Homozygous Variant of Antithrombin III that Lacks Affinity for Heparin, AT III Kumamoto

Summary

Abnormal antithrombin III (AT III) was found in the plasma of a 31-year-old female who suffered from recurrent thrombotic episodes. Heparin cofactor activity was 28% of normal and undetectable when measured by inhibition of thrombin and factor Xa (F. Xa), while both progressive antithrombin and antifactor Xa activities were normal. The concentration of plasma AT III antigen was 37 mg/dl. Analysis by crossed-immunoelec- trophoresis (CIE) in the presence of heparin and affinity chromatography on heparin-Sepharose revealed that the propositus’ AT III did not bind to heparin. When heparin cofactor II (HC II) was removed from propositus’ plasma, heparin cofactor activity of AT III was not detected. Thus, HC II seemed to account for the plasma heparin cofactor activity found in the presence of thrombin. The patient’s parents and three of her brothers demonstrated qualitative abnormality of AT III; heparin cofactor activity was 30-50% of normal levels in the presence of both thrombin and F. Xa. These findings indicate that the propositus’ AT III lacks affinity for heparin and the mode of its inheritance seems to be autosomal dominant and, hence, the propositus would be a homozygote. For this variant, the name of AT III Kumamoto is proposed.

Key words

Antithrombin III - Abnormal antithrombin III - Heparin cofactor activity - Thrombosis - Heparin cofactor II

• References

• 1 Abilgaard U. A review of antithrombin III. In: The physiological Inhibitors of Coagulation and Fibrinolysis. Collen D, Wiman B, Verstaete W. eds Elsevier; Amsterdam: 1979. pp 19-29
• 2 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Hemorrh 1965; 13: 516-530
• 3 Abilgaard U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with “new” chromogenic substrates (S-2238 and chromozym TH). Thromb Res 1977; 11: 549-553
• 4 Dezelic N, Dezelic GJ. A photometric method for the determination of serum titers by latex particle agglutination. Croatica Chem Acta 1970; 42: 457-466
• 5 Macini G, Carbonara AO, Hermans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 1965; 2: 235-254
• 6 Sakuragawa N, Takahasi K, Kondo S, Koide T. Antithrombin III Toyama; A hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis. Thromb Res 1983; 31: 305-317
• 7 Pelzer H, Schwarz A, Heimburger N. Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemostas 1988; 59: 101-106
• 8 Tran TH, Duckert F. Heparin cofactor II determination-levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation. Thromb Haemostas 1984; 52: 112-116
• 9 Laurell CB. Antigen-antibody crossed electrophoresis. Anal Biochem 1965; 10: 358-361
• 10 Francies RB, Patch MJ. A functional assay for protein C in human plasma. Thromb Res 1983; 32: 605-613
• 11 Bertina RM, van Wijngaarden A, Reinalda-Poot J, Poort SR, Bom VJ J. Determination of plasma protein S. The protein cofactor of activated protein C deficiency Thromb Haemostas 1985; 53: 268-272
• 12 Largo R, Heller V, Straub W. Detection of soluble intermediates of the fibrinogen-fibrin conversion using erythrocytes coated with fibrin monomers. Blood 1976; 47: 0991-1002
• 13 Sambrano JE, Jacobson JL, Reeve EB, Manco-Jhonson MJ, Hataway WE. Abnormal antithrombin III with defective serine protease binding (Antithrombin III “Denver”). J Clin Invest 1986; 77: 887-893
• 14 Sas G, Pepper DS, Cash JD. Plasma and serum antithrombin III: differentiation by crossed immunoelectrophoresis. Thromb Res 1975; 6: 87-91
• 15 Sas G, Blasko G, Banhegyi D, Jako J, Palos LA. Abnormal antithrombin III (antithrombin III “Budapest”) as a cause of a familial thrombophilia. Thromb Diathes Hemorrh 1975; 33: 564-573
• 16 Tran TH, Bounameaux H, Bondeli C, Honkanen H, Marbet GA, Duckert F. Purification and partial characterization of a hereditary abnormal antithrombin III fraction of a patient with recurrent thrombophlebitis. Thromb Haemostas 1980; 44: 87-91
• 17 Wolf M, Boyer C, Lavergne JM, Larrieu MJ. A new familial variant of antithrombin III: Antithrombin III Paris. Br J Haematol 1982; 51: 285-295
• 18 Fischer AM, Cornu P, Sternberg C, Mériane F, Dautzenberg MD, Chafa O, Beguin S, Densos M. Antithrombin III Alger: A new homozygous AT III variant. Thromb Haemostas 1986; 55: 218-221
• 19 Boyer C, Wolf M, Verdrenne J, Meyer D, Larrieu MJ. Homozygous variant of antithrombin III: AT III Fontainebleau. Thromb Haemostas 1986; 56: 18-22
• 20 Owen MC, Borg JY, Soria C, Soria J, Caen J, Carell RW. Heparin binding defect in a new antithrombin III variant: Rouen, 47 Arg to His. Blood 1987; 69: 1275-1279
• 21 Bauer KA, Ashenhurst JB, Chediak J, Rosenberg RD. Antithrombin “Chicago”: A functionally abnormal molecule with increased heparin affinity causing familial thrombophilia. Blood 1983; 62: 1242-1250
• 22 Wolf M, Boyer C, Tripodi A, Meyer D, Larrieu MJ, Mannucci PM. Antithrombin Milano: A new variant with monomeric and dimeric inactive antithrombin III. Blood 1985; 65: 496-500
• 23 Sorenson PJ, Sas G, Peto I, Blasko G, Kremer T, Samu A. Distinction of two pathological antithrombin III molecules. Antithrombin III Aalborg and antithrombin III Budapest. Thromb Res 1982; 26: 211-219
• 24 Girolami A, Pengo A, Patrassi GM, Capellato G, Vianello C, Cartei L. A “new” congenital antithrombin III abnormality with normal or near normal antigen, abnormal migration and non thrombotic disease. Folia Hematol 1983; 110: 98-111
• 25 Girolami A, Rubetelli M, Marafiotti F, Zamboni A, Vicarioto MA. Crossed immunoelectrophoresis in the study of abnormal antithrombin III Behavior of AT III Trento. Br J Hematol 1983; 55: 559-561
• 26 Howarth DJ, Samson D, Stirling Y, Seghatchian MJ. Antithrombin III “Northwick Park”: A variant antithrombin with normal affinity for heparin but reduced heparin cofactor activity. Thromb Haemostas 1985; 53: 314-319
• 27 Barbui T, Finazzi G, Rodeghiero F, Dini E. Immunoelectrophoresis evidence of a thrombin-induced abnormality in a new variant of hereditary dysfunctional antithrombin III (AT III “Vicenza”). Br J Haematol 1983; 54: 561-565
• 28 Aiach M, Nora M, Fiessinger JN, Rocato M, Francois D, Gelas MA. A functional abnormal antithrombin III (AT III) deficiency: AT III Charleville. Thromb Res 1985; 39: 559-570
• 29 Koide T, Odani S, Takahashi K, Ono T, Sakuragawa N. Antithrombin III Toyama: Replacement of arginine-47 by cysteine in hereditary abnormal antithrombin III that lacks heparin-binding ability. Proc Natl Acad Sci 1984; 81: 289-293
• 30 Chang JY, Tran TH. Antithrombin III Basel, identification of a proleu substitution in a hereditary abnormal antithrombin with impaired heparin cofactor activity. J Biol Chem 1986; 261: 1174-1176