• Clinical science

Hypercoagulable states


A hypercoagulable state, i.e., thrombophilia, is characterized by an increased predisposition to form blood clots. Depending on the etiology, one or more factors from Virchow's triad (stasis, hypercoagulability, endothelial damage) may be involved. Hypercoagulability may be acquired or inherited and can affect veins and/or arteries. The most common presentation is recurrent deep venous thrombosis of the lower extremities and pulmonary embolism. Arterial involvement increases the risk of myocardial infarction, stroke, and spontaneous abortion. Evaluation for hypercoagulability includes assessment of potential risk factors (e.g., immobilization, smoking, oral contraceptive use, and malignancy) and laboratory tests to assess anomalies of the clotting cascade (e.g., factor V Leiden, antiphospholipid antibody syndrome). Treatment is based on the underlying condition and typically includes a reduction of risk factors and/or the administration of anticoagulants.


The etiology of thrombophilia can be classified into two categories:




Clinical features

Thrombophilia is characterized by recurrent thromboembolisms.


Hereditary thrombophilia

Defect Pathophysiology Prevalence in general population

Activated protein C resistance (APC-R)

Factor V Leiden

Heterozygosity: ∼ 5%
Homozygosity: < 1%
Elevated factor VIII
  • In combination with factor IXa, factor VIIIa activates factor X → increases thrombotic events.
∼ 5%
Prothrombin mutation ∼ 3%
Protein S deficiency
  • Normally, endothelial cells express thrombomodulin, which binds activated thrombin → activates protein C → complexes with protein S to inhibit factor Va and factor VIIIa (both procoagulant factors in the clotting cascade).
  • A deficiency of protein S results in overactivity of factors V and VIII (factor Va and factor VIIIa) → increases thrombotic events.
∼ 1%
Protein C deficiency

< 1%

Antithrombin III deficiency ∼ 0.1%


  • Changes in thrombomodulin function are due to increased activation of factor VIIa and V, inhibition of protein C, increased blood viscosity, and decreased endothelial antithrombotic activity.
  • Homocysteine levels are elevated in patients with vitamin B6 deficiency and mutations in enzymes that metabolize homocysteine (autosomal recessive).

∼ 5–7%


Acquired thrombophilia

Etiology Pathophysiology
  • Extended immobilization during procedure → blood stasis
  • Vessel instrumentation → endothelial damage
  • Results in decreased venous blood flow, immobilization (blood stasis), and release of tissue factor (hypercoagulability) → increased clotting


  • Cancers excrete procoagulant factors (e.g., tissue factor and cancer procoagulant).
  • The risk of thromboembolism is highest during first hospitalization and initiation of chemotherapy.


  • Prolonged immobilization (e.g., extended travel, hospitalization, bed rest) → increased venous stasis
  • Causes endothelial damage
  • The risk is significantly higher in women who also use oral contraceptives.
  • Leads to chronic systemic inflammation and impaired fibrinolysis
  • The risk of thromboembolism increases with increasing BMI.

Antiphospholipid syndrome

  • Acquired antibodies directed against plasma proteins bound to phospholipids (e.g., lupus anticoagulant, anti-cardiolipin, beta2-glycoprotein I antibodies) → aggregation of plasma proteins (e.g., clotting factors) → induces venous and arterial clotting
  • Associated with miscarriages, DVTs, portal vein thrombosis, and strokes

Nephrotic syndrome

  • Loss of plasma antithrombin in urine and an increase in blood viscosity due to extravasation of fluid from albumin loss in urine

Oral Contraceptive Pills (OCPs) or Hormone Replacement Therapy (HRT)

Heparin-induced thrombophilia
  • Antibodies against platelet factor 4 (PF-4) → increased activation of platelets (hypercoagulability) and a depletion of platelets
  • Clotting factors increase (hypercoagulability)
  • Protein C and protein S decrease
  • Venous return from lower body slows (stasis) as the uterus enlarges
Advanced Age
  • Progressive endothelial damage
  • Increase in pro-clotting factors without a concomitant increase in protein C
  • Increase in other pro-clotting comorbidities (e.g., malignancy)
  • Decreased physical activity






  • Anticoagulant administration: (therapeutic heparin bridged to warfarin): for pulmonary embolus or deep vein thrombosis
    • 1st episode: 3 months
    • 2nd episode: minimum of 6 months
    • > 3 events: lifetime anticoagulation
  • Consider an inferior vena cava filter if anticoagulant therapy is contraindicated.
  • Reduce risk factors

Special considerations

The risk of venous thromboembolism is reduced with administration of an anticoagulant (e.g., heparin) following surgery!



Consider prophylaxis in the following high-risk groups:

  • Postoperative patients
  • Prolonged immobilization or hospitalization
  • Malignancy
  • Orthopedic conditions