Hypercoagulable States

Sarah Fittro

Background

  • Virchow’s triad: 1. Hypercoagulability 2. Stasis 3. Endothelial injury
  • Diagnostic thrombophilia testing indications
    • Recurrent unprovoked VTE
    • Severe first VTE (e.g., massive PE, no cause)
    • First VTE at <50 years old (e.g., 32-year-old with spontaneous DVT)
    • VTE in the setting of strong family history
    • VTE in unusual vascular site (cerebral, renal, mesenteric)
    • Recurrent pregnancy loss
    • Arterial thrombosis at a young age
    • Strong family history
  • Must consider if thrombophilia testing will change clinical management
    • If the unprovoked VTE warrants indefinite anticoagulation then testing may not be helpful
    • However, if VTE provoked by minor risk factor (OCPs) with an underlying thrombophilia might change the decision, then testing may be informative
  • Separated into hereditary and acquired conditions
    • Hereditary:
      • Factor V Leiden mutation
      • Prothrombin mutation
      • Protein C or S deficiency
      • Antithrombin deficiency
      • Dysfibrinogenemia (rare)
      • Elevated factor VIII (possible genetic component)
      • Hyperhomocysteinemia (inherited component due to mutations (e.g., MTHFR))
    • Acquired
      • Antiphospholipid syndrome
      • Active cancer or occult malignancy
      • Immobilization (bedridden, hip/knee replacement)
      • Major surgery/trauma
      • Smoking
      • Obesity (BMI ≥30 kg/m², especially visceral fat)
      • Pregnancy and postpartum period (first 6 weeks)
      • Hormonal therapy (OCPs (especially estrogen-containing), hormone replacement therapy, or selective estrogen receptor modulators (e.g., tamoxifen).
      • Myeloproliferative neoplasms (e.g., polycythemia vera or essential thrombocytopenia)
      • Paroxysmal nocturnal hemoglobinuria
      • Heparin induced thrombocytopenia
      • Nephrotic syndrome (risk correlates with albumin <2.0 g/dL)
      • Inflammatory states like inflammatory bowel disease, rheumatoid arthritis, or acute infections (e.g., sepsis).
      • Acquired hyperhomocysteinemia (elevated homocysteine from B12/folate deficiency, renal failure, or smoking)
      • Note: Travel (plane, train, automobile) is NOT on this list and this is NOT considered a provoking risk factor -
  • Testing: All specific testing for hereditary disorders and APS should be performed at least 4-6 weeks after an acute thrombotic event or discontinuation of anticoagulant/thrombolytic therapies to avoid interference.

Antiphospholipid Antibody Syndrome (APLS)

Background 

  • Most common acquired disorder (anti-phospholipid antibodies present in 3-5% population)
  • Thrombotic Risk: Venous (DVT, PE), arterial (stroke, MI), or microvascular thrombosis; recurrent pregnancy loss.

Evaluation

  • This is a clinicopathologic diagnosis (need both clinical and laboratory criteria)
  • Triggers: Often associated with systemic lupus erythematosus (SLE) or standalone (“primary APS”).
  • Diagnosis requires clinical event (thrombosis or pregnancy morbidity) + positive antibody test on two occasions, 12 weeks apart:
    • Lupus anticoagulant: can occur in relation to drugs or infection o
    • Anticardiolipin antibodies
    • β 2GP1 (anti- β2-glycoprotein) antibodies

Evaluation

  • TTE if structural disease suspected
  • Ambulatory cardiac monitoring if frequently symptomatic

Management

  • Consider aspirin for primary prevention (persistent aPL without thrombosis/pregnancy loss) if high risk.
  • VTE: indefinite warfarin (INR 2-3)
  • Arterial thrombosis: warfarin +/- antiplatelet agent such as aspirin
  • Do NOT use DOACs for triple positive APLS (see TRAPS trial: rivaroxaban inferior to warfarin)
  • Hydroxychloroquine: reduces aPL levels and thrombosis risk in SLE-associated APS
  • Statins: considered in arterial APS for endothelial protection
  • Rituximab for recurrent thrombosis despite anticoagulation (controversial): call Hematology

Catastrophic APS (CAPS)

Presentation 

  • Rapid Onset: Thrombosis in ≥3 organs, systems, or tissues within a week.
  • Common Sites:
    • Kidneys (renal failure, hypertension).
    • Lungs (acute respiratory distress syndrome [ARDS], pulmonary embolism).
    • Brain (stroke, seizures, encephalopathy).
    • Heart (myocardial infarction, valve thrombosis).
    • Skin (livedo reticularis, purpura, necrosis).
    • Adrenals (adrenal insufficiency).
  • Systemic Inflammatory Response: Fever, elevated inflammatory markers (e.g., CRP, ESR), often mimicking sepsis.
  • Triggers: Identified in ~50% of cases—e.g., infection (most common), surgery, trauma, pregnancy, or anticoagulation withdrawal. - 

Criteria for definite CAPS 

  • Evidence of multi-organ involvement (3 or more)
    • Clinical or imaging evidence of thrombosis or dysfunction (e.g., CT/MRI showing stroke, renal infarcts).
  • Confirmation by histopathology of small vessel occlusion
  • Laboratory confirmation of aPL antibodies (detected on 2 occasions 12 weeks apart)
  • Absence of alternative diagnoses (Exclude mimics like TTP, HUS, DIC or HIT)

Management 

  • IV heparin and high dose steroids o For refractory cases: consider PLEX, IVIG, rituximab

Heparin-induced Thrombocytopenia (HIT)

Type 1

Non-immune, benign thrombocytopenia due to direct heparin effects.

