Hypercoagulable states

Virchow triad, pathogenesis of thrombosis

• 1. Endothelial injury / dysfunction: trauma, surgery, smoking, atherosclerosis, indwelling lines, vasculitis, sepsis.
• 2. Stasis / venous flow disturbance: immobility, surgery, hospitalization, paralysis, pregnancy, obesity, congestive heart failure, atrial fibrillation.
• 3. Hypercoagulability: inherited thrombophilias, acquired conditions (cancer, antiphospholipid syndrome, OCPs/HRT, pregnancy, MPNs, PNH, nephrotic syndrome, IBD, smoking).

Inherited thrombophilias

• Factor V Leiden (FVL): Arg506Gln; ~5% Caucasian; ~3 to 7-fold ↑ VTE heterozygous; ~18-fold homozygous (older estimates up to 80-fold).
• Prothrombin G20210A (PGM): ~2% Caucasian; ~3-fold ↑ VTE heterozygous; homozygous rare with increased but poorly quantified risk.
• Protein C deficiency: autosomal dominant; type I quantitative or II dysfunctional; 4 to 8-fold ↑ VTE; neonatal purpura if homozygous.
• Protein S deficiency: autosomal dominant; type I (↓ total and free), II (normal antigen, ↓ activity), III (normal total, ↓ free); 2 to 8-fold ↑ VTE.
• Antithrombin (AT) deficiency: most thrombotic (10-fold ↑ VTE); type I quantitative or II dysfunctional; heparin resistance hallmark.

Inherited thrombophilias, mechanism and how to test

• Factor V Leiden (FVL): Arg506Gln substitution makes factor Va resistant to cleavage by activated protein C (APC). Test with APC resistance functional assay, confirm with genetic testing (PCR) if positive. Warfarin / DOACs do not affect mutation testing. FVL accounts for >90% of APC resistance (others: FV Cambridge, Liverpool, Bonn, and Nara mutations, protein S deficiency, APLS, pregnancy, and cancer).
• Prothrombin G20210A: 3' UTR mutation increases prothrombin (factor II) levels ~30%. Genetic test by PCR (no functional assay); do not check antigen or activity levels.
• Antithrombin deficiency: type I (low antigen + activity); type II (low activity, normal antigen, defective protein). Acute thrombosis and acute heparin can lower AT, so re-check at 2 to 4 weeks off heparin.
• Protein C / S deficiency: type I (low antigen + activity); type II (normal antigen, low activity). Low free protein S more sensitive than total. Acute thrombosis, warfarin, OCPs, pregnancy, liver disease can lower levels.
• Coagulation factor levels do not correlate with mutation: e.g., FVL patients have normal factor V level and activity.

The "Seven strong thrombophilias" framework

• Strong (high-risk) thrombophilias that may justify long-term anticoagulation:
• 1. Antiphospholipid syndrome (APS), especially triple-positive.
• 2. Antithrombin deficiency.
• 3. Protein C deficiency.
• 4. Protein S deficiency.
• 5. Homozygous factor V Leiden.
• 6. Homozygous prothrombin G20210A.
• 7. Compound heterozygous FVL + prothrombin G20210A.

Relative risk of first VTE and of recurrence by thrombophilia

Acquired hypercoagulable states

• Antiphospholipid syndrome (APS): ≥1 clinical + ≥1 lab criterion; triple-positive (LA + aCL + aβ2GPI) = highest risk; warfarin INR 2 to 3 (DOACs failed).
• Myeloproliferative neoplasm (MPN): JAK2 V617F (PV ~95%, plus exon 12; ET/PMF ~50 to 60%); CALR or MPL drive ET/PMF, not PV; high thrombotic risk; cytoreductive + aspirin ± anticoagulation.
• Paroxysmal nocturnal hemoglobinuria (PNH): complement-mediated hemolysis; thrombosis (esp. venous/hepatic, Budd-Chiari) even with normal Plt; complement inhibition is central to reducing thrombosis; primary anticoagulant prophylaxis is individualized, not routine.
• Heparin-induced thrombocytopenia (HIT): type II, immune; anti-PF4/H IgG, thrombocytopenia paradox + thrombosis; stop heparin, start argatroban/fondaparinux.
• Malignancy: TF expression + microparticles, VTE; cancer itself is a high-risk VTE factor.
• Nephrotic syndrome: ↑ fibrinogen, ↓ AT/protein S, VTE risk ↑ if serum albumin <2.5 g/dL.
• OCP/HRT: 3 to 4-fold ↑ VTE; higher with 3rd/4th gen; avoid if inherited thrombophilia.
• Pregnancy/postpartum: ↑ factors II, VII, VIII, X; ↓ protein S/fibrinolysis; postpartum peak weeks 1 to 6.
• Immobilization: surgery, ICU, flights; transient ↑ VTE; reversible with mobilization.

