Thrombophilias and VTE management

VTE diagnosis

• Pretest probability: Wells score (DVT or PE).
• D-dimer: high sensitivity (NPV ~99% in low pretest probability outpatients) but low specificity. Age-adjusted D-dimer cutoff (age × 10 in pts >50) improves specificity.
• DVT confirmation: compression duplex ultrasound (proximal). For inconclusive or isolated calf-vein, repeat US in 5 to 7 days OR alternative imaging (CT venography, MRV).
• PE confirmation: CT pulmonary angiography (CTPA) preferred; V/Q scan as an alternative when CTPA is less desirable (contrast allergy, significant renal impairment); in pregnancy both CTPA and V/Q are acceptable, guided by chest radiograph; echo for hemodynamic risk stratification.
• PE risk stratification: massive (hemodynamic instability), submassive (RV dysfunction or elevated troponin/BNP without instability), low-risk PE.

PE, initial treatment by risk

• Massive PE (SBP <90, shock): systemic tPA 100 mg over 2 h OR catheter-directed thrombolysis; mortality ↓ with intervention; ↑ bleeding but survival benefit outweighs.
• Submassive PE (RV dysfunction or ↑ troponin/BNP, without hypotension): anticoagulation standard; consider thrombolysis if high decompensation risk (PEITHO: ↓ hemodynamic decompensation but ↑ major bleeding).
• Low-risk PE (sPESI 0, normal RV, negative biomarkers): outpatient anticoagulation, apixaban or rivaroxaban monotherapy; excellent outcomes.

PE risk-based management

• sPESI (simplified PE Severity Index): 0 pts if age ≤80 + no cancer + no cardiopulmonary disease + HR <110 + SBP ≥100 + O₂ sat ≥90%. sPESI 0 = low-risk (<1% mortality outpatient).
• BOVA score: combines SBP 90 to 100 mmHg + elevated troponin + RV dysfunction + HR ≥110; stratifies intermediate-risk PE; high BOVA, consider thrombolysis.
• ESC 2019: low-risk (PESI I to II or sPESI 0, no RV strain, normal biomarkers); intermediate-low (elevated PESI/sPESI with at most one of RV strain or ↑ biomarkers, or either finding present); intermediate-high (elevated PESI/sPESI plus both RV strain and ↑ biomarkers); high-risk (shock/hypotension).
• 2026 AHA/ACC PE guideline (Circulation 2026): retires massive/submassive for clinical categories A to E (A incidental; B symptomatic, PESI I to II or sPESI 0; C elevated score with or without RV dysfunction/biomarkers, C1 to C3; D incipient cardiopulmonary failure, e.g., normotensive shock; E overt failure, E1 persistent hypotension, E2 refractory shock/arrest). Advanced therapy (systemic lysis, catheter-directed therapy, embolectomy) reasonable in E1, may be considered in D1 to D2; DOAC over VKA and LMWH over UFH.

VTE anticoagulation duration

• Provoked VTE (surgery, trauma, hospitalization, OCP/HRT, pregnancy): anticoagulate 3 months if transient risk; may stop if risk resolved.
• Unprovoked VTE: extended/indefinite recommended if low bleeding risk; HERDOO2 in women (score 0 to 1, low recurrence, can stop after 5 to 12 months of anticoagulation); men have higher recurrence, consider indefinite.
• Recurrent unprovoked VTE: indefinite anticoagulation recommended if bleeding risk acceptable; if both events were provoked by transient factors, stopping after primary treatment is reasonable.
• Cancer-associated VTE: minimum 6 months; often extended while cancer active or indefinite; reassess q3 to 6 mo.
• API-CAT (Mahé NEJM 2025; NCT03692065): after 6 mo of full-dose anticoagulation for cancer-associated VTE, randomized to apixaban 2.5 mg BID vs 5 mg BID for 12 mo. Reduced-dose non-inferior for recurrence (2.1% vs 2.8%) and lower major/CRNM bleeding (HR 0.75). Supports step-down to prophylactic-dose apixaban after 6 mo in active cancer.

Choice of anticoagulant for VTE

• First-line for most non-cancer VTE: DOACs, apixaban (10 mg BID × 7 days, then 5 mg BID), rivaroxaban (15 mg BID × 21 days, then 20 mg daily). Edoxaban and dabigatran require parenteral lead-in.
• Cancer-associated VTE: apixaban or edoxaban first-line (CARAVAGGIO, Hokusai-VTE Cancer); LMWH for GI/GU malignancies with bleeding risk, intracranial mets, or DOAC interactions.
• Antiphospholipid syndrome: warfarin (especially triple-positive, TRAPS).
• Mechanical valves: warfarin only.
• Pregnancy: LMWH (preferred); UFH peripartum.
• Severe renal failure (CrCl <15): warfarin (UFH bridge) preferred; LMWH generally avoided (if used, dose-reduce with anti-Xa monitoring). Avoid DOACs (US apixaban label includes dialysis dosing, limited data).
• Severe hepatic failure: avoid DOACs (especially rivaroxaban, dabigatran).
• Long-term VTE prevention: consider apixaban 2.5 mg BID or rivaroxaban 10 mg daily after the initial 6 months (AMPLIFY-EXT, EINSTEIN-CHOICE).

