Hereditary Thrombophilias
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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Risk factors
- Family history of VTE before age 50, recurrent VTE, or VTE at unusual sites
- First-degree relative with known thrombophilia
- Personal history of unprovoked or recurrent VTE
- Combined heterozygosity (e.g., FVL + prothrombin G20210A) — multiplicative risk
Pathophysiology
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
- Pulmonary embolism — dyspnea, pleuritic chest pain, syncope
- Cerebral venous sinus thrombosis — headache, seizures, focal deficits
- Splanchnic vein thrombosis (Budd-Chiari, portal, mesenteric) — abdominal pain, ascites
- Recurrent miscarriage, IUGR, preeclampsia (especially protein S deficiency, FVL)
- Neonatal/childhood purpura fulminans — severe protein C deficiency
Signs / physical exam
- Asymmetric calf swelling, Homans sign (insensitive)
- Tachypnea, hypoxia, tachycardia in PE
- Warfarin-induced skin necrosis at warfarin initiation (protein C/S deficiency)
Classic findings
Unprovoked VTE in a patient <50 years old, or recurrent VTE, or VTE in unusual location, or strong family history.
Differential diagnosis
- Antiphospholipid syndrome — Acquired; arterial AND venous thrombosis; pregnancy loss; lupus anticoagulant, anti-cardiolipin, anti-β2GP1 antibodies
- Malignancy-associated thrombosis (Trousseau) — Migratory superficial thrombophlebitis, recurrent VTE; underlying occult cancer
- Myeloproliferative neoplasms (JAK2) — Polycythemia vera, essential thrombocythemia; splanchnic vein thrombosis; check JAK2 V617F
- Paroxysmal nocturnal hemoglobinuria — Coombs-negative hemolysis + unusual-site thrombosis (Budd-Chiari); flow cytometry for GPI-deficient clone
- 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.
Labs
- Initial VTE evaluation: CBC, PT/INR, aPTT, fibrinogen, D-dimer
- 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
- Antithrombin activity (functional/chromogenic assay)
- 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)
- Chronic thromboembolic pulmonary hypertension (CTEPH)
- Pregnancy complications: recurrent miscarriage, IUGR, preeclampsia, placental abruption
- 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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