Antithrombin III is Not a Prothrombin Gene Mutation
No, antithrombin III (ATIII) is not a prothrombin gene mutation but rather a distinct protein in the natural anticoagulant system that functions as a serine protease inhibitor (SERPIN). 1, 2
Understanding Antithrombin III
Antithrombin III is a key component of the body's natural anticoagulant system with the following characteristics:
- ATIII is a serine protease inhibitor (SERPIN) that acts as a pseudosubstrate to irreversibly inhibit thrombin by covalently binding to the thrombin enzymatic active site 1
- It is produced mainly in the liver and the mature molecule consists of 432 amino acids 2
- ATIII inhibits multiple activated coagulation factors including thrombin, factor Xa, factor IXa, factor XIa, factor XIIa, kallikrein, and plasmin 2
- The rate of thrombin inhibition by antithrombin III is markedly increased by glycosaminoglycans such as heparin 1
Distinction from Prothrombin Gene Mutations
Antithrombin III differs from prothrombin gene mutations in several important ways:
- The ATIII gene is located on chromosome 1q23-25, while the prothrombin gene is located elsewhere 3
- Prothrombin gene mutation (specifically the 20210A variant) is a single nucleotide change in the 3' untranslated region of the prothrombin gene that results in elevated circulating prothrombin levels 1
- ATIII deficiency is caused by various mutations in the ATIII gene, not by mutations in the prothrombin gene 2, 3
- The ATIII gene contains six exons and five introns distributed over approximately 19 kilobases of DNA, with a structure that differs from other members of the serine protease inhibitor superfamily 4
Clinical Significance of Antithrombin III
Understanding the distinction between ATIII and prothrombin gene mutations is clinically important:
- Deficiencies of ATIII are associated with increased risk of venous thromboembolism 1, 2
- ATIII deficiency can be hereditary or acquired (due to conditions like severe hepatic dysfunction, nephrotic syndrome, or intravascular coagulation) 5
- Testing for ATIII deficiency is typically done through functional or immunological assays rather than genetic testing, as numerous mutations can cause ATIII deficiency 2
- When evaluating patients for thrombophilia, it's important to test for multiple risk factors including ATIII deficiency, protein C and S deficiencies, factor V Leiden, and prothrombin 20210A mutations, as many patients have more than one risk factor 6
Testing Considerations
When evaluating thrombophilia, healthcare providers should consider:
- ATIII amidolytic assays are recommended for initial testing for ATIII deficiency 2
- Immunological assays for ATIII are useful to distinguish between type I (reduced protein levels) and type II (dysfunctional protein) hereditary ATIII deficiency 2
- Patients testing positive for one thrombophilic factor (such as factor V Leiden) should be considered for testing of other common thrombophilias, including functional coagulation assays for antithrombin III, protein C, and protein S 1
- The "multiple hit" concept of thrombophilia suggests that laboratory screening should include all known genetic risk factors even if the clinical situation seems to provide sufficient explanation for a thrombotic event 6