Acquired hypercoagulability, management pearls

• Antiphospholipid syndrome: triple-positive highest risk; warfarin INR 2 to 3.
• MPN: risk-adapted; low-risk PV = phlebotomy + aspirin, low-risk ET = aspirin; cytoreduction + aspirin for high-risk; consider anticoagulation if prior thrombosis.
• Malignancy: Khorana score ≥2 starting systemic therapy, consider apixaban/rivaroxaban/LMWH prophylaxis after bleeding-risk assessment; active cancer = indefinite anticoagulation if VTE.
• Nephrotic syndrome: albumin <2.5 g/dL + proteinuria >3.5 g/day, prophylaxis consideration.
• OCP/HRT: 3 to 4-fold ↑ VTE; counsel on contraindications + smoking cessation.
• Postpartum (6 weeks): peak thrombotic window; prophylaxis if additional risk factors.

Risk factors for first VTE

• Strong/major (OR >10): fracture of hip/leg, hip/knee replacement, major general surgery, major trauma, spinal cord injury, hospitalization for acute illness; previous VTE (strongest predictor of recurrent VTE).
• Moderate (OR 2 to 9): pregnancy, postpartum, OCP/HRT, cancer, indwelling central venous catheter, chemotherapy, congestive heart failure, paralysis, thrombophilia, tamoxifen.
• Weak (OR <2): bed rest >3 d, immobility (sitting, long-haul travel), age, obesity, varicose veins, pregnancy 1st trimester only.

Risk factors for first arterial thrombosis

• Atherosclerotic (CV): age, smoking, HTN, hyperlipidemia, diabetes, obesity, family history.
• Hematologic / thrombophilic (less common, especially in younger pts): APS, paradoxical embolism (PFO), hyperhomocysteinemia, MPN with thrombocytosis, PNH, HIT, vasculitis, sickle cell, severe inherited thrombophilia.

Who NOT to test for thrombophilia (generally)

• Provoked first VTE with transient risk factor (surgery, trauma, hospitalization, immobility, OCP/HRT, pregnancy): testing rarely changes management (anticoagulate at least 3 months; for pregnancy-associated VTE continue through pregnancy and at least 6 weeks postpartum).
• Active malignancy: cancer drives thrombosis; thrombophilia testing does not change anticoagulation duration.
• Inflammatory bowel disease (active): IBD itself drives thrombosis.
• Myeloproliferative disorders: test for JAK2 if not already known; not for inherited thrombophilias.
• HIT with thrombosis: diagnose HIT; inherited thrombophilias do not change management.
• Retinal vein occlusion (including the preeclampsia setting): not associated with inherited thrombophilias.
• Routine screening of asymptomatic relatives: controversial; counseling about provocation avoidance is reasonable; routine prophylaxis not recommended.

When to consider thrombophilia testing

• Unprovoked VTE in a young patient (<45).
• Strong family history of VTE (especially first-degree relatives at young ages).
• Recurrent VTE.
• Unusual sites (cerebral, splanchnic, hepatic vein, upper extremity unprovoked).
• Pregnancy losses (recurrent, APS).
• Warfarin-induced skin necrosis (protein C deficiency).
• Purpura fulminans in a newborn (homozygous protein C or S deficiency).

Thrombophilia tests for VTE, what to order

• Factor V Leiden mutation and activated protein C resistance.
• Prothrombin G20210A mutation.
• Protein C activity.
• Protein S activity, free protein S antigen.
• Antithrombin activity.
• Anticardiolipin IgG and IgM antibodies.
• Anti-β2-glycoprotein I IgG and IgM antibodies.
• Lupus anticoagulant.
• Hemoglobin, platelet count, JAK2 V617F and PNH (in splanchnic vein thrombosis).
• Lipoprotein(a) (in pediatrics).

How to test (timing matters)

• Tests largely NOT influenced by anticoagulation (start with these; clotting-based lupus anticoagulant is the exception, see below):
  • Lupus anticoagulant (LA): clotting-based, so it IS affected by heparin, warfarin, and DOACs (false positives); interpret with caution (see below).
  • Anti-cardiolipin and anti-β2GPI antibodies.
  • Factor V Leiden (genetic; APC resistance assay can be affected by DOAC).
  • Prothrombin G20210A (genetic).
• Tests AFFECTED by anticoagulation (defer 2 to 4 weeks off therapy):
  • Protein C and S activity (warfarin lowers; DOAC may artifactually elevate).
  • Antithrombin activity (heparin lowers).
  • Functional clotting-based LA tests (DOAC interferes, can be falsely positive).
  • Factor levels do NOT correlate with mutation; e.g., FVL patients have normal factor V level/activity.

