Antithrombin III (Human), THROMBATE III® is a sterile, nonpyrogenic, stable, lyophilized preparation of purified human antithrombin III.
THROMBATE III is prepared from pooled units of human plasma from normal donors by modifications and refinements of the cold ethanol method of Cohn. 1 When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0-7.5, a sodium content of 110-210 mEq/L, a chloride content of 110-210 mEq/L, an alanine content of 0.075-0.125 M, and a heparin content of not more than 0.004 unit/IU AT-III. THROMBATE III contains no preservative and must be administered by the intravenous route. In addition, THROMBATE III has been heat-treated in solution at 60°C ± 0.5°C for not less than 10 hours.
Each vial of THROMBATE III contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation.
Antithrombin III (AT-III), an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL2,3 and is the major plasma inhibitor of thrombin.4 Inactivation of thrombin by AT-III occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on AT-III. 4 AT-III is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin.4
The neutralization rate of serine proteases by AT-III proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin.4 As the therapeutic antithrombotic effect in vivo of heparin is mediated by AT-III, heparin is ineffective in the absence or near absence of AT-III. 4-8
The prevalence of the hereditary deficiency of AT-III is estimated to be one per 2000 to 5000 in the general population.4-7 The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with AT-III levels of 40%-60% of normal.7 These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary antithrombin III (AT-III) deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deficiency have been reported. 9-11 In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism.7 Greater than 85% of individuals with hereditary AT-III deficiency have had at least one thrombotic episode by the age of 50 years. 7 In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. 7 In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of AT-III, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals. 6,7
In clinical studies of Antithrombin III (Human), THROMBATE III® conducted in 10 asymptomatic subjects with hereditary deficiency of AT-III, the mean in vivo recovery of AT-III was 1.6% per unit per kg administered based on immunologic AT-III assays, and 1.4% per unit per kg administered based on functional AT-III assays. 12 The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of AT-III. 12 These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8-4.8 days. 13-15
In clinical studies of THROMBATE III, none of the 13 patients with hereditary AT-III deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures and all 5 deliveries. Eight patients with hereditary AT-III deficiency were treated therapeutically with THROMBATE III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE III reversed heparin resistance in two patients with hereditary AT-III deficiency being treated for thrombosis or thromboembolism.
During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of 8 months (range 2-19 months) after receiving THROMBATE III, became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for >/= 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B.