Thromb Haemost 1985; 53(03): 314-319
DOI: 10.1055/s-0038-1661305
Original Article
Schattauer GmbH Stuttgart

Antithrombin III “Northwick Park”: A Variant Antithrombin with Normal Affinity for Heparin but Reduced Heparin Cofactor Activity

D J Howarth
The M.R.C. Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, UK
,
Diana Samson
1   The Department of Haematology, Northwick Park Hospital, Harrow, UK
The M.R.C. Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, UK
,
Yvonne Stirling
The M.R.C. Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, UK
,
M J Seghatchian
The M.R.C. Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, UK
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 07. Juli 1984

Accepted 19. Februar 1985

Publikationsdatum:
18. Juli 2018 (online)

Summary

Further studies have been carried out in a previously reported family with congenital antithrombin III (AT III) deficiency due to an abnormal variant of AT III (AT III Northwick Park). The variant has been identified in five members of the family, three of whom had a history of venous thrombosis. Inheritance followed an autosomal dominant pattern. The affected family members have reduced levels of antithrombin heparin cofactor (41–67%) and progressive antithrombin activity (44–62%) but normal levels of immunoreactive AT III (91–162%). Two dimensional immunoelectrophoresis (2 DIE) of AT III in the absence of heparin revealed an abnormal fast-moving peak in addition to the normal peak but 2 DIE in the presence of heparin appeared normal. Further studies confirmed that the abnormal AT III binds completely to heparin but has no heparin cofactor or progressive antithrombin activity. These results would be consistent with a mutation affecting the binding site for thrombin.

