MOLECULAR-GENETICS OF ANTITHROMBIN DEFICIENCY

Antithrombin is the major proteinase inhibitor of thrombin and other b lood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inac tivates the proteinase). Its deficiency results in an increased risk o f venous thromboembolism, Appreciable progress has been made in recent years in understanding the structure and function of this protein, th e genetic cause of inherited deficiency and its clinical consequence, The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive l oop. The structural organization of the antithrombin gene has been def ined and numerous mutations have been identifed that are responsible f or antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II defici ency, altering heparin binding or reactive sites), or even have multip le or 'pleiotropic effects' (Type II deficiency, altering both functio nal domains and the level of protein).