Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency

 

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Summary

Antithrombin (AT) functions as a potent natural anticoagulant and serine protease inhibitor that inactivates many enzymes in the coagulation cascade. Antithrombin also possesses anti-inflammatory properties, many of which are mediated by its actions as an anticoagulant. Hereditary AT deficiency is a rare, underrecognised medical condition that is associated with inadequate endogenous anticoagulation thought to result from impaired inhibition of serine protease coagulation factors. Inherited as an autosomal dominant trait, congenital AT deficiency typically reduces functional AT levels to 40–60% of normal. As a result, individuals with hereditary AT deficiency have a ≥50% lifetime risk of venous thromboembolism (VTE). Specifically, AT deficiency is associated with a three- to seven-fold higher risk of VTE compared with other thrombophilias. Thus, maintaining adequate levels of AT during high-risk periods is an important treatment goal. Long-term anticoagulant thromboprophylaxis is not recommended in asymptomatic patients with AT deficiency because of the increased risk of haemorrhage. However, treatment guidelines recommend short-term thromboprophylaxis in high-risk clinical settings, including surgery, trauma, and management of pregnancy, labour, and delivery. The goal of treatment for patients with hereditary AT deficiency is an initial increase in AT activity to ≥120% of normal levels followed by maintenance of AT activity at ≥80% of normal levels. Plasma-derived AT, heparin, fresh frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency. The objective of this review is to discuss hereditary AT deficiency and the role of AT replacement therapy in the treatment of patients with this congenital disorder.

