Olav Egeberg,
a Norwegian physician,
was the first to describe a family in which several members experienced venous thrombosis.

Men and women are
equally affected.

What is Hereditary Antithrombin Deficiency?

	Technical Discussion Anticoagulant Properties of Antithrombin The principal natural anticoagulant systems that are able to exert damping effects on multiple steps of the coagulation cascade are the heparin-antithrombin and protein C-thrombomodulin mechanisms, which respectively regulate the serine proteases and the cofactors or activated cofactors [1]. Antithrombin (AT), a serine protease inhibitor (serpin), also known as antithrombin III or AT-III, is the main regulator of many serine proteases generated during activation of the clotting cascade.   AT is a 58 kilodalton single-chain glycoprotein with a plasma concentration of approximately 150 µg/ml (2-3 µM).   It is composed of 432 amino acids, carries four N-linked oligosaccharide chains and has three disulfide bonds.  In the presence of heparin, it is not only a strong inhibitor of thrombin and factor Xa, but it is an equally effective inhibitor of factors IX, as well as, to a lesser extent, factors XIa, XIIa, trypsin, plasmin, kallikrein, and factor VIIa [2-9].  This broad-spectrum inhibitory action of antithrombin makes it a central regulator of the coagulation system.  AT has also been demonstrated to have anti-inflammatory properties independent of its inhibition of serine proteases of the coagulation cascade. Heparin, the first-line anticoagulant in cardiovascular medicine, works as an anticoagulant because its binding to AT induces an AT conformational change, making AT more than a thousand-fold more active towards thrombin [10].   AT forms a 1:1 stoichiometric complex with thrombin via a reactive site (arginine)-active center (serine) interaction.  Once the equimolar thrombin-antihrombin (TAT) complex is formed, both molecules are incapacitated.  The short-lived TAT complex, with a 5-minute half-life, is then removed by a hepatic receptor identified as the LDL Receptor-related protein [11, 12]. Since, for the inactivation of thrombin, heparin must specifically attach to thrombin while simultaneously binding AT, unfractionated high molecular weight formulations of heparin that contain multiple pentasaccharide AT binding sites are effective in activating AT's thrombin inhibition.  This simultaneous interaction with heparin is not needed for AT to inactivate other serine proteases such as factor Xa or the contact factors.   This explains why low molecular weight heparin fails to directly inhibit thrombin yet is active against other coagulation factors [13]. AT Deficiency: Introduction Hereditary antithrombin deficiency (HD) was first described by Egeberg in 1965 [14].  A Norwegian patient and members of his family had recurrent venous thrombosis associated with about half-normal levels of AT. Following this first report, several groups reported individual patients and families with thrombosis associated with AT deficiency [15-29]. The inheritance pattern of the congenital abnormality was found to be autosomal dominant and was primarily associated with venous thromboses.  The patients are generally heterozygous, with AT levels of 40 to 60% of normal.  Very few homozygotes have been described [30, 31].  Two siblings with homozygous AT deficiency died 3 weeks after birth from a syndrome similar to purpura fulminans neonatorum produced by protein C deficiency. It is probable that complete absence of AT activity is incompatible with human life.  In knock-out mice, it causes intrauterine death from an extreme hypercoagulable state associated with consumptive coagulopathy [32]. Molecular Basis of AT Deficiency Extensive genetic analyses using AT deficiency cases assigned the AT locus to chromosome 1 [34, 34].   Isolation of the cDNA for human AT [35, 36] led to a molecular analysis of the mutations associated with AT deficiency.   The molecular defects underlying inherited AT deficiency have been reviewed extensively [37-40] and a database has been generated [41]. Type I deficiency is a true physiologic deficiency characterized by reduced levels (~ 50%) of immunologically and functionally determined antithrombin; both activity and antigen are low.  The molecular basis of this type of disorder is characterized either by alterations of the AT gene, such as nonsense or missense mutations, or by the deletion of a large segment of the gene. Type II deficiency is characterized by reduced functional AT but not AT antigen levels and approximately 50% of antithrombin is provided by a variant protein.  These types of AT deficiencies are produced by discrete molecular defects within the AT protein generally caused by missense mutations of the AT gene. The variants may have functional abnormalities of the reactive site (RS) or the heparin-binding site (HBS).   In other cases the mutations causing these deficiencies have been classified as Type II PE since they comprise multiple (pleiotropic) functional abnormalities affecting the reactive site, the heparin-binding site and the plasma concentration.  Type II HBS variants are not generally associated with increase risk of thrombosis unless the individual is homozygous [42].  Type II RS variants exhibit abnormal binding of AT to factor Xa and thrombin and can exhibit a very high incidence of thrombosis. AT Deficiency and "High-Risk Situations" AT deficiencies are characterized by distinct thromboses in the venous system, in the extremities, as well as the mesenteric, renal, hepatic, portal veins and vena cava [44].  In one analysis, more than half of Type I HD patients suffered at least one thrombotic event [43]. A retrospective study [45] assessing the risk of thrombosis in patients with HD established that the probability of developing thrombosis by 60 years of age was more than 80%.  AT-deficient women had a high thrombotic risk associated with pregnancy (up to 40%) with the use of contraceptive [45].  This confirms other findings [45-48] that indicated an early onset of venous thromboembolism and a 50-fold increase in the prevalence of HD patients suffering a first DVT event compared with the healthy population.  A large proportion, 42%, of these thrombotic events occurs spontaneously.  The remainder are associated with "high-risk situations" such as: surgery, pregnancy, delivery, trauma, and/or use of oral contraceptives. Surgery increases the risk of thromboembolism due to a number of factors such as blood loss, immobilization, etc.   Risk is further increased in procedures that are associated with significant tissue damage and hemorrhage [49], such as hip and knee replacements.  In these cases, in the absence of prophylaxis, the prevalence of thromboembolism has been estimated to range from 40% to 84% in non-thrombophilic patients [50]. Pregnancy is a risk because it is typically a hypercoagulable state, due to a physiologic increase in coagulation factors and a decrease in fibrinolytic activity [51].  Therefore, pregnant women with HD are often given anticoagulant prophylaxis.  Warfarin is usually avoided during the first 3 months of pregnancy due to its teratogenic potential, and during the last week of pregnancy due to the bleeding risk for the fetus [52-56].   Heparin is often the anticoagulant of choice for these patients, as it does not cross the placenta.  However, when heparin is used in AT deficient patients, heparin resistance may occur.  This may be managed by using high doses of heparin or using AT concentrates along with fractionated or unfractionated heparin [51].

What is the Disease Profle for HD?

References