Revisiting antithrombin in health and disease, congenital deficiencies and genetic variants, and laboratory studies on α and β forms

Transfus Apher Sci. 2018 Apr;57(2):291-297. doi: 10.1016/j.transci.2018.04.010. Epub 2018 Apr 19.

Abstract

Antithrombin [AT] is the main inhibitor for activated plasma coagulation serine esterases, inhibiting thrombin, Factors Xa and IXa, but also Factors XIIa, XIa, VIIa, kallicrein, and plasmin. Its activity is highly enhanced by heparin, through binding to the pentasaccharide sequences, for inhibition of all coagulation proteases, except thrombin, which inhibition requires its additional binding to the heparin polysaccharide chain. However, AT is the major inhibitor of thrombin in the blood circulation. Congenital or acquired deficiencies of AT expose affected patients to an increased risk of developing unprovoked and recurrent thrombo-embolic diseases. Antithrombin can be measured with various laboratory techniques, by either immunological or functional methods. Earlier, a radial immunodiffusion immunoassay allowed measurement of the protein antigenic content. Functional assays are mainly designed with Anti-Thrombin or Anti-Factor Xa chromogenic methods and are useful for detecting genetic molecular mutations with decreased inhibitory activity and contributed to study the conformational changes of antithrombin and its variants, which potentially regulate the activity of this serine protease inhibitor. These assays are not equivalent in terms of diagnosing protein abnormalities, associated with increased thrombotic incidence, and they have variable performance for reflecting impaired antithrombin binding capacity for heparin, reduced progressive inhibition of serine proteases, or accelerated switch rates to the latent and less active forms. A small proportion of AT (<10%) is present in blood in the β-form, with a lower oligosaccharide content, a lower Molecular Weight, a higher binding rate to endothelial glycosaminoglycans, and a higher anticoagulant activity, hence requiring specific laboratory methods for its measurement. The β-AT form is then of critical importance for controlling blood activation by tissue injury and preventing development of thrombo-embolic diseases. This article reviews the performance characteristics of the currently available assays, and their usefulness for monitoring the use of AT concentrates in intensive care units, disseminated intravascular coagulation or severe infections, to restore the anticoagulant protective effect of heparin by supplementing the requested AT concentration. The issues of automation, harmonization and standardization are also revisited and discussed.

Keywords: Antithrombin; Diagnostic strategy; Genetic variants; Laboratory assays; α and β-AT.

Publication types

  • Review

MeSH terms

  • Antithrombin III / administration & dosage
  • Antithrombin III / analysis*
  • Antithrombin III / genetics
  • Antithrombin III / metabolism
  • Antithrombin III Deficiency / congenital
  • Antithrombin III Deficiency / diagnosis*
  • Antithrombin III Deficiency / drug therapy
  • Antithrombin III Deficiency / genetics
  • Clinical Laboratory Techniques / methods*
  • Genetic Variation
  • Humans
  • Protein Isoforms

Substances

  • Protein Isoforms
  • Antithrombin III