• Clinical science

Hypercoagulable states

Abstract

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.

Etiology

The etiology of thrombophilia can be classified into two categories:

Hereditary

Acquired

References:[1]

Clinical features

Thrombophilia is characterized by recurrent thromboembolisms.

References:[2][3]

Hereditary thrombophilia

  • The hereditary thrombophilias below follow an autosomal dominant inheritance pattern, with the exception of hyperhomocysteinemia.
  • Very rare: hereditary plasminogen deficiency, dysfibrinogenemia
Defect Pathophysiology Prevalence in general population Risk of thromboembolism

Activated protein C resistance (APC-R)

Factor V Leiden

  • Normally, activated protein C inactivates factor V in the clotting cascade → decreases the activation of thrombin.
  • However, in patients with these defects, factor V remains active → activates prothrombin → increases thrombotic events.
Heterozygosity: ∼ 5%

Heterozygosity: 8x higher

Homozygosity: < 1% Homozygosity: 80x higher
Elevated factor VIII
  • In combination with factor IXa, factor VIIIa activates factor X → increases thrombotic events.
∼ 5% 7x higher
Prothrombin mutation ∼ 3% Heterozygosity: 3x higher

Homozygosity: 50x higher

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 VII factor Va and factor VIIIa → increases thrombotic events.
∼ 1% 10x higher
Protein C deficiency

< 1%

10x higher
Antithrombin III deficiency ∼ 0.1% > 10x higher

Hyperhomocysteinemia

  • 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%

∼ 2x higher

References:[4][5][6][7][8]

Acquired thrombophilia

Etiology Pathophysiology Risk of thromboembolism
Surgery
  • Extended immobilization during procedure → blood stasis
  • Vessel instrumentation → endothelial damage

Operative risk (OR):∼ 1.2x higher/hr of surgery

Trauma
  • Results in decreased venous blood flow, immobilization (blood stasis), and release of tissue factor (hypercoagulability) → increased clotting

Lower extremity fracture OR: ∼ 1.9x higher

Head injury OR:∼ 1.2x higher

Ventilator days > 3OR: ∼ 8.08x higher

Major operative procedure OR: 1.5x higher

Malignancy

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

Cancer alone: ∼ 4.1x higher

Chemotherapy: ∼ 6.5x higher

Immobilization

  • Prolonged immobilization (e.g., extended travel, hospitalization, bed rest) → increased venous stasis

∼ 1.9x higher

Smoking
  • Causes endothelial damage
  • The risk is significantly higher in women who also use oral contraceptives.

Only smoking: ∼ 1.3–3.3x higher

With OCPs: ∼ 8.8x higher

Obesity

∼ 2.5x higher

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

Lupus anticoagulant OR: ∼ 5.6x higher

Anti-cardiolipin antibodies OR: ∼ 2.2x higher

Nephrotic syndrome

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

∼ 1.7x higher

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

Combined OCP OR: ∼ 3.5x higher

HRT OR: ∼ 1.2x higher

Heparin-induced thrombophilia

∼ 30x higher

Pregnancy
  • Clotting factors increase (hypercoagulability)
  • Protein C and protein S decrease
  • Venous return from lower body slows (stasis) as the uterus enlarges

> 5x higher per hour of surgery

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

Increases exponentially with age

References:[3][9][10][11]

Diagnostics

References:[2]

Treatment

Approach

  • 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!

References:[1][12][13]

Prevention

Consider prophylaxis in the following high-risk groups:

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