Antithrombin deficiency

Nakahara Y., Tsuji H Nakagawa K et al. Genetic analysis in Japanese kindreds of congenital type I antithrombin deficiency causing thrombosis. Thromb Haemost 1997 77,616-9. 

Plasma-derived antithrombin concentrates have been used medically since the 1980s for the treatment of hereditary and acquired antithrombin deficiency. Hereditary (genetic) deficiency is characterized by the presence of little/no native antithrombin activity in plasma and results in an increased risk of inappropriate blood clot/emboli formation. Acquired antithrombin deficiency can be induced by drugs (e.g. heparin and oestrogens), liver disease (decreased antithrombin... 

Antithrombin and activated protein C concentrates are available for the appropriate indications that include thrombosis in the setting of antithrombin deficiency and sepsis respectively. 

Data from the Leiden Thrombophilia Study have been used to construct a case-control study, based on contraceptive users who had experienced a first episode of objectively proven deep vein thrombosis (100). Patients and controls were considered thrombophilic when they had protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, or a prothrombin 20210 A mutation. Among healthy women, the risk of developing deep vein thrombosis was trebled in the first 6 months and doubled in the first year of contraceptive use. Among women with thrombophilia, the risk of deep vein thrombosis was increased 19-fold during the first 6 months and 11-fold (95% Cl = 2.1, 57) in the first year of use. Venous thrombosis during the first period of oral contraceptive use might actually point to the presence of an inherited clotting defect. 

Deficiency of antithrombin predisposes the patient to thrombotic complications. Antithrombin deficiencies can be the result of low protein levels or due to functionally abnormal molecules. Low protein levels can be brought about by reduced synthesis or an increased turnover of the molecule, Functional deficiencies can be brought about by mutations in either the reactive site or heparin binding sites, A number of such mutations have been documented (81,86,87),... 

The hypercoagulable states can be inherited or acquired. One inherited hypercoagulable state is antithrombin (AT) deficiency. AT deficiency is an autosomal dominant condition. The type I antithrombin deficiency is characterized by reduced synthesis of normal protease inhibitor molecules. The antigenic and functional activities of antithrombin are reduced due to small deletions or insertions or single base substitutions. Type II antithrombin deficiency is due to defects within the protease inhibitor. While the immunologic activity levels are normal, the plasma levels of antithrombin are reduced. About 42% of afflicted individuals develop clinical manifestations spontaneously. Manifestations related to pregnancy, parturition, oral contraceptives, or trauma occur in 58% of AT deficient individuals (190). 

The inherited (primary) hypercoagulable states include activated protein C resistance due to the factor V Leiden mutation, prothrombin gene mutation, antithrombin deficiency, protein C or protein S deficiency, and dysfibrino-genemia. The most important cause of activated Protein C resistance is the defect in factor V involving the mutation of Arg506 to Gln506 (191). 

Resistance to heparin. Patients with antithrombin deficiency require large doses of heparin therapy for anticoagulant effect. (The action of heparin is dependent on the presence of antithrombin in the plasma.)... 

Proteinase Inactivation Antithrombin Deficiency-homozygous-only with 1 per 5,000 to 1 125 2.3 Liver 61-92 lANT, lATH, ANT3 HUMAN... 

Many patients with acute VTE and myocardial infarction have a diminished response to heparin, presumably because of variations in the plasma concentrations of heparin-binding proteins. Some patients have been reported to have acute elevations in factor VIII, preventing the prolongation of the aPTT by UEH. In some cases, antithrombin deficiency may be the culprit. The recommended management of patients with heparin resistance is to adjust the UEH dose based on anti-factor Xa concentrations. Approximately 50% of patients with this heparin resistance have dissociation between aPTT and heparin concentration as a result of an elevated factor VIII concentration. If anti-factor Xa concentrations cannot be measured readily, the dose of UEH should be increased until a therapeutic aPTT is achieved. 

Konkle BA, Bauer KA, Weinstein R, et al. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion, 2003 43(3) 390-394. 

A 39-year-old woman with familial type 1 antithrombin deficiency and a history of extensive deep vein thrombosis and pulmonary embolism, taking warfarin, was given levonorgestrel for emergency contraception. 

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