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Thrombophilia and Hypercoagulable States

Touqir Zahra, MD, FACP
Raksha Sharma, MD

BASICS

DESCRIPTION

  • Inherited or acquired disorder of coagulation predisposing to thromboembolism (usually venous, rarely arterial)

  • Venous thrombosis: manifests as DVT (lower extremity/pelvis) or PE

  • Synonyms: hypercoagulable disorder, prothrombotic state

EPIDEMIOLOGY

  • VTE incidence higher in ages 16–44, higher in men >45

  • Higher in African American populations

  • Inherited thrombophilia: found in up to 50% of VTE patients

    • Factor V Leiden (FVL): most common, ~50% of inherited cases, heterozygous in up to 20% with VTE

    • Prothrombin G20210A: 2nd most common, up to 8% with VTE

  • Acquired thrombophilias:

    • Pregnancy: 1–2/1,000 pregnancies

    • Cancer: 20% of VTEs with active cancer, 6% unprovoked VTE have undiagnosed cancer

    • Antiphospholipid antibodies: 50% of SLE, up to 5% of general population

  • First-time VTE: 100/100,000/year general, <1/100,000 (<15y), 1,000/100,000 (β‰₯85y)

  • 40–80% of lower extremity orthopedic procedures can cause DVT if no prophylaxis

ETIOLOGY AND PATHOPHYSIOLOGY

  • Virchow triad: venous stasis, vascular endothelial injury, abnormal blood constituents

  • VTE = inherited + acquired risks

  • Upper extremity DVT: >60% related to catheters; malignancy also a risk

  • Genetics:

    • Common: FVL, prothrombin G20210A, protein C/S/ATIII defects

    • Homozygous mutations = higher VTE risk

    • FVL: heterozygous = 3–5x risk, homozygous = 18x risk

    • Prothrombin G20210A: heterozygous = 3x risk

    • Protein C/S defects: vitamin K-dependent, made in liver; risk ↑ with deficiency (acquired: sepsis, liver disease, DIC, HIV, nephrosis)

RISK FACTORS

Acquired:

  • Previous VTE

  • 1st-degree relative with VTE (2–4x risk)

  • Immobilization, travel

  • Trauma, orthopedic surgery

  • Malignancy (esp. pancreas, ovary, brain, lymphoma)

  • Pregnancy (5–10x), postpartum (15–35x)

  • Acute illness (pneumonia incl. COVID, SARS, MERS)

  • Exogenous female hormones/OCPs

  • Androgen-deprivation therapy

  • Obesity

  • Nephrotic syndrome, hypoalbuminemia

  • APS and lupus anticoagulant

  • Myeloproliferative disorders

  • Hyperviscosity (sickle cell, paraproteinemia)

  • Hyperhomocysteinemia (B6, B12, folate deficiency)

  • Drugs: tamoxifen, thalidomide, lenalidomide, bevacizumab, L-asparaginase, ESAs, tranexamic acid

  • Dehydration

  • Central venous catheter

  • Heart failure, congenital heart disease

  • Severe liver disease

Genetic:

  • FVL, prothrombin G20210A, protein C/S/ATIII defects

  • Rare: dysfibrinogenemia

  • Indeterminate: ↑ factor VIII

  • Age >65 years

GENERAL PREVENTION

  • Pharmacologic prophylaxis in hospitalized VTE risk patients

  • Mechanical prophylaxis if anticoagulation contraindicated

  • LMWH + aspirin in pregnant APS

  • DOACs for VTE risk in solid tumors with additional risks

  • UFH/LMWH in high genetic/acquired risk with immobilization

  • Caution with procoagulant drugs (e.g., OCPs) in hereditary predisposition

DIAGNOSIS

HISTORY

  • Consider prothrombotic assessment for:

    • Recurrent VTE

    • VTE <50y (esp. if unprovoked)

    • Strong family history

    • Skin necrosis with vitamin K antagonists

    • Recurrent pregnancy loss

PHYSICAL EXAM

  • DVT: swelling, pain, warmth, redness (usually unilateral)