Khorana score for primary VTE prophylaxis (ambulatory cancer pts)

• Score ≥2: consider primary VTE prophylaxis, apixaban 2.5 mg BID or rivaroxaban 10 mg daily during chemo (CASSINI, AVERT trials).
• Inpatient cancer pts hospitalized with acute medical illness: pharmacologic prophylaxis (LMWH or fondaparinux) standard.

Management of thrombophilia WITH VTE

• Anticoagulate 3 to 6 months for a provoked VTE. If anticoagulation is stopped, still provide postoperative prophylaxis, ante- and postpartum anticoagulation, and routine care and education (recognize VTE, avoid estrogen OCP, consider prophylactic anticoagulation during surgery and ante-/postpartum).
• Consider indefinite anticoagulation for:
  • Unprovoked VTE.
  • Life-threatening PE and extensive proximal DVT.
  • Male sex.
  • Atypical-site VTE.
  • Homozygous or double-heterozygous thrombophilia.
  • More than one thrombophilia.

Management of thrombophilia WITHOUT VTE

• Antithrombin deficiency: postoperative prophylaxis and ante- and postpartum anticoagulation.
• All other thrombophilias: routine care and education (recognize VTE, avoid estrogen OCP, consider prophylactic anticoagulation during surgery and ante-/postpartum).

Thrombophilia and family testing

• For a heterozygous FVL or prothrombin G20210A carrier with no history of VTE, do not test family members; provide prophylaxis for high-risk surgery, use non-estrogen contraception, and anticoagulate during pregnancy/postpartum only if other risk factors are present.

Factor V Leiden (FVL)

• Autosomal dominant. Heterozygous FVL prevalence 3% to 8% (white), 1.2% (African American), rare in native African and Asian populations. Homozygous FVL occurs in 1 in 500 to 1,600 whites.
• Thrombin (FII) activates FV; activated FV is a cofactor for the prothrombinase complex (II to IIa), a positive feedback loop. Thrombin also converts protein C to activated protein C (APC), which inactivates FVa and FVIIIa, a negative feedback loop.
• The point mutation (G1691A) eliminates a protein C cleavage site, making factor Va resistant to APC and increasing thrombin generation.
• Testing: APC resistance functional assay first (in normal plasma, APC prolongs aPTT dose-dependently; in FVL it does not). If positive, confirm with genetic PCR. FVL accounts for >90% of APC resistance.
• After a first VTE provoked by a hormonal risk factor (OCP, pregnancy, postpartum), the presence of FVL may justify indefinite anticoagulation.

Prothrombin G20210A mutation

• Autosomal dominant; point mutation, ↑ prothrombin. Second most common inherited thrombophilia. Prevalence 2% in the US, 0.5% (African American); homozygosity 1 in 4,000.
• Test by PCR; do not check antigen or activity levels.

Protein C deficiency

• Autosomal dominant. Heterozygous 1 in 500; homozygous or double-heterozygous 1 in 1 million.
• Type I (quantitative, ~85%): ↓ activity and ↓ antigen. Type II (qualitative, ~15%): ↓ activity, normal antigen.
• Do not check PCR (>160 mutations) and check activity first (low in both types); if persistently low after excluding acquired causes, antigen distinguishes type I (low) from type II (normal); check activity, which is low in both types.
• Low protein C can be due to ↑ FVIII, liver disease, lupus anticoagulant, and warfarin. DOACs falsely elevate clot-based protein C/S activity (assay interference); use chromogenic protein C or protein S antigen assays, or DOAC removal, rather than routinely interrupting anticoagulation.
• Patients with protein C deficiency are at high risk for warfarin-induced skin necrosis.