  • Platelet drop within 1–4 days of heparin start.
  • Mild decrease (e.g., 10–30% from baseline).
  • No thrombosis or skin lesions.
  • No intervention needed; continue heparin if clinically indicated.
  • Platelet count normalizes with continued heparin therapy

Type 2

Immune-mediated, prothrombotic condition requiring urgent intervention.

  • Risk Factors: UFH > LMWH, surgical patients (especially orthopedic/cardiac), females, higher heparin doses.
  • Platelet count drops ≥50% from baseline.
    • Typical onset: 5–14 days after heparin exposure (first exposure).
    • Rapid onset: Within 24 hours if prior heparin exposure within 30–100 days (antibody persistence). -
  • Thrombosis:
    • Venous (DVT, PE) > arterial (stroke, MI, limb ischemia).
    • Unusual sites: adrenal vein (hemorrhage), skin necrosis at injection sites.
    • Occurs in 30–50% of untreated cases; risk persists 4–6 weeks post-heparin cessation.
  • Symptoms:
    • Thrombosis-related (e.g., leg swelling, chest pain).
    • Skin lesions (erythema, necrosis) in ~10%.
    • Bleeding rare unless severe thrombocytopenia

Evaluation

  • 4T score (0-8 points):
    • Thrombocytopenia (0-2 pts): degree and nadir of platelet count drop
    • Timing (0-2 pts): timing of fall after initial or recurrent heparin exposure
    • Thrombosis (0-2 pts): thrombosis, skin necrosis, non-necrotizing lesions, acute systemic reaction to heparin
    • Other causes of thrombocytopenia (0-2 pts): more points if no alternate cause
  • Interpretation: Low (0–3), Intermediate (4–5), High (6–8)
  • Screening: Anti-PF4/heparin ELISA (IgG-specific); optical density (OD) >0.4 suggests positivity (higher OD = higher risk).
  • Confirmation: Functional assay (e.g., serotonin release assay [SRA], heparin-induced platelet activation [HIPA]); >20% serotonin release confirms HIT.
    • The lab at VUMC will perform functional SRA reflexively for all values >0.2

Management

  • 0-3 points: Low concern for HIT; can restart heparin
  • 4-5 points: Intermediate probability (~10%); hold heparin, start non-heparin anticoagulant
  • 6 points: High probability (~50%); hold heparin, start non-heparin anticoagulant
  • Argatroban (direct thrombin inhibitor) for prophylaxis and treatment of thrombosis
    • Avoid platelet transfusions as can increase thrombogenic effect
    • Avoid warfarin until complete platelet recovery as may cause microthrombosis
  • Hematology consult for all confirmed HIT

Factor V Leiden Mutation

Factor V Leiden (FVL) is the most common inherited thrombophilia, caused by a point mutation (G1691A) in the F5 gene, leading to resistance of activated Factor V to inactivation by activated protein C (APC).

Evaluation

  • Screen with activated protein C resistance assay in select cases (unprovoked VTE, family history).
    • APC ratio in pt vs. normal
    • Normal >2.0, heterozygotes 1.5-2.0, homozygotes <1.5
  • Factor V Leiden mutation can then be confirmed via PCR
  • Screen with APC assay rather than PCR initially; cost effective

Management

  • VTE treatment same as general population
    • VTE 3-8x risk in heterozygotes; 50-80x risk in homozygotes
  • Avoid combined oral contraceptives/HRT; progestin-only options safer.

Prothrombin Gene Mutation

  • Evaluation: PCR of G20210A mutation (2-4% prevalence)
  • Thrombotic Risk: Primarily affects venous system; minimal impact on arterial thrombosis (e.g., stroke, MI) unless combined with other risk factors.
  • Management: Treat VTE as usual; extend anticoagulation for unprovoked/recurrent cases; prophylaxis in high-risk settings for carriers. Avoid OCPs

Protein C and S Deficiency

Background 

  • Pathophysiology: Impaired inactivation of Factors Va/VIIIa increases clotting.
  • Both are autosomal dominant; first event occurs between 10-50 years of age
  • Synthesized in liver and Vit K dependent; therefore, low levels in hepatic dysfunction and warfarin use/vitamin K deficiency
  • Protein C: low in settings of thrombosis, DIC, nephrotic syndrome, intra/post-op
  • Protein S: low in infectious (HIV) and autoimmune processes (IBD)
  • Protein S decreases during pregnancy (decreased free protein S, normal total protein S)
    • Do not misdiagnose a pregnant pt with PS deficiency

Evaluation

  • Functional Protein C and S assays

Management

  • VTE treatment same as general population
  • Avoid OCPs/HRT
  • High risk pts may require protein C concentrate prior to surgery
  • Increased risk of warfarin-induced skin necrosis

Antithrombin Deficiency

Background 

  • Autosomal dominant with variable penetrance.
  • Unprovoked VTE (DVT, PE) often <40–50 years; 50–70% lifetime risk by age 60.
  • Unusual sites: Cerebral, mesenteric, portal vein thrombosis.
  • Acquired deficiency can be caused by liver disease (decreased synthesis), nephrotic syndrome (urinary loss), DIC, or heparin therapy (consumption).
    • Transient, not genetic; managed by treating underlying condition.

Evaluation 

  • Functional antithrombin activity (AT-heparin cofactor assay)
  • Then perform antigen quantity testing

Management 

  • Treat VTE as usual; indefinite anticoagulation for unprovoked cases; prophylaxis in triggers; antithrombin concentrate for severe/homozygous cases.
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