SCIENTIFIC BACKGROUND

SERPINC1

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SCIENTIFIC BACKGROUND

Antithrombin (also known as antithrombin III (ATIII)) is one of the most important factors of the coagulation system with anticoagulant activity. It belongs to the serine protease inhibitor family and is synthesized by hepatocytes. Antithrombin is encoded by the gene SERPINC1. The two most significant domains of the protein are the thrombin-binding domain and a specific domain for binding heparin. An antithrombin deficiency results in decreased inhibition of procoagulant factors. As a result, patients with hereditary antithrombin deficiency have up to a 50-fold increased risk of venous thrombosis. The mode of action of antithrombin is mainly based on the inhibition of thrombin. Other interaction partners involved in coagulation that are inactivated by complex formation are factor IXa, factor Xa, factor XIa, and factor XIIa. The inhibitory response is enhanced by a factor of at least 1,000 by the cofactor heparin or interaction with endothelial heparin sulfate. Therefore, the lack of efficacy of heparin therapy or the need for higher dosing may indicate antithrombin deficiency.

 

Antithrombin deficiency is usually inherited in an autosomal dominant manner since homozygous or combined heterozygous alterations in SERPINC1 are largely lethal in utero. The prevalence in the population is estimated to be 1:500 to 1:5,000. Based on functional and immunochemical antithrombin analyses, antithrombin deficiency is divided into two distinct types:

  • Type I: quantitative defect, reduced antithrombin as well as antithrombin activity (caused by a synthesis defect, e.g., deletion, insertion, or splice site variant)
  • Type II: qualitative defect, decreased antithrombin activity at normal plasma concentration (caused by a structural defect, e.g., amino acid exchange in the thrombin or heparin-binding domain)

 

Maintenance of adequate antithrombin activity of at least 70% of normal functional levels is essential to ensure effective inhibition of blood coagulation proteases. Typically, functional antithrombin levels are reduced to below 50% of normal due to type I or type II antithrombin deficiency. Risk factors that may intensify the effect of hereditary antithrombin deficiency include pregnancy, smoking, and contraceptive use. Genetic analysis of the SERPINC1 gene is strongly recommended when hereditary antithrombin deficiency is suspected, as a significant proportion of patients escape diagnosis by activity assays, and variants in SERPINC1 are detected in 80% of patients. In addition to the hereditary form, decreased antithrombin synthesis in the liver, e.g., due to liver cirrhosis, can lead to acquired antithrombin deficiency. Diseases such as nephrotic syndrome and disseminated intravascular coagulopathy can also lead to the reduction of antithrombin.

 

References

Mulder et al. 2017, Br. J. Haematol 178:279 / Zeng et al. 2015, Thromb Haemost 113.2:262 / Cooper et al. 2012, Semin Thromb Haemost 38:600 / de la Morena-Barrio et al. 2012, Thromb Haemost 107.3:430

GENES
SERPINC1
ASSOCIATED TESTS
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