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Antithrombin III (AT-III), an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5mg/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® (antithrombin) 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 (antithrombin) III, none of the 13 patients with hereditary AT-III deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE (antithrombin) 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 (antithrombin) III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE (antithrombin) III reversed heparin resistance in two patients with hereditary AT-III deficiency being treated for thrombosis or thromboembolism.

During clinical investigation of THROMBATE (antithrombin) III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving THROMBATE (antithrombin) 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.


2. Rosenberg RD, Bauer KA, Marcum JA: Antithrombin III "the heparin-antithrombin system." Rev Hematol 2:351-416, 1986.

3. Murano G, Williams L, Miller-Andersson M: Some properties of antithrombin-III and its concentration in human plasma. Thromb Res 18(1-2):259-62, 1980.

4. Rosenberg RD: Action and interactions of antithrombin and heparin. N Engl J Med 292(3):146-51, 1975.

5. Winter JH, Fenech A, Ridley W, et al: Familial antithrombin III deficiency. Q J Med 51(204):373-95, 1982.

6. Marciniak E, Farley CH, DeSimone PA: Familial thrombosis due to antithrombin III deficiency. Blood 43(2):219-31, 1974.

7. Thaler E, Lechner K: Antithrombin III deficiency and thromboembolism. Clin Haematol 10(2):369-90, 1981.

8. Blauhut B, Necek S, Kramar H, et al: Activity of antithrombin III and effect of heparin on coagulation in shock. Thromb Res 19(6):775-82, 1980.

9.Samson D, Stirling Y, Woolf L, et al: Management of planned pregnancy in a patient with congenital antithrombin III deficiency. Br J Haematol 56(2):243-9, 1984.

10. Brandt P: Observations during the treatment of antithrombin-III deficient women with heparin and antithrombin concentrate during pregnancy, parturition, and abortion. Thromb Res 22(1-2):15-24, 1981.

11. Hellgren M, Tengborn L, Abildgaard U: Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 14(2):127-41, 1982.

12. Schwartz RS, Bauer KA, Rosenberg RD, et al: Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med 87 (Suppl 3B): 53S-60S, 1989.

13. Collen D, Schetz J, de Cock F, et al: Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest 7(1):27-35, 1977.

14. Knot EAR, de Jong E, ten Cate JW, et al: Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model. Blood 67(1):93-8, 1986.

15. Tengborn L, Frohm B, Nilsson LE, et al: Antithrombin III concentrate: its catabolism in health and in antithrombin III deficiency. Scand J Clin Lab Invest 41(5):469-77, 1981.

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