 
  • References

  • 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thrombos Diathes Haemorrh 1965; 13: 516-530
  • 2 Van der Meer J, Stoepman van Dalen EA, Jansen JM S. Antithrombin III deficiency in a Dutch family. J Clin Pathol 1973; 26: 532-538
  • 3 Marciniak E, Farley CH, de Simone PA. Familial thrombosis due to antithrombin III deficiency. Blood 1974; 43: 219-231
  • 4 Sas G, Blasko G, Banhegyi D, Jako J, Palos LA. Abnormal antithrombin III (antithrombin III Budapest) as a cause of familial thrombophilia. Thrombos Diathes Haemorrh 1974; 32: 105-115
  • 5 Gruenberg JC, Smallridge RC, Rosenberg RD. Inherited antithrom bin III deficiency causing mesenteric venous infarction. Ann Surg 1975; 181: 791-794
  • 6 Carvalho A, Ellman L. Hereditary antithrombin III deficiency. Effect of antithrombin III deficiency on platelet function Am J Med 1976; 61: 179-183
  • 7 Filip DJ, Eckstein JD, Veitkamp JJ. Hereditary antithrombin III deficiency and thromboembolic disease. Am J Haematol 1976; 2: 343-349
  • 8 Stathakis NE, Papayannis AG, Antonopoulos M, Gardikas C. Familial thrombosis due to antithrombin III deficiency in a Greek family. Acta Haematol 1977; 57: 47-54
  • 9 Brozovic M, Stirling Y, Hamlyn AN. Thrombotic tendency and probable antithrombin III deficiency. Thromb Haemostas 1978; 39: 778-779
  • 10 Mackie M, Bennett B, Ogston D, Douglas AS. Familial thrombosis: Inherited deficiency of antithrombin III. Br Med J 1978; 1: 136-138
  • 11 Johansson L, Hedner U, Nilsson IM. Familial antithrombin III deficiency as pathogenesis of deep venous thrombosis. Acta Med Scand 1978; 204: 491-495
  • 12 Gyde GH B, Middleton MD, Vaughan ER, Fletcher DO. Antithrombin III deficiency, hypertriglyceridaemia and venous thrombosis. Br Med J 1978; 1: 621-622
  • 13 Fenner JA, Hassouna M, Flunter MJ, Chokley MA. A clinically silent antithrombin III defect in an Ann Arbor family. Thromb Haemostas 1979; 42: 189 (Abstr.)
  • 14 Matsuo T, Ohki Y, Kando S, Matsuo D. Familial antithrombin III deficiency in a Japanese family. Thromb Res 1979; 16: 815-823
  • 15 Ambruso DR, Jacobson LO, Hathaway WE. Inherited antithrombin III deficiency and cerebral thrombosis in a child. Paediatrics 1980; 65: 121-131
  • 16 Scully MF, de Haas H, Chan P, Kakkar VV. Hereditary antithrombin III deficiency in an English family. Br J Haematol 1981; 47: 235-240
  • 17 Sorensen PJ, Dyerberg J, Stoffersen E, Jensen MK. Familial functional antithrombin III deficiency. Scand J Haematol 1980; 24: 105-109
  • 18 Tran TH, Bounameaux H, Bondeli C, Honkanen H, Marbet GA, Duckert F. Purification and partial characterisation of a hereditary abnormal antithrombin III fraction of a patient with recurrent thrombophlebitis. Thromb Haemostas 1980; 44: 87-91
  • 19 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
  • 20 Sorensen 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
  • 21 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: 501-565
  • 22 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 Haematologica 1983; 110: 98-111
  • 23 Girolami A, Fabris F, Capellato 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: 1-11
  • 24 Girolami A, Rubetelli M, Marafiotti F, Zamboni A, Vicarioto MA. Crossed immunoelectrophoresis in the study of abnormal antithrombin II. Behaviour of AT III Trento Br J Haematol 1983; 55: 559-561
  • 25 Sakuragawa N, Takahashi 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
  • 26 Bauer KA, Asherhurst JB, Chediak J, Rosenberg RD. Antithrombin Chicago. A functionally abnormal molecule with increased heparin affinity causing familial thrombophilia Blood 1983; 62: 1242-1250
  • 27 Samson D, Stirling Y, Woolf L, Howarth D, Seghatchian MJ, de Chazal R. Management of planned pregnancy in a patient with congenital antithrombin III deficiency. Br J Haematol 1984; 56: 243-249
  • 28 Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966; 15: 45-52
  • 29 Laurell CE. Antigen-antibody crossed immunoelectrophoresis. Anal Biochem 1965; 10: 358-361
  • 30 Sas G, Pepper D, Cash J. Further investigations on antithrombin III in the plasma of patients with the abnormality of antithrombin III Budapest. Thrombos Diathes Haemorrh 1975; 33: 95-97
  • 31 Sas G, Pepper D. Detection of thrombin-antithrombin III complex by crossed immunoelectrophoresis. Thromb Res 1976; 9: 95-97
  • 32 Seghatchian MJ. The usefulness of chromogenic substrates in the diagnosis of haemophilia and control of blood products in: Chromogenic peptide substrates, chemistry and clinical usage. pp 102-118 Scully MF, Kakkar VV. (eds) Churchill; London: 1979
  • 33 Chandra T, Stackhouse R, Kidd VJ, Woo SL C. Isolation and sequence characterisation of a DNA clone of human antithrombin III. Proc Natl Acad Sci USA 1983; 80: 1845-1848
  • 34 Longas MO, Finlay TH. The covalent nature of the human antithrombin III - thrombin bond. Biochem J 1980; 189: 481-489
  • 35 Bjork J, Jackson CM, Jornvall H, Lavine KK, Nordling K, Salsgiver WJ. The active site of antithrombin. Release of the same proteolyti- cally cleaved form of the inhibitor from complexes with factor IXa, factor Xa, and thrombin J Biol Chem 1982; 257: 2406-2411
  • 36 Travis J, Salvesen GS. Human plasma proteinase inhibitors. Ann Rev Biochem 1983; 52: 655-709
  • 37 Rosenberg RD, Darmos PS. The purification and mechanism of action of human antithrombin heparin cofactor. J Biol Chem 1973; 248: 6490-6505
  • 38 Blackburn MN, Sibley CC. The heparin binding site of antithrombin III. Evidence for a critical tryptophan residue J Biol Chem 1980; 255: 824-826
  • 39 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 USA 1984; 81: 289-293
  • 40 Prochovnik EV, Antonarakis S, Bauer KA, Rosenberg RD, Fearon ER, Orkin SH. Molecular heterogeneity of inherited antithrombin III deficiency. N Eng J Med 1983; 308: 1550-1552
  • 41 Boyer C, Tripodi A, Wolf M, Mannucci PM, Larrieu MJ. A new familial variant of antithrombin III: Antithrombin III Milano. Thromb Haemostas 1983; 50: 51 (Abstr.)