Protein S deficiency

• Autosomal dominant. Prevalence 1 in 800 to 3,000. Protein S is free (40%) or bound to C4b-BP (60%).
• Type I (quantitative): both free and total antigen low. Type II (qualitative): activity low, free and total antigen normal. Type III (quantitative): free antigen low, total normal (high C4b-BP or abnormal binding).
• Protein S level is low with ↑ estrogens (OCP, pregnancy, post-menopausal hormone therapy), acute thrombosis, warfarin, DIC, and liver disease; this does not reflect inherited deficiency. Warfarin must be stopped ≥3 weeks before reliable levels.
• Protein S activity is low with ↑ FVIII, FVL mutation, or APLS. DOACs ↑ C and S activity.
• Diagnose by functional assay: check free and total antigen and activity. Associated with warfarin-induced skin necrosis.

Antithrombin deficiency

• Autosomal dominant. Prevalence 1 in 500 to 5,000. Homozygous type I (null) is generally incompatible with life; homozygous type II heparin-binding-site variants can survive but cause severe thrombosis.
• Antithrombin targets XIIa, XIa, IXa, Xa, IIa, and VIIa, plus kallikrein, plasmin, trypsin, and the C1s subunit; it does not affect FV and FVIII (those are inactivated by protein C and S).
• Type I (quantitative, ~12%); type II (qualitative, ~88%, defects in the thrombin- or heparin-binding region and other functions).
• Acquired AT deficiency: VTE, heparin (↓ AT by ~30%), liver disease, nephrotic syndrome, protein-losing enteropathy, DIC, sepsis, asparaginase chemotherapy.
• Diagnose by functional assay (level and activity); test off anticoagulation after completing treatment (at least 3 months from the acute VTE), with adequate drug washout. Specialized AT assays (activity in the absence of heparin) or gene sequencing distinguish subtypes.
• Treat per thrombophilia management; AT concentrate (THROMBATE III, ATryn) is FDA-approved for peri-operative and peripartum thromboprophylaxis in hereditary AT deficiency; it is not used for routine lifelong replacement.

Homocysteine, MTHFR, and elevated FVIII

• Hyperhomocysteinemia: mild to moderate elevations arise from deficiency of B6, B12, or folate, renal failure, drugs (fibrates, nicotinic acid, metformin), smoking, and enzyme polymorphisms. B vitamin replacement lowers homocysteine but does NOT lower VTE risk. Testing has no good indication unless a young individual; levels >100 μM/L can indicate homocystinuria.
• MTHFR: C677T and A1298C polymorphisms can raise homocysteine, but in North America (folate-supplemented food) they are not risk factors for venous or arterial thrombosis or pregnancy complications. Do not test for MTHFR.
• Elevated factor VIII: an acute-phase reactant; FVIII >150% confers a ~4.8-fold greater risk of first VTE than levels <100%, with some evidence of increased recurrence. Very high activity (>200% to 250%) may support long-term anticoagulation, but FVIII is not a useful routine tool to predict recurrent VTE.

VTE and cancer

• About 20% of all VTEs occur in patients with cancer. About 4% of patients with unprovoked VTE have cancer detected at the initial evaluation, with a 12-month cumulative occult-cancer prevalence of about 5% (initial evaluation plus first year combined). In unprovoked VTE, ask about B symptoms and recommend age-appropriate cancer screening.
• Use LMWH or DOACs; prefer LMWH with high-bleeding-risk luminal GI tumors. DOACs (especially edoxaban, rivaroxaban) raise GI bleeding; apixaban may be acceptable in selected patients.

Special situations

• IVC filter indications: absolute contraindication to anticoagulation, recurrent VTE despite therapeutic anticoagulation (not indicated for PE severity or clot burden alone when anticoagulation can be given; confirm true recurrence and check adherence/dose before a filter). Removable filters preferred; remove when no longer indicated.
• Phlegmasia cerulea dolens: severe iliofemoral DVT with limb-threatening ischemia, catheter-directed thrombolysis ± thrombectomy.
• May-Thurner syndrome: left iliac vein compression by the right common iliac artery, recurrent left-sided DVT. Stenting may be beneficial.
• Paget-Schroetter syndrome: effort-induced upper extremity DVT (typically subclavian); anatomic compression at the thoracic outlet. Tx: anticoagulation + thoracic outlet decompression.

High yield

• Wells score, D-dimer if low/intermediate, then US (DVT) or CTPA (PE).
• Massive PE (hemodynamic instability), systemic thrombolysis if no contraindications.
• Cancer-associated VTE: apixaban/edoxaban preferred; LMWH for GI/GU bleeding risk.
• Khorana ≥2, consider primary prophylaxis (CASSINI/AVERT).
• Provoked, 3 months. Unprovoked + low bleeding risk, indefinite consideration. APS triple-positive: warfarin (DOACs inferior). AT deficiency with VTE: long-term anticoagulation often appropriate (DOAC or warfarin), duration individualized; asymptomatic carriers not routinely anticoagulated.
• IVC filter = backup, not primary therapy. Remove when feasible.