  • PE: dyspnea, chest pain, hemoptysis, hypoxia, tachycardia

DIAGNOSTIC TESTS & INTERPRETATION

  • Delay thrombophilia testing until after 3 months of anticoagulation

  • Screening rationale: predict recurrence, guide therapy duration, manage family risk

  • Appropriate tests for unprovoked/recurrent VTE, VTE <50y, family history, unusual site, pregnancy/OCP/HRT-related:

    • FVL (aPC resistance), protein C/S, ATIII, prothrombin G20210A

    • Antiphospholipid antibody (if autoimmune or no family history)

  • Arterial thrombosis: antiphospholipid antibody, FVL, G20210A, protein C/S, ATIII; vasculitis (ANCA)

  • Do not test for hereditary defects if known atherosclerosis

Initial Tests

  • CBC

  • aPC resistance: ≀2 implies FVL mutation (95–100% sensitivity)

  • Prothrombin G20210A genetic assay

  • ATIII/protein C/S functional assays (can be altered by acute VTE, anticoagulants)

  • Antiphospholipid antibodies: unreliable on heparin/DOACs

  • Cancer screening in unprovoked VTE >40y

  • HIT antibody if suspected

Follow-Up/Special Considerations

  • Antiphospholipid syndrome: test for lupus anticoagulant, anticardiolipin, anti-Ξ²2-glycoprotein 1

  • Malignancy: increased VTE risk, especially mucinous adenocarcinoma (do not test for thrombophilia in active cancer/VTE)

  • Unusual sites: splanchnic/cerebral vein thrombosis in young = thrombophilia test; consider cirrhosis, tumor, PNH, MPN

Pediatric Considerations

  • Warfarin is teratogenic

  • LMWH/UFH preferred in pregnancy; DOAC safety unproven

TREATMENT

Assess VTE risk

  • Low risk: heterozygous FVL/prothrombin G20210A

  • High risk: protein C/S/ATIII deficiency

Duration

  • Isolated heterozygosity for FVL/prothrombin G20210A does not mandate indefinite therapy

  • Extended thromboprophylaxis post-discharge for major risk (if bleeding risk low)

MEDICATION

  • First line: DOACs (apixaban, dabigatran, edoxaban, rivaroxaban) over warfarin for initial/long-term anticoagulation

    • OK for low-risk inherited thrombophilia

    • Limited data for rare thrombophilias (ATIII, protein C/S)

    • May use DOACs in cancer; LMWH preferred

  • Parenteral anticoagulation: LMWH > UFH (esp. in cancer, min. 6 mo)

  • Warfarin: requires INR monitoring (goal 2–3), drug/diet interactions

  • Pregnancy: low-dose aspirin and/or LMWH/UFH (warfarin contraindicated)

  • APS: warfarin/LMWH

  • Second line: If heparin/LMWH contraindicatedβ€”fondaparinux, argatroban

SURGERY/PROCEDURES

  • IVC filter: short-term PE risk if anticoagulation contraindicated; may ↑ long-term DVT recurrence

ONGOING CARE

FOLLOW-UP

  • Warfarin: monitor INR 2–3

  • Diet: stable vitamin K if on warfarin; rivaroxaban with large meal

PATIENT EDUCATION

  • Medical alert bracelet

  • Avoid contact sports

  • Seek evaluation for any trauma

PROGNOSIS

  • Anticoagulation β‰₯3 months (longer for unprovoked VTE)

  • Provoked VTE (no chronic anticoagulation): recurrence 7% (1y), 16% (5y), 23% (10y)

  • Unprovoked VTE: recurrence 15% (1y), 41% (5y), 53% (10y)

  • No RCT data for indefinite anticoagulation in all

REFERENCE

  1. Middeldorp S, Nieuwlaat R, Kreuziger LB, et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv. 2023;7(22):7101-7138.

Codes:

  • ICD10: D68.59 Other primary thrombophilia, D68.51 Activated protein C resistance, D68.2 Hereditary deficiency

Clinical Pearls

  • FVL (aPC resistance) is the most common inherited thrombophilia

  • Patients <45 with VTE: test for inherited thrombophilia

  • Rule out malignancy, especially if >50 years

End of note