What are the causes of hypercoagulable states?

Causes of Hypercoagulable States

Hypercoagulable states are primarily caused by inherited genetic mutations affecting coagulation factors and acquired conditions that promote thrombosis, with antiphospholipid syndrome being the most common acquired cause and Factor V Leiden and prothrombin G20210A mutations being the most common inherited causes.

Inherited Hypercoagulable States

Inherited thrombophilias are genetic abnormalities that increase the risk of thrombosis through various mechanisms:

• Factor V Leiden mutation: One of the two most common genetic causes of thrombophilia, increasing the risk of venous thromboembolism 2-10 times 1

• Prothrombin G20210A mutation: The second most common genetic thrombophilia, with particularly high risk when combined with other factors such as PFO (OR 10.09) 1

• Deficiencies of natural anticoagulants:

  • Protein C deficiency (increases thromboembolism risk 16.2 times) 1
  • Protein S deficiency (increases thromboembolism risk 16.2 times) 1
  • Antithrombin III deficiency (increases thromboembolism risk 18.4 times) 1

• Other inherited factors associated with stroke:

  • Fibrinogen level abnormalities
  • β-chain–455 G/A fibrinogen
  • Factor VIII elevations
  • Factor XIII Val34Leu
  • von Willebrand factor polymorphisms
  • Tissue-type plasminogen activator −7351 C/T 1

Acquired Hypercoagulable States

Acquired conditions that promote a hypercoagulable state include:

• Antiphospholipid syndrome (APS): The most common acquired cause of thrombophilia 1

  • Characterized by lupus anticoagulant and anticardiolipin antibodies
  • Increases risk of both arterial and venous thrombosis
  • High-risk profile (positive lupus anticoagulant, positive aCL, and positive β2GPI) has 5.3% annual thromboembolism rate 1

• Malignancy: Present in 7.4% of cerebral venous thrombosis cases 2

  • Particularly hematological neoplasms
  • Can cause thrombosis through direct compression, invasion, or hypercoagulable state

• Pregnancy and puerperium: Second most common predisposing factor after hypercoagulable states 2

• Oral contraceptive use: Increases cerebral venous thrombosis risk 5.6-15.9 times 2

  • Risk dramatically higher when combined with prothrombotic disorders:
    • With Factor V Leiden: OR 30.0
    • With prothrombin mutation: OR 79.3

• Myeloproliferative disorders:

  • Polycythemia vera
  • Essential thrombocytosis
  • Most common cause of Budd-Chiari syndrome (hepatic vein occlusion) 1

• Autoimmune diseases:

  • Systemic lupus erythematosus
  • Inflammatory bowel disease
  • Behçet's disease 2

• Other acquired conditions:

  • Hyperhomocysteinemia (can be hereditary or acquired)
  • Heparin-induced thrombocytopenia
  • Thrombotic thrombocytopenic purpura
  • Infections (especially parameningeal infections and meningitis)
  • Dehydration (particularly in children)
  • Iron deficiency anemia
  • Chronic hemolytic anemia
  • Diabetes mellitus 2, 3, 4

Clinical Implications

The risk of thrombosis is often multifactorial, with inherited and acquired factors combining to exceed a critical threshold for thrombosis. Important considerations include:

• Venous thromboembolism occurs in about 50% of cases during high-risk periods (surgery, pregnancy, immobilization) 5

• Hypercoagulable states may be more frequent in stroke patients with patent foramen ovale (PFO) than those without 1

• Children have different risk profiles, with 20-50% of pediatric arterial ischemic stroke and 33-99% of cerebral venous thrombosis cases showing prothrombotic abnormalities 1

• Thrombophilia screening for primary prevention of venous thromboembolism is generally not indicated except in specific high-risk scenarios 1

Understanding the specific cause of hypercoagulability is essential for determining appropriate preventive strategies and treatment approaches, which may include anticoagulation, antiplatelet therapy, or treatment of underlying conditions.