Antithrombin Deficiency

Antithrombin Deficiency is a topic covered in the 5-Minute Clinical Consult.

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Basics

Description

  • Antithrombin is a protease inhibitor that inhibits multiple proteins in the coagulation cascade. Most notably, antithrombin inhibits thrombin (factor IIa) by forming an irreversible complex.
  • There are two active sites: one that binds to heparin and one that binds to thrombin/target enzyme.
  • Antithrombin can also inhibit factors Xa, IXa, and XIa. This process is catalyzed by the presence of heparin.
  • Patients deficient in antithrombin have an increased incidence of venous thrombosis, including deep vein thrombosis (DVT) of the lower extremity. Arterial thrombosis is much less common in patients deficient in antithrombin.
  • System(s) affected: cardiovascular, nervous, pulmonary, reproductive, hematologic, lymphatic/immunologic
  • Synonym(s): antithrombin III deficiency

Epidemiology

  • Predominant age: Mean age of first thrombosis is in 2nd decade, usually after puberty.
  • Predominant sex: male = female
  • No racial or ethnic predisposition

Incidence
1/20 to 1/200 with thrombophilia (1)

Prevalence
1/500 to 1/5,000 of normal individuals (2)

Etiology and Pathophysiology

  • Hereditary deficiency
    • Type I deficiency is characterized by low levels of antigen (decreased synthesis). Plasma levels of antithrombin are often <50% (3).
    • Type I deficiency is associated with a more severe clinical phenotype (2).
    • Type II deficiency is found when the antithrombin molecule is dysfunctional (decreased function) (3).
    • Type II deficiencies are due to mutations in either the active center of antithrombin that binds the target enzyme or the heparin-binding site (3).
    • Up to 80% of patients with antithrombin deficiency have SERPINC1 gene mutation (2).
    • No patients homozygous for defects in the active center have been described, suggesting that this is a lethal condition. Patients heterozygous for mutations in the heparin-binding site rarely have thrombotic episodes (3).
  • Acquired deficiency (3)
    • Many clinical conditions are associated with antithrombin deficiency, such as those listed under “Follow-Up Tests & Special Considerations,” but limited evidence suggests these deficiencies contribute to increased thrombosis.

Genetics
Autosomal dominant with variable clinical penetrance

Risk Factors

  • Oral contraceptives, pregnancy, surgery, trauma, and the use of hormone replacement therapy (HRT) increase the risk of venous thrombosis in patients with antithrombin deficiency.
  • Patients with antithrombin deficiency and another prothrombotic state, such as factor V Leiden or the prothrombin G20210A mutation, have increased rates of thrombosis.

Pregnancy Considerations
Increased thrombotic risk from 18% to 70% and specific complications may include preeclampsia, eclampsia, placental abruption, HELLP, premature birth, and recurrent pregnancy loss (4).

General Prevention

Patients with antithrombin deficiency without a history of thrombosis do not require prophylactic treatment.

Commonly Associated Conditions

Venous thromboembolism

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