TY - CHAP M1 - Book, Section TI - Antithrombin Deficiency A1 - Tollefsen, Douglas M. A2 - Valle, David L. A2 - Antonarakis, Stylianos A2 - Ballabio, Andrea A2 - Beaudet, Arthur L. A2 - Mitchell, Grant A. PY - 2019 T2 - The Online Metabolic and Molecular Bases of Inherited Disease AB - Antithrombin is a 58-kDa glycoprotein that is present in human plasma at a concentration of ~2.6 μM. It inhibits several activated coagulation factors, including thrombin, factor IXa, and factor Xa. Inhibition occurs by formation of a stable 1:1 complex between antithrombin and the protease.Heparin and heparan sulfate increase the rate of the antithrombin-protease reaction at least 1000 times by a catalytic mechanism that requires binding of the glycosaminoglycan chain to antithrombin. The binding site for antithrombin is a specific pentasaccharide sequence that contains an unusual 3-O-sulfated glucosamine residue. This structure occurs in ~30 percent of heparin molecules isolated from mast cells and in 1 to 10 percent of heparan sulfate molecules synthesized by vascular endothelial cells. Current evidence suggests that heparan sulfate proteoglycans anchored in the vessel wall interact with circulating antithrombin to inhibit thrombus formation.Antithrombin deficiency (MIM 107300) is present in ~2 percent of patients with venous thromboembolic disease, in whom it is generally inherited as an autosomal dominant trait. The prevalence of symptomatic antithrombin deficiency is estimated to range from 1 per 2000 to 1 per 5000 in the general population. Affected heterozygous individuals have ~50 percent of the normal plasma antithrombin activity. Deficiency results from mutations that affect the biosynthesis or stability of antithrombin and hence lower the amount of antithrombin antigen detectable in plasma, or from mutations that affect the protease and/or heparin-binding sites and are associated with essentially normal levels of antithrombin antigen. Mutations confined to the heparin binding site appear to be more common than the other types of mutations and are usually asymptomatic unless present in a homozygous state.Clinical manifestations of antithrombin deficiency include deep vein thrombosis and pulmonary embolism. Thrombosis may occur spontaneously or in association with pregnancy, trauma, or surgery. Arterial thrombosis is rare. Many patients experience recurrent thromboembolic disease beginning in early adulthood. It has been estimated that by 30 years of age ~60 percent of patients with antithrombin deficiency will have had at least one thrombotic episode. Acute episodes are generally treated with a 5- to 7-day infusion of heparin followed by oral anticoagulant therapy for an indefinite period of time. Prophylactic therapy of asymptomatic patients remains controversial.Heparin cofactor II, which is homologous to antithrombin, inhibits thrombin in the presence of heparin or dermatan sulfate but does not inhibit other coagulation proteases. The concentration of heparin cofactor II in plasma is normal (~1.2 μM) in patients with inherited antithrombin deficiency. Several patients with thrombosis and inherited deficiency of heparin cofactor II have been reported (MIM 142360), but a causal relationship between these phenomena has not been established. SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/10/05 UR - ommbid.mhmedical.com/content.aspx?aid=1181455807 ER -