in up to 20% of patients with unexplained venous thromboembolism, so recognizing it can explain early or recurrent clots and guide management.
Typically a young adult with an unprovoked DVT or PE (often under age 45). May be triggered by risk factors like estrogen exposure (oral contraceptives or pregnancy), surgery, or immobility.
Often there is a family history of venous clots. Many carriers remain asymptomatic (only ~10% of those with the mutation develop clots), so a second hit (e.g. OCP use, trauma, long flight) often precipitates the first VTE.
May also present as recurrent pregnancy losses or complications (e.g. miscarriage in second trimester) in women, although most pregnancies in FVL carriers are normal. FVL is only a mild risk factor for obstetric complications compared to antiphospholipid syndrome.
Suspect FVL in patients with unprovoked VTE at a young age or recurrent VTE/miscarriages with no other explanation.
Initial screening test: a functional APC resistance assay (looks for poor prolongation of clotting when activated protein C is added). If positive (abnormal), confirm with genetic testing for the F5 gene mutation.
Don't routinely test for FVL after a single provoked clot or in older patients (>50) with VTE, as yield is low. Only test if results would change management (e.g. in a young patient with idiopathic VTE or strong family history).
Remember that many FVL carriers never clot; assess for additional risk factors (estrogen use, smoking, immobilization) and manage those to reduce overall risk.
Rare inherited cause of hypercoagulability; can cause warfarin-induced skin necrosis due to lack of protein C.
Treat acute VTE in FVL carriers the same as any other patient: e.g. start heparin or a DOAC, then appropriate duration of anticoagulation. FVL status does not change first-line therapy or standard duration (3–6 months for a first VTE).
Decide on long-term anticoagulation based on clinical factors (provoked vs unprovoked, recurrent events) rather than FVL alone. A heterozygous FVL patient with a single provoked DVT usually does not require lifelong anticoagulation. If the VTE was unprovoked or life-threatening (or if patient is homozygous FVL), consider extended anticoagulation, weighing bleeding risk.
For asymptomatic carriers, no prophylactic anticoagulation is given. Emphasize risk reduction: avoid smoking, manage weight, and caution with estrogen-containing contraceptives (seek alternatives if possible).
In high-risk situations (e.g. surgery, prolonged immobilization, postpartum period), provide prophylactic anticoagulation (e.g. low-dose heparin) especially if the patient is homozygous or has a strong family history. During pregnancy, heterozygous FVL women without prior clots are usually managed with close observation or low-dose aspirin, but those with a history of VTE or homozygous FVL may require prophylactic LMWH during pregnancy and 6 weeks postpartum.
Mnemonic: Leiden = 'Leaden' (heavy) — Factor V is "leaden" and won't get turned off by Protein C, leading to overactive clotting.
Most heterozygous carriers won't have clots without a trigger – so always look for a precipitant (surgery, estrogen, immobilization) on top of FVL before blaming it for thrombosis.
Unprovoked VTE at a young age (especially <45) – consider inherited thrombophilia testing (including FVL).
Recurrent venous thromboses or VTE in unusual sites (like cerebral or hepatic veins) – suspect a hypercoagulable disorder like FVL.
Unexplained pregnancy complications (recurrent miscarriage, severe preeclampsia, placental abruption) – evaluate for thrombophilias (FVL is a mild risk factor for these).
Risk factors present (young age, family history, recurrent/unusual clots) or suspicion of inherited thrombophilia → Consider testing for Factor V Leiden.
Order an activated protein C (APC) resistance assay as an initial screen for FVL (will be abnormal if factor V is resistant to APC).
If APC resistance test is positive → perform DNA testing for the factor V Leiden mutation (confirmatory genetic test).
If FVL mutation confirmed and patient has active VTE → treat acute thrombosis with standard anticoagulation (no modifications needed for FVL).
After acute treatment, determine duration of anticoagulation based on provoked vs unprovoked and patient risk profile (FVL heterozygosity alone is not an indication for lifelong anticoagulation). Provide patient education on lifestyle changes to minimize risk and use prophylaxis during high-risk periods.
Young woman on oral contraceptives with a DVT (especially with a family history of clots) → think Factor V Leiden mutation.
Patient with recurrent DVTs/PEs in their 20s-30s, normal PT/PTT, and a positive APC resistance assay → inherited thrombophilia like Factor V Leiden.
Woman with multiple 2nd-trimester miscarriages and a prior unprovoked DVT → suspect Factor V Leiden (after ruling out antiphospholipid syndrome).
Case 1
A 30‑year‑old woman develops a DVT in her left leg 2 months after starting oral contraceptive pills. Her mother and sister both had deep vein thromboses in their twenties.
Diagram illustrating the pathophysiology of Factor V Leiden mutation: the mutated factor V (Factor V Leiden) cannot be inactivated by activated protein C, leading to continued thrombin generation and clot formation.
