ANTITHROMBIN AND ITS INHERITED DEFICIENCIES

Human antithrombin is the major inhibitor of the coagulation serine pr oteases accounting for similar to 80% of the thrombin inhibitory activ ity of plasma. It is a member of the serpin family of serine protease inhibitors and in common with some other members of this family it und ergoes a dramatic increase in its inhibitory activity in the presence of heparin and other sulphated glycosaminoglycans. Two functional doma ins in antithrombin are recognised, the reactive site domain which int eracts with the active site serine residue of the protease and the hep arin binding domain. The gene for antithrombin has been cloned and its entire nucleotide sequence determined. A deficiency or functional abn ormality of antithrombin may result in an increased risk of thromboemb olic disease. Such deficiencies are estimated to affect as many as 1:3 00 of the general population of 3 to 5% of patients with thrombotic di sease. On the basis of functional and immunological antithrombin assay s, antithrombin deficiency may be subdivided into types I and II. Type I disease is due to a wide variety of heterogeneous DNA mutations whi lst in Type II disease missense mutations leading to single amino acid substitutions have been identified in all cases. Clinically, Type I a ntithrombin deficiency is associated with recurrent thromboembolic dis ease whereas in Type II deficiency the risk of thrombosis is closely r elated to the position of the mutation within the protein. Thus, heter ozygotes with mutations within the heparin binding domain of antithrom bin have a relatively low risk of thrombosis compared to those with mu tations at or close to the reactive site of the molecule.