Antithrombin III Geneva: A Hereditary Abnormal AT III with Defective Heparin Cofactor Activity

Summary

A 43-year-old man presented a pulmonary embolism. The unusual circumstances of apparition, the age and the increased heparin requirements suggested an antithrombin III (AT III) deficiency. AT III activity was low in the propositus and seven other members of his family (mean 55%), but immunologic levels were normal (mean 110%). Crossed immunoelectrophoresis in absence of heparin showed a normal pattern, but in presence of heparin showed an abnormal peak as compared with controls. Kinetics experiments showed a normal inhibition of thrombin and Xa in absence of heparin, but abnormal in presence of heparin. Affinity chromatography on heparin-Sepharose revealed two populations of AT III, one of which was devoid of heparin cofactor activity. The toponym AT III Geneva is proposed for this new familial abnormal AT III with defective heparin cofactor activity.

Keywords

Antithrombin III - Heparin cofactor

• References

• 1 Sas G, Blasko G, Banhegyi D, Jako J, Palos JA. Abnormal antithrombin III (antithrombin III “Budapest”) as a cause of a familial thrombophilia. Thromb Diath Haemorrh 1974; 32: 105-115
• 2 Pepper DS, Hasouna H, Hunter MJ, Chockley MA. A clinically silent antithrombin III defect in an Ann Arbor family. Thromb Haemostas 1979; 42: 186 (Abstr)
• 3 Tran TH, Bounameaux H, Bondeli C, Honkanen H, Marbet GG, Duckert F. Purification and characterisation of a hereditary abnormal antithrombin III fraction of a patient with recurrent thrombophlebitis. Thromb Haemostas 1980; 44: 92-95
• 4 Wolf M, Boyer C, Lavergne JM, Larrieu MJ. A new familial variant of antithrombin III: “antithrombin III Paris”. Brit J Haematol 1982; 51: 285-295
• 5 Girolami A, Fabris F, Cappellato G, Sainati L, Boeri G. Antithrombin III (AT III) Padua 2: a new congenital abnormality with defective heparin cofactor activities but no thrombotic disease. Blut 1983; 47: 93-103
• 6 Sakuragawa N, Takabhashi 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 Fischer AM, Gazengel C, Dautzenberg MD, Benhammo J, Beguin S, Vergoz D. A new case of abnormal antithrombin III (AT III): biological characteristics and thromboembolic accidents management. Thromb Haemostas 1983; 50: 358 (Abstr)
• 8 Chasse JF, Esnard F, Guitton JD, Mouray H, Perigois F, Fauconneau G, Gauthier F. An abnormal plasma antithrombin with no apparent affinity for heparin. Thromb Res 1984; 34: 297-302
• 9 Fischer AM, Cornu P, Sternberg C, Meriane F, Dautzenberg MM, Chafa O, Beguin S, Besnos M. Antithrombin III Alger: a new homozygous AT III variant. Thromb Haemostas 1986; 55: 218-221
• 10 Sorensen PJ, Dyeberg J, Stoffersen E, Krogh Jensen M. Familial functional antithrombin III deficiency. Scand J Haematol 1980; 24: 105-109
• 11 Barbui R, Finazzi G. Characterization of a new variant of inherited dysfunctional antithrombin (AT Vicenza). Thromb Haemostas 1983; 50: 360 (Abstr)
• 12 Jorgensen M, Petersen LC, Thorsen S. Purification and characterisation of a hereditary abnormal antithrombin III with impaired thrombin binding. J Lab Clin Med 1984; 104: 245-256
• 13 Aiach M, Mindy N, Fiessinger J-N, Roncato M, François D, Alhenc Gelas M. A functional abnormal antithrombin III (AT III) deficiency: AT III Charleville. Thromb Res 1985; 39: 559-570
• 14 Sambrano JE, Jacobson LJ, Basil Reeve E, Manco-Johnson MJ, Hathaway W ME. Abnormal antithrombin III with defective serine protease binding (antithrombin III “Denver”). J Clin Invest 1986; 77: 887-893
• 15 Sorensen PJ, Sas G, Peto I, Blasko G, Kremmer T, Samu A. Distinction of two pathologic antithrombin III molecules: antithrombin III “Aalborg” and antithrombin III “Budapest”. Thromb Res 1982; 26: 211-219
• 16 Bauer KA, Ashenjurst JB, Chediak J, Rosenberg RD. Antithrombin “Chicago”: a functionally abnormal molecule with increased heparin affinity causing familial thrombophilia. Blood 1983; 62: 1242-1250
• 17 Girolami A, Marafioti F, Rubertelli M, Vicarioto MA, Capellato G, Mazzucato M. Antithrombin III Trento. A “new” congenital AT III abnormality with a peculiar crossed immunoelectrophoretic pattern in the absence of heparin Acta Haematol 1984; 72: 73-82
• 18 Wolf M, Boyer C, Tripodi D, Meyer D, Larrieu MM, Mannucci PM. Antithrombin Milano: a new variant with monomeric and dimeric inactive antithrombin III. Blood 1985; 65: 496-450
• 19 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
• 20 Abildgaard U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates (S-2238 and chromozym TH). Thromb Res 1977; 11: 549-553
• 21 Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966; 15: 45-52
• 22 Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 1965; 2: 235-254
• 23 Girolami A, Ruzza G, Saggin L, Sticchi A, Melizzi R. The role of laser nephelometer in the study of abnormal clotting factors: characterization of two abnormal antithrombins (AT III Padua and AT III Padua 2). Am J Clin Pathol 1984; 81: 323-328
• 24 Sas G, Pepper DS, Cash JD. Further investigations on antithrombin in the plasma of patients with the abnormality “antithrombin III Budapest”. Thromb Diath Haemorrh 1975; 38: 494-503
• 25 Tran TH, Bondeli C, Marbet GA, Duckert F. Reactivity of hereditary abnormal antithrombin III fraction in the inhibition of thrombin and factor Xa. Thromb Haemostas 1980; 44: 92-95
• 26 McKay EJ. A simple two-step procedure for the isolation of antithrombin III from biological fluids. Thromb Res 1981; 21: 375-382
• 27 Blackburn MN, Sibley CC. The heparin binding site of antithrombin III. Evidence for a critical tryptophan residue. J Biol Chem 1980; 255: 824-826
• 28 Ferguson WS, Finlay TH. Localisation of the disulfide bond in human AT III required for heparin accelerated thrombin inactivation. Arch Biochem Biophys 1983; 221: 304-307
• 29 Koide T, Odani S, Takahashi K, Ono T, Sakuragawa N. Antithrombin III Tokoyama: replacement of arginine-47 by Cysteine in hereditary abnormal antithrombin III that lacks heparin-binding ability. Proc Natl Acad Sci USA 1984; 81: 289-293
• 30 Chang JY, Tran TH. Antithrombin III Basle: Identification of a proleu substitution in hereditary abnormal antithrombin with impaired Heparin Cofactor activity. J Biol Chem 1986; 261: 1174-1176
• 31 Prochownik EV, Antonarakis S, Bauer KA, Rosenberg RR, Fearon ER, Orkin Sh. Molecular heterogeneity of inherited antithrombin III deficiency. N Engl J Med 1983; 308: 1459-1462