Mutational Analysis in Antithrombin Deficiency

Human antithrombin is a single-chain glycoprotein of MW 58 kDa and the most important plasma inhibitor of the coagulation serine proteases. It is a member of the serine protease inhibitor (SERPIN) family of proteins and in common with several other members of this family, its inhibitory activity is increased many thousand-fold in the presence of heparin and other sulphated glycosaminoglycans. Type I antithrombin deficiency, i.e., a 50% reduction in the total amount of plasma antithrombin is estimated to affect approx 1 in 4200 of the general population, whereas Type II deficiency—characterized by the presence of a dysfunctional protein in the plasma of affected individuals, which may be present in normal or reduced amounts—may affect as many as 1 in 600. Approximately 4–6% of individuals with thromboembolic disease will have antithrombin deficiency. A deficiency of antithrombin or a functional abnormality is a recognized cause of recurrent thromboembolic disease, although the risk is dependent upon the precise molecular abnormality. Individuals with Type I antithrombin deficiency or with mutations affecting the reactive site of the molecule or with multiple (pleiotropic) functional abnormalities are at high risk of venous thromboembolic disease, while those with mutations affecting the heparin binding domain are at relatively low risk from thrombosis.