• References

• 1 Maclean PS, Tait RC. Hereditary and acquired anti-thrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007; 67: 1429-1440.
  CrossrefPubMedGoogle Scholar
• 2 Bauer KA. Selective inhibition of coagulation factors: advances in antithrombotic therapy. Semin Thromb Hemost 2002; 28 (Suppl. 02) 15-24.
  PubMedGoogle Scholar
• 3 Bucur SZ, Levy JH, Despotis GJ. et al. Uses of anti-thrombin III concentrate in congenital and acquired deficiency states. Transfusion 1998; 38: 481-498.
  CrossrefPubMedGoogle Scholar
• 4 Roemisch J, Gray E, Hoffmann JN. et al. Anti-thrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13: 657-670.
  CrossrefPubMedGoogle Scholar
• 5 Römisch J, Dönges R, Stauss H. et al. Quantification of antithrombin isoform proportions in plasma samples of healthy subjects, sepsis patients, and in anti-thrombin concentrates. Pathophysiol Haemost Thromb 2002; 32: 143-150.
  CrossrefPubMedGoogle Scholar
• 6 Tanaka KA, Levy JH. Regulation of thrombin activity--pharmacologic and structural aspects. Hematol Oncol Clin North Am 2007; 21: 33-50.
  CrossrefPubMedGoogle Scholar
• 7 Blajchman MA. An overview of the mechanism of action of antithrombin and its inherited deficiency states. Blood Coagul Fibrinolysis 1994; 05 (Suppl. 01) S5-11 discussion S59-64.
  PubMedGoogle Scholar
• 8 Muñoz EM, Linhardt RJ. Heparin-binding domains in vascular biology. Arterioscler Thromb Vasc Biol 2004; 24: 1549-1557.
  CrossrefPubMedGoogle Scholar
• 9 Opal SM. Interactions between coagulation and inflammation. Scand J Infect Dis 2003; 35: 545-554.
  CrossrefPubMedGoogle Scholar
• 10 Senden NH, Jeunhomme TM, Heemskerk JW. et al. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol 1998; 161: 4318-4324.
  PubMedGoogle Scholar
• 11 Schwartz RS, Bauer KA, Rosenberg RD. et al. The Antithrombin III Study Group. Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med 1989; 87 Suppl 3B 53S-60S.
  PubMedGoogle Scholar
• 12 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-350.
  PubMedGoogle Scholar
• 13 Hirsh J, Piovellá F, Pini M. Congenital antithrombin III deficiency. Incidence and clinical features. Am J Med 1989; 87 Suppl 3B 34S-38S.
  PubMedGoogle Scholar
• 14 Franchini M, Veneri D, Salvagno GL. et al. Inherited thrombophilia. Crit Rev Clin Lab Sci 2006; 43: 249-290.
  CrossrefPubMedGoogle Scholar
• 15 Wells PS, Blajchman MA, Henderson P. et al. Prevalence of antithrombin deficiency in healthy blood donors: a cross-sectional study. Am J Hematol 1994; 45: 321-324.
  CrossrefPubMedGoogle Scholar
• 16 Buller HR, ten Cate JW. Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate. Am J Med 1989; 87 3B 44S-48S.
  PubMedGoogle Scholar
• 17 Ranucci M, Frigiola A, Menicanti L. et al. Postoperative antithrombin levels and outcome in cardiac operations. Crit Care Med 2005; 33: 355-360.
  CrossrefPubMedGoogle Scholar
• 18 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
  PubMedGoogle Scholar
• 19 Flanders MM, Phansalkar AR, Crist RA. et al. Pediatric reference intervals for uncommon bleeding and thrombotic disorders. J Pediatr 2006; 149: 275-277.
  CrossrefPubMedGoogle Scholar
• 20 Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology.. Investigation and management of heritable thrombophilia. Br J Haematol 2001; 114: 512-528.
  CrossrefPubMedGoogle Scholar
• 21 Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med 2002; 126: 1326-1336.
  PubMedGoogle Scholar
• 22 Lane DA, Kunz G, Olds RJ. et al. Molecular genetics of antithrombin deficiency. Blood Rev 1996; 10: 59-74.
  CrossrefPubMedGoogle Scholar
• 23 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
  CrossrefPubMedGoogle Scholar
• 24 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-112.
  CrossrefPubMedGoogle Scholar
• 25 Martinelli I, Mannucci PM, De Stefano V. et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 2353-2358.
  PubMedGoogle Scholar
• 26 Perry SL, Ortel TL. Clinical and laboratory evaluation of thrombophilia. Clin Chest Med 2003; 24: 153-170.
  CrossrefPubMedGoogle Scholar
• 27 van Boven HH, Reitsma PH, Rosendaal FR. et al. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417-421.
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol 1981; 10: 369-390.
  PubMedGoogle Scholar
• 29 Rossi E, Sz T, Ciminello A. et al. The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophila. Thromb Haemost 2008; 99: 1030-1034.
  Article in Thieme ConnectPubMedGoogle Scholar
• 30 Bates SM, Greer IA, Pabinger I. et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 844S-886S.
  CrossrefPubMedGoogle Scholar
• 31 Bharadwaj J, Jayaraman C, Shrivastava R. Heparin resistance. Lab Hematol 2003; 09: 125-131.
  PubMedGoogle Scholar
• 32 Avidan MS, Levy JH, Scholz J. et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology 2005; 102: 276-284.
  CrossrefPubMedGoogle Scholar
• 33 Avidan MS, Levy JH, van Aken H. et al. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005; 130: 107-113.
  CrossrefPubMedGoogle Scholar
• 34 Edmunds Jr LH, Colman RW. Thrombin during cardiopulmonary bypass. Ann Thorac Surg 2006; 82: 2315-2322.
  CrossrefPubMedGoogle Scholar
• 35 Ranucci M, Isgró G, Cazzaniga A. et al. Different patterns of heparin resistance: therapeutic implications. Perfusion 2002; 17: 199-204.
  CrossrefPubMedGoogle Scholar
• 36 Staples MH, Dunton RF, Karlson KJ. et al. Heparin resistance after preoperative heparin therapy or intraaortic balloon pumping. Ann Thorac Surg 1994; 57: 1211-1216.
  CrossrefPubMedGoogle Scholar
• 37 Williams MR, D’Ambra AB, Beck JR. et al. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg 2000; 70: 873-877.
  CrossrefPubMedGoogle Scholar
• 38 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin. Chest 2004; 126: 188S-203S.
