Partial Characterization of an Autoantibody Recognizing the Secondary Binding Site(s) of Thrombin in a Patient with Recurrent Spontaneous Arterial Thrombosis

J M Costa; J N Fiessinger; L Capron; M Aiach

doi:10.1055/s-0038-1648411

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1992; 67(02): 193-199
DOI: 10.1055/s-0038-1648411

Original Articles

Schattauer GmbH Stuttgart

Partial Characterization of an Autoantibody Recognizing the Secondary Binding Site(s) of Thrombin in a Patient with Recurrent Spontaneous Arterial Thrombosis

J M Costa

Laboratoire d’Hémostase et Centre Claude Bernard de Recherche sur les Maladies vasculaires périphériques, Hôpital Broussais, Paris, France

,

J N Fiessinger

Laboratoire d’Hémostase et Centre Claude Bernard de Recherche sur les Maladies vasculaires périphériques, Hôpital Broussais, Paris, France

,

L Capron

Laboratoire d’Hémostase et Centre Claude Bernard de Recherche sur les Maladies vasculaires périphériques, Hôpital Broussais, Paris, France

,

M Aiach

Laboratoire d’Hémostase et Centre Claude Bernard de Recherche sur les Maladies vasculaires périphériques, Hôpital Broussais, Paris, France

› Institutsangaben

Abstract

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Summary

A patient with an 18 year history of recurrent arterial thrombosis and no evidence of atherosclerosis or embolism of cardiac origin presented with a prolonged thrombin clotting time when performed with human thrombin. The bovine thrombin clotting time was only slightly prolonged. During 30 months of follow-up, the thrombin time fluctuated, but remained prolonged. The patient has been treated with an oral anticoagulant for the past 8 years, with no thrombotic recurrence.

The inhibitor activity was due to the presence of polyclonal IgGs which bound to thrombin-Sepharose. The influence of IgGs purified from the patient’s serum was compared to the influence of normal IgGs in several systems exploring the catalytic activity of thrombin and the binding of the enzyme to macromolecular substrates through secondary binding site(s). We found that the IgGs did not impair the catalytic activity toward small synthetic substrates, but inhibited the binding of thrombin to fibrinogen, thrombomodulin and heparin cofactor II. Such proteins are known to require a secondary binding site of thrombin to interact with the enzyme.

The anti-thrombin antibody might have resulted from an abnormal generation of thrombin. This would be the consequence of the process favouring thrombosis. Alternatively, the autoantibody might have favoured thrombosis primarily, by impairing natural antithrombotic mechanisms triggered by thrombin.