Protein C, S, and AT: activity testing and acquired deficiency

• Check protein C, S, and AT activity; free protein S antigen can be added. Antigen level alone can miss patients with normal antigen but low activity (type II). Diagnose by functional activity, not routine mutation testing (protein C has >100 variants, protein S similar); reserve selective gene testing for a confirmed deficiency when it will guide management or family evaluation.
• Acquired causes of low levels:
  • Liver disease (C, S, AT): ↓ synthesis.
  • Warfarin therapy (C, S): ↓ levels.
  • Estrogens, pregnancy (S): ↓ levels.
  • Inflammatory diseases (S): ↓ levels.
  • Heparin therapy (AT): ↓.
  • Acute thrombosis (S, AT): ↓.
  • DOACs: ↑ C and S activity (falsely elevated).
• Protein S activity is typically low on estrogens (OCP, pregnancy, post-menopausal hormone therapy), during acute thrombosis, on warfarin, and with liver disease; this does not reflect inherited deficiency. Warfarin must be discontinued for ≥3 weeks before reliable protein S levels can be obtained.
• Treatment: AT concentrate is very rarely used; protein C concentrate for severe neonatal protein C deficiency (very rare).

Intermediate-risk thrombophilia workup algorithm

• In the intermediate-risk group, at about 3 months on anticoagulation check D-dimer and start the thrombophilia workup with tests not influenced by anticoagulation (antiphospholipid antibodies: anticardiolipin and anti-β2GPI; FVL; and prothrombin G20210A).
• If those are negative, D-dimer is low, and provoking factors, recurrence history, and bleeding risk favor stopping, stop anticoagulation, recheck D-dimer in 4 weeks, and complete the workup with protein C, protein S, AT activity, and lupus anticoagulant.
• Base duration on provoking factors, recurrence history, and bleeding risk; negative thrombophilia testing and low D-dimer do not establish that stopping is safe after unprovoked VTE. If D-dimer is positive while on anticoagulation, or becomes positive during the 4-week off-therapy window, continue long-term anticoagulation.

D-dimer in management

• After VTE provoked by a major transient risk factor: stop anticoagulation at 3 months; D-dimer is not needed for this decision.
• After unprovoked VTE: D-dimer ~4 weeks AFTER stopping anticoagulation; if elevated, consider resuming (PROLONG). Note HERDOO2/REVERSE used D-dimer measured while ON anticoagulation.

Special populations

• Pregnancy + inherited thrombophilia: risk varies by mutation. AT deficiency, homozygous FVL, and combined defects, high risk, LMWH prophylaxis throughout pregnancy + 6 weeks postpartum. Heterozygous FVL or PT G20210A alone, individualized.
• Recurrent pregnancy loss + APS: prophylactic LMWH + low-dose ASA throughout pregnancy.
• Women considering OCP/HRT with FH of VTE: weigh risk versus benefit; do not routinely screen for thrombophilia before OCP based on family history of VTE alone when the familial defect is unknown; consider selective testing only for a known high-risk familial deficiency (AT, protein C, protein S) that would change estrogen use.

High yield

• Provoked VTE, 3 months, stop. Do not test for thrombophilia.
• Unprovoked VTE, assess bleeding risk. If low, consider indefinite anticoagulation. Thrombophilia testing rarely changes duration.
• Triple-positive APS = warfarin (target INR 2 to 3); DOACs inferior (TRAPS trial).
• Antithrombin deficiency: "heparin resistance", give AT concentrate or FFP.
• Protein C deficiency: warfarin-induced skin necrosis. Bridge with heparin.
• Lupus anticoagulant prolongs aPTT in vitro but causes thrombosis in vivo.
• Hyperhomocysteinemia: B vitamin replacement lowers homocysteine but does NOT lower VTE risk (VITRO, NORVIT, HOPE-2).
• Catastrophic APS: anticoagulation + steroids + IVIG/PEX ± rituximab.
• Splanchnic vein thrombosis: screen for MPN (JAK2 V617F), PNH, malignancy, cirrhosis.
• Cerebral venous thrombosis: anticoagulate even with hemorrhagic infarct; workup OCP, pregnancy, mastoiditis, thrombophilia.