  CrossrefPubMedGoogle Scholar
• 39 MacLennan S, Barbara JA. Risks and side effects of therapy with plasma and plasma fractions. Best Pract Res Clin Haematol 2006; 19: 169-189.
  CrossrefPubMedGoogle Scholar
• 40 Stramer SL, Fang CT, Foster GA. et al. West Nile virus among blood donors in the United States, 2003 and 2004. N Engl J Med 2005; 353: 451-459.
  CrossrefPubMedGoogle Scholar
• 41 Thrombate III^® [package insert]. Research Triangle Park, NC: Talecris Biotherapeutics, Inc; 2005
  Google Scholar
• 42 Hoffman DL. Purification and large-scale preparation of antithrombin III. Am J Med 1989; 87 3B 23S-26S.
  PubMedGoogle Scholar
• 43 Morrica A, Nardini C, Falbo A. et al. Manufacturing process of anti-thrombin III concentrate: viral safety validation studies and effect of column re-use on viral clearance. Biologicals 2003; 31: 165-173.
  CrossrefPubMedGoogle Scholar
• 44 Menache D, O’Malley JP, Schorr JB. et al. Cooperative Study Group. Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Blood 1990; 75: 33-39.
  PubMedGoogle Scholar
• 45 Preiss DU, Abdullah D, Eberspacher B. et al. Safety of virus inactivated antithrombin III concentrate anti-thrombin III immuno (AT III). Thromb Res 1992; 65: 677-686.
  CrossrefPubMedGoogle Scholar
• 46 Edmunds T, Van Patten SM, Pollock J. et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived anti-thrombin. Blood 1998; 91: 4561-4571.
  PubMedGoogle Scholar
• 47 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: 390-394.
  CrossrefPubMedGoogle Scholar
• 48 Tiede A, Tait RC, Shaffer DW. et al. Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost 2008; 99: 616-622.
  Article in Thieme ConnectPubMedGoogle Scholar
• 49 Lockwood CJ. Inherited thrombophilias in pregnant patients: detection and treatment paradigm. Obstet Gynecol 2002; 99: 333-341.
  PubMedGoogle Scholar
• 50 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-908.
  CrossrefPubMedGoogle Scholar
• 51 Robertson L, Wu O, Langhorne P. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2005; 132: 171-196.
  PubMedGoogle Scholar
• 52 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 1982; 14: 127-141.
  CrossrefPubMedGoogle Scholar
• 53 Folkeringa N, Brouwer JL, Korteweg FJ. et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Br J Haematol 2007; 136: 656-661.
  CrossrefPubMedGoogle Scholar
• 54 Yamada T, Yamada H, Morikawa M. et al. Management of pregnancy with congenital antithrombin III deficiency: two case reports and a review of the literature. J Obstet Gynaecol Res 2001; 27: 189-197.
  CrossrefPubMedGoogle Scholar
• 55 British Committee for Standards in Haematology.. Guidelines on the investigation and management of thrombophilia. The British Committee for Standards in Haematology. J Clin Pathol 1990; 43: 703-709.
  CrossrefPubMedGoogle Scholar
• 56 Brenner B, Tavori S, Tatarsky I. Prophylaxis of thromboembolism during pregnancy in hereditary ATIII deficiency. Am J Hematol 1992; 39: 71-72.
  CrossrefPubMedGoogle Scholar
• 57 Inomoto T, Takamoto M, Tamura R. et al. Effective prophylaxis of thrombosis by antithrombin III concentrate in a pregnant woman with congenital antithrombin III deficiency: relations between plasma antithrombin III activity and the plasma levels of hemostatic molecular markers. Haemostasis 1991; 21: 147-154.
  PubMedGoogle Scholar
• 58 Megha A, Finzi G, Poli T. et al. Pregnancy, anti-thrombin III deficiency and venous thrombosis: report of another case. Acta Haematol 1990; 83: 111.
  CrossrefPubMedGoogle Scholar
• 59 Shiozaki A, Arai T, Izumi R. et al. Congenital anti-thrombin III deficient neonate treated with antithrombin III concentrates. Thromb Res 1993; 70: 211-216.
  CrossrefPubMedGoogle Scholar
• 60 Tengborn L, Bengtsson T. Antithrombin III concentrate. Thromboprophylaxis during pregnancy in a patient with congenital antithrombin III deficiency. Acta Obstet Gynecol Scand 1986; 65: 375-376.
  CrossrefPubMedGoogle Scholar
• 61 De Stefano V, Leone G, De Carolis S. et al. Management of pregnancy in women with antithrombin III congenital defect: report of four cases. Thromb Haemost 1988; 59: 193-196.
  Article in Thieme ConnectPubMedGoogle Scholar
• 62 Michiels JJ, Stibbe J, Vellenga E. et al. Prophylaxis of thrombosis in antithrombin III-deficient women during pregnancy and delivery. Eur J Obstet Gynecol Re-prod Biol 1984; 18: 149-153.
  CrossrefPubMedGoogle Scholar
• 63 Samson D, Stirling Y, Woolf L. et al. Management of planned pregnancy in a patient with congenital anti-thrombin III deficiency. Br J Haematol 1984; 56: 243-249.
  CrossrefPubMedGoogle Scholar
• 64 Blanco AN, Meschengieser S, Penalva LB. et al. Prophylaxis during surgery in antithrombin III deficiency with low dose of concentrates. Thromb Res 1989; 56: 497-499.
  CrossrefPubMedGoogle Scholar
• 65 Jackson MR, Olsen SB, Gomez ER. et al. Use of antithrombin III concentrates to correct antithrombin III deficiency during vascular surgery. J Vasc Surg 1995; 22: 804-807.
  CrossrefPubMedGoogle Scholar
• 66 Mannucci PM, Boyer C, Wolf M. et al. Treatment of congenital antithrombin III deficiency with concentrates. Br J Haematol 1982; 50: 531-535.
  CrossrefPubMedGoogle Scholar
• 67 Van Norman GA, Gernsheimer T, Chandler WL. et al. Indicators of fibrinolysis during cardiopulmonary bypass after exogenous antithrombin-III administration for acquired antithrombin III deficiency. J Cardiothorac Vasc Anesth 1997; 11: 760-763.
  CrossrefPubMedGoogle Scholar
• 68 Red Book. 2006 ed. Montvale, NJ: Thomson PDR; 2006: 678.
  Google Scholar
• 69 Brown ME, Gallagher JM, Armitage JM. The use of antithrombin III concentrate for treatment of heparin resistance during cardiopulmonary bypass. J Extra-Corporeal Tech 2000; 32: 75-78.
  PubMedGoogle Scholar