Pathophysiology And Types

Pathophysiology and Types

Antithrombin (also called antithrombin III) is a 432-amino-acid plasma glycoprotein synthesized in the liver that acts as a serine protease inhibitor (serpin). It primarily inhibits thrombin (factor IIa) and factor Xa, as well as factors IXa, XIa, and XIIa, thereby preventing excessive clot formation. The anticoagulant activity of antithrombin is markedly accelerated by heparin.

Deficiency is classified into two types:

  • Type I (quantitative): Reduced synthesis leads to low antithrombin antigen and activity levels.
  • Type II (qualitative): Normal antigen levels but impaired functional activity due to structural abnormalities.
  • The condition is inherited in an autosomal dominant pattern, most commonly due to mutations in the SERPINC1 gene. Heterozygous deficiency has a prevalence of approximately 0.02% to 0.2%, with about half of affected individuals developing venous thromboses.

Clinical Presentation

Individuals with antithrombin deficiency are at substantially increased risk for venous thromboembolism, including deep vein thrombosis (DVT) of the lower extremities and pulmonary embolism (PE). Arterial thrombosis (stroke, myocardial infarction) is less common but can occur.

Pregnancy and the postpartum period confer particularly high thrombotic risk in affected women, with increased rates of pregnancy-related complications. Acquired reductions in antithrombin levels may also occur in liver disease, nephrotic syndrome, disseminated intravascular coagulation, malnutrition, or with oral contraceptive use.

Diagnosis and Management

Diagnosis involves measuring antithrombin activity and antigen levels, along with genetic testing for SERPINC1 mutations when indicated. Routine coagulation tests (PT, PTT, thrombin time) are typically normal.

Treatment focuses on thrombosis prevention and management:

  • Anticoagulation: Direct oral anticoagulants or warfarin for long-term management in patients with prior venous thromboembolism.
  • Heparin: Used for acute thrombosis, though higher doses may be required due to reduced antithrombin availability.
  • Antithrombin concentrate: Administered perioperatively or peripartum in high-risk situations to restore antithrombin levels.
  • Lifestyle modifications: Weight management, regular exercise, smoking cessation, and avoidance of pro-coagulant states (e.g., oral contraceptives, hormone replacement therapy).
  • Patients without a history of thrombosis generally do not require prophylactic anticoagulation but should receive thromboprophylaxis during high-risk periods such as surgery or pregnancy.