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Thromb Haemost 1986; 56(03): 349-352
DOI: 10.1055/s-0038-1661681
Original Article
Schattauer GmbH Stuttgart

Characterization of an Abnormal Antithrombin (Milano 2) with Defective Thrombin Binding

A Tripodi
The A. Bianchi Bonomi Hemophilia and Thrombosis Center and Institute of Internal Medicine, University of Milano, Italy
,
A Krachmalnicoff
The A. Bianchi Bonomi Hemophilia and Thrombosis Center and Institute of Internal Medicine, University of Milano, Italy
,
P M Mannucci
The A. Bianchi Bonomi Hemophilia and Thrombosis Center and Institute of Internal Medicine, University of Milano, Italy
› Author Affiliations
Further Information

Publication History

Received 20 June 1986

Accepted after revision 12 September 1986

Publication Date:
18 July 2018 (online)

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Summary

Four members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and halfnormal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus’ plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus’ plasma to human α-thrombin immobilized on sepharose beads revealed defective binding of the anti thrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

Keywords

Congenital thrombosis - Anti thrombin III - Deep-vein thrombosis
 

  • References

  • 1 Odegard OR, Lie M, Abildgaard U. Heparin cofactor activity measured with an amidolytic method. Thromb Res 1975; 6: 287-294
    CrossrefPubMedGoogle Scholar
  • 2 Odegard OR, Lie M, Abildgaard U. Antifactor Xa activity measured with amidolytic method. Haemostasis 1976; 5: 265-275
    PubMedGoogle Scholar
  • 3 Sas G, Pepper DS, Cash JD. Plasma and serum antithrombin III: differentiation by crossed immunoelectrophoresis. Thromb Res 1975; 6: 87-91
    CrossrefPubMedGoogle Scholar
  • 4 Sas G. Hereditary antithrombin III deficiency: biochemical aspects. Haematologia 1984; 17: 81-85
    PubMedGoogle Scholar
  • 5 Sas G, Pepper DS, Cash D. Further investigations on antithrombin III in the plasmas of patients with the abnormality of antithrombin III Budapest. Thromb Diath Haemorrh 1975; 33: 564-572
    PubMedGoogle Scholar
  • 6 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
    PubMedGoogle Scholar
  • 7 Girolami A, Marafioti F, Rubertelli M, Vicarioto MA, Cappellato MG, Mazzuccato M. Antithrombin III Trento, a "new" congenital AT III abnormality with a peculiar crossed immunoelectrophoretic pattern in the absence of heparin. Acta Haemat 1984; 72: 73-82
    CrossrefPubMedGoogle Scholar
  • 8 Howart DJ, Samson D, Stirling Y, Seghatchian MJ. Antithrombin III "Northwick Park": a new variant antithrombin with normal affinity for heparin but reduced heparin cofactor activity. Thromb Haemostas 1985; 53: 314-319
    PubMedGoogle Scholar
  • 9 Bauer KA, Ashenhurst JB, Chediak J, Rosenberg RD. Antithrombin III "Chicago": a functionally abnormal molecule with increased heparin affinity causing familial thrombophilia. Blood 1983; 62: 1242-1250
    PubMedGoogle Scholar
  • 10 Tengborn L, Frohm B, Nilsson LE, Nilsson IM. A Swedish family with abnormal antithrombin III. Scand J Haematol 1985; 34: 412-416
    PubMedGoogle Scholar
  • 11 Murayama H, Matsuda M. Abnormal antithrombin III with defective biological functions found in a thrombophilic patient: "antithrombin III Tokyo". Thrombos Haemostas 1983; 50: 358
    PubMedGoogle Scholar
  • 12 Sambrano JE, Jacobson LJ, Reeve EB, Manco-Johnson MJ, Hathaway WE. Abnormal antithrombin III with defective serine protease binding (antithrombin III "Denver"). J Clin Invest 1986; 77: 887-893
    CrossrefPubMedGoogle Scholar
  • 13 Sorensen PJ, Sas G, Peto I, Blasko GY, Kremmer T, Samu A. Distinction of two patologic antithrombin III molecules: antithrombin III "Aalborg" and antithrombin III "Budapest". Thromb Res 1982; 26: 211-219
    CrossrefPubMedGoogle Scholar
  • 14 Jorgensen M, Petersen LC, Thorsen S. Purification and characterization of hereditary abnormal antithrombin III with impaired thrombin binding. J Lab Clin Med 1984; 104: 245-256
    PubMedGoogle Scholar
  • 15 Finazzi G, Tran TH, Barbui T, Duckert F. Purification of antithrombin "Vicenza" a molecule with normal heparin affinity and impaired reactivity to thrombin. Brit J Haematol 1985; 59: 259-263
    CrossrefPubMedGoogle Scholar
  • 16 Aiach M, Mindy N, Fiessinger JN, Roncato M, Francois D, Gelas MA. A functional abnormal antithrombin III (AT III) deficiency: AT III Charleville. Thromb Res 1985; 39: 559-570
    CrossrefPubMedGoogle Scholar
  • 17 Penner JA, Hassouna H, Hunter MJ, Chockley M. A clinically silent antithrombin III defect in an Ann Arbor family. Thromb Haemostas 1979; 42: 186
    PubMedGoogle Scholar
  • 18 Tran TH, Bondeli C, Marbet GA, Duckert F. Reactivity of a hereditary abnormal antithrombin III fraction in the inhibition of thrombin and factor Xa. Thromb Haemostas 1980; 44: 92-95
    PubMedGoogle Scholar
  • 19 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
    CrossrefPubMedGoogle Scholar
  • 20 Sakuragawa N, Takahashi K, Koide T. Antithrombin III Toyama: a hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis. Thromb Res 1983; 31: 305-317
    CrossrefPubMedGoogle Scholar
  • 21 Girolami A, Pengo A, Patrassi GM, Cappellato G, Vianello C, Cartei L. A "new" congenital antithrombin III abnormality with normal or near normal activity, normal antigen, abnormal migration and non thrombotic disease. Folia Haematologica 1983; 110: 98-101
    PubMedGoogle Scholar
  • 22 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; 46: 1-4
    CrossrefPubMedGoogle Scholar
  • 23 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
    PubMedGoogle Scholar
  • 24 Chasse JF, Esnard F, Guitton JD, Mouray F, Perigois F, Fanconneau G, Gauthier F. An abnormal plasma antithrombin with no apparent affinity for heparin. Thromb Res 1984; 34: 297-302
    CrossrefPubMedGoogle Scholar
  • 25 Mannucci PM, Tripodi A, Mari D. Congenital deficiencies of anticoagulant proteins (antithrombin III and protein C). Haematologica 1984; 69: 730-746
    PubMedGoogle Scholar
  • 26 Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose gels containing antibodies. Anal Biochem 1966; 15: 45-52
    CrossrefPubMedGoogle Scholar
  • 27 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
    PubMedGoogle Scholar
  • 28 Barbui T, Finazzi G, Rodeghiero F, Dini E. Immunoelectrophoretic 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
    CrossrefPubMedGoogle Scholar