Inherited hypercoagulable states increasing risk of venous thromboembolism — Factor V Leiden, prothrombin G20210A, protein C/S, antithrombin deficiency.
Also known as: thrombophilia, Factor V Leiden, FVL, prothrombin gene mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, inherited hypercoagulability
Overview
Group of inherited mutations affecting components of the coagulation cascade or natural anticoagulant pathways, predisposing to venous thromboembolism. The five most clinically relevant: Factor V Leiden (FVL), prothrombin G20210A, protein C deficiency, protein S deficiency, and antithrombin deficiency.
Epidemiology
Factor V Leiden — most common (3-8% of Europeans; rare in Asian/African populations); prothrombin G20210A — 1-3% of Europeans; protein C, S, and antithrombin deficiencies each <1% of general population but more frequent in patients with VTE and family history. Combined defects are not rare and multiply risk.
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Factor V Leiden — G1691A point mutation makes activated factor V resistant to cleavage by activated protein C → sustained thrombin generation. Prothrombin G20210A — 3' UTR mutation increases prothrombin transcription and plasma levels. Protein C and S deficiencies — reduce inactivation of factors Va and VIIIa. Antithrombin deficiency — reduces inhibition of thrombin and factors Xa, IXa, XIa. Net effect: shift of hemostatic balance toward thrombosis, primarily venous.
Clinical presentation
Symptoms
Deep vein thrombosis — unilateral leg swelling, pain, warmth
HIT — Heparin exposure with platelet drop and thrombosis
Estrogen/OCP- or pregnancy-related thrombosis — Acquired transient hypercoagulability; resolves with discontinuation/postpartum
Diagnostic workup
Diagnostic criteria
Diagnosis is laboratory-based once acute thrombus and anticoagulation effects have resolved. Testing should only be pursued if results will alter management (duration of anticoagulation, family counseling) — many experts argue against routine thrombophilia screening because results rarely change management.
Thrombophilia testing — DEFER until ≥3 months after acute event and ≥2 weeks off anticoagulation (acute thrombus and anticoagulants alter functional assays)
Factor V Leiden — activated protein C (APC) resistance assay; confirm with FVL genetic testing
Prothrombin G20210A — PCR-based genetic test
Protein C activity (functional assay)
Protein S — free protein S antigen plus protein S activity
Antiphospholipid panel concurrently to exclude APS
Imaging
Compression ultrasound for suspected DVT
CT pulmonary angiogram or V/Q scan for PE
MR venography for cerebral sinus or splanchnic thrombosis
Treatment
First-line
Acute VTE — therapeutic anticoagulation: LMWH (enoxaparin) bridge to warfarin, or DOAC (apixaban, rivaroxaban, edoxaban, dabigatran) — same as VTE without thrombophilia
Direct oral anticoagulants are first-line for most inherited thrombophilias; warfarin still preferred in severe antithrombin deficiency or triple-positive APS
Avoid combined oral contraceptives and estrogen-containing HRT in carriers
First unprovoked VTE + heterozygous FVL or prothrombin G20210A
3-6 months full-dose anticoagulation
Consider extended/indefinite therapy based on bleeding risk and patient preference (modest VTE recurrence reduction)
Homozygous FVL, homozygous prothrombin, or compound heterozygotes
Indefinite anticoagulation often recommended after first unprovoked VTE
Same approach for severe protein C, S, or antithrombin deficiency
Antithrombin deficiency with acute VTE
Heparin may have blunted response; consider antithrombin concentrate
Long-term anticoagulation; warfarin often preferred; DOACs increasingly used
Pregnancy in known thrombophilia
LMWH (enoxaparin, dalteparin) prophylactic or therapeutic dosing based on personal/family history
Avoid warfarin (teratogen) and DOACs (limited data) in pregnancy
Continue 6 weeks postpartum
Second-line / adjunct
Antithrombin concentrate for surgery/childbirth in antithrombin deficiency
Genetic counseling for family members; cascade testing in symptomatic relatives only
Complications
Recurrent VTE
Post-thrombotic syndrome (chronic leg pain, swelling, ulceration)
Warfarin-induced skin necrosis in protein C/S deficiency
Neonatal purpura fulminans in homozygous protein C or S deficiency
PANCE pearls
Do not order thrombophilia panels during acute thrombosis or while on anticoagulation — functional assays will be inaccurate.
The strongest indication for testing is when results would alter management (treatment duration, family planning); for most provoked VTEs, testing changes nothing.
Factor V Leiden heterozygosity is common but a relatively weak risk factor — provoking factors (estrogen, surgery, immobility) drive most events.
Combined estrogen contraceptives raise VTE risk 30-35x in homozygous FVL carriers; progestin-only or non-hormonal methods are preferred.
Antithrombin deficiency confers the highest absolute thrombosis risk among hereditary thrombophilias.
Warfarin initiation in protein C/S deficiency can transiently worsen the procoagulant state — always overlap with heparin/LMWH until INR therapeutic for ≥48 hours.
References
ASH 2023 Guidelines — Middeldorp S et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv 2023.
ISTH Subcommittee — Connors JM. Thrombophilia testing and venous thrombosis. N Engl J Med 2017; 377:1177-1187.
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