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Referenzen

References
1 Machovich R, Horvath I. Thrombin and haemostasis: Regulation of the biological functions of thrombin. (Facts and perspectives.). Haematologia 1981; 14: 339-359
2 Fenton II JW. Bioregulatory functions of thrombin. Part I. Structure of thrombin and thrombin derivatives. Thrombin^a . Ann NY Acad Sci 1986; 485: 5-15
3 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746
4 Fenton II JW, Fasco MJ, Stackrow AB. Human thrombins. Production, evaluation, and properties of a-thrombin. J Biol Chem 1977; 262: 3587-3598
5 Hortin GL, Tollefsen DM, Benutto BM. Antithrombin activity of a peptide corresponding to residues 54-75 of heparin cofactor II. J Biol Chem 1989; 264: 1379-1382
6 Jakubowski HV, Owen WG. Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin. J Biol Chem 1989; 264: 11117-11121
7 Aiach M, Léon M, Michaud A, Capron L. Adaptation of synthetic peptide substrate based assays on a discrete analyzer. Semin Thromb Haemostas 1983; 9: 206-216
8 Martinoli JL, Stocker K. Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res 1986; 43: 253-264
9 Toulon P, Jacquot C, Capron L, Frydman MO, Vignon D, Aiach M. Antithrombin III and heparin cofactor II in patients with chronic renal failure undergoing regular hemodialysis. Thromb Haemostas 1987; 57: 263-268
10 Comb PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-508
11 Haverkate F, Koopman J, Kluft C, D’Angelo A, Cattaneo M, Mannucci PM. Fibrinogen Milano II: a congenital dysfibrinogenaemia associated with juvenile arterial and venous thrombosis. Thromb Haemostas 1986; 55: 131-135
12 Angles-Canq E. A spectrophotometric solid-phase fibrin-tissue plasminogen activator activity assay (SOFIA-tPA) for high-fibrin-affinity tissue plasminogen activators. Anal Biochem 1986; 153: 201-210
13 Hofsteenge J, Braun PJ, Stone SR. Enzymatic properties of proteolytic derivatives of human a-thrombin. Biochemistry 1988; 27: 2144-2151
14 Toulon P, Chadeuf G, Aiach M. Heparin cofactor II: Purification from human plasma. J Chromatogr 1991; 539: 493-500
15 De Roux N, Chadeuf G, Molho-Sabatier P, Plouin PF, Aiach M. Clinical and biochemical characterization of AT III Franconville, a variant with Pro 41 Leu mutation. Br J Haematol 1990; 75: 222-227
16 Briault S, Courtois-Capella M, Duarte F, Aucouturier P, Preud’homme JL. Isotype of serum monoclonal immunoglobulins in human immunodeficiency virus-infected adult. Clin Exp Immunol 1988; 74: 181-186
17 Loeliger A, Hers JFP. Chronic antithrombinaemia (antithrombin V) with haemorrhagic diathesis in a case of rheumatoid arthritis with hypergammaglobulinaemia. Thromb Diath Haemorrh 1957; 1: 499-528
18 Strieker RB, Lane PK, Leffert JD, Rodgers GM, Shuman MA, Corash L. Development of antithrombin antibodies following surgery in patients with prosthetic cardiac valves. Blood 1988; 72: 1375-1380
19 Flaherty MJ, Wener MH. Antibodies to thrombin in postsurgical patients. Blood 1989; 73: 1386 (Letter)
20 Flaherty MJ, Henderson R, Wener MH. Iatrogenic immunization with bovine thrombin: A mechanism for prolonged thrombin times after surgery. Ann Intern Med 1989; 111: 631-634
21 Zehnder JL, Leung LLK. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood 1990; 76: 2011-2016
22 Lawson JH, Pennell BJ, Oison JD, Mann KG. Isolation and characterization of an acquired antithrombin antibody. Blood 1990; 76: 2249-2257
23 Hawiger J, Hanicki Z, Struzick T. On the immunologic nature of antithrombin in the course of lupus erythematosus disseminatus. Acta Med Polona 1964; 5: 53-60
24 Galanakis DK, Newman J, Summers D. Circulating thrombin time anticoagulant in a procainamide-induced syndrome. JAMA 1978; 239: 1873-1874
25 Barthels M, Heimburger N. Acquired thrombin inhibitor in a patient with liver cirrhosis. Haemostasis 1985; 15: 395-401
26 Gabriel DA, Carr ME, Cook L, Roberts HR. Spontaneous antithrombin in a patient with benign paraprotein. Am J Hematol 1987; 25: 85-93
27 Scully MF, Ellis V, Kakkar W, Savidge GF, Williams YF, Stemdale H. An acquired coagulation inhibitor to factor II. Br J Haematol 1982; 50: 655-664
28 Sié P, Bezeaud A, Dupouy D, Archipoff G, Freyssinet JM, Dugoujon JM, Serre G, Guillin MC, Boneu B. An acquired antithrombin antibody directed toward the catalytic center of the enzyme. J Clin Invest 1991; 88: 290-296
29 Fenton II JW, Olson TA, Zabinski MP, Wilner GD. Anion-binding exosite of human a-thrombin and fibrin(ogen) recognition. Biochemistry 1988; 27: 7106-7112
30 Davie EW. The blood coagulation factors: their cDNAs, genes, and expression. In: Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. (eds). 2nd edn. JB Lippincott Company; Philadelphia, PA: 1987. pp 242-267
31 Boissel JP, Le Bonniec B, Rabiet MJ, Labié D, Elion J. Covalent structures of an autolytic derivative of human a-thrombin. J Biol Chem 1984; 259: 5691-5697
32 Noé G, Hofsteenge J, Rovelli G, Stone SR. The use of sequence-specific antibodies to identify a secondary binding site in thrombin. J Biol Chem 1988; 263: 11729-11735
33 Mann KG, Lundblad RL. Biochemistry of thrombin. In: Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. (eds). 2nd edn. J B Lippincott Company; Philadelphia, PA: 1987. pp 148-161
34 Lord ST, Byrd PA, Hede HL, Wei C, Colby TJ. Analysis of fibrinogen A - fusion proteins. Mutants which inhibit thrombin equivalently are not equally good substrates. J Biol Chem 1990; 265: 838-843
35 Preissner KT, Koyama T, Müller D, Tschopp J, Müller-Berghaus G. Domain structure of the endothelial cell receptor thrombomodulin as deduced from modulation of its anticoagulant functions. Evidence for a glycosaminoglycan-dependent secondary binding site for thrombin. J Biol Chem 1990; 265: 4915-4922
36 Bourin MC, Lindahl U. Functional role of the polysaccharide component of rabbit thrombomodulin proteoglycan. Effects on inactivation of thrombin by antithrombin, cleavage of fibrinogen by thrombin and thrombin-catalyzed activation of factor V. Biochem J 1991; 270: 419-425
37 Maraganore JM, Chao B, Joseph ML, Jablonski J, Ramachandran KL. Anticoagulant activity of synthetic hirudin peptides. J Biol Chem 1989; 264: 8692-8696
38 Hortin GL, Banutto BM. Inhibition of thrombin’s clotting activity by synthetic peptide segments of its inhibitors and substrates. Biochem Biophys Res Commun 1990; 169: 437-441
39 Carlson TH. Clearance of thrombin in vivo: significance of alternative pathways. Mol Cell Biochem 1986; 71: 97-105
40 Maruyama I, Majerus PW. The turnover of thrombin-thrombomodulin complex in cultured human umbilical vein endothelial cells and A549 lung cancer cells. Endocytosis and degradation of thrombin. J Biol Chem 1985; 260: 15432-15438
41 Rosenberg RD, Rosenberg JS. Natural anticoagulant mechanisms. J Clin Invest 1984; 74: 1-6
42 Pizzo SV. Serpin receptor 1: A hepatic receptor that mediates the clearance of antithrombin Ill-proteinase complexes. Am J Med 1984; 87 Suppl (03) B 10-14
43 Schild H, Rôtzschke O, Kalbacher H, Rammensee HG. Limit of T cell tolerance to self proteins by peptide presentation. Science 1990; 247: 1587-1589
44 Prescott SM, Seeger AR, Zimmerman GA, McIntyre TM, Maraganore JM. Hirudin-based peptides block the inflammatory effects of thrombin on endothelial cells. J Biol Chem 1990; 265: 9614-9616