Download PDF
Thromb Haemost 1996; 75(03): 456-459
DOI: 10.1055/s-0038-1650296
Original Article
Schattauer GmbH Stuttgart

Antibodies to Prothrombin Imply a Risk of Myocardial Infarction in Middle-Aged Men

Outi Vaarala
1   The Department of Immunobiology, National Public Health Institute, Helsinki
,
Marja Puurunen
1   The Department of Immunobiology, National Public Health Institute, Helsinki
,
Matti Mänttäri
2   Department of Medicine, University of Helsinki, Finland
,
Vesa Manninen
2   Department of Medicine, University of Helsinki, Finland
,
Kimmo Aho
1   The Department of Immunobiology, National Public Health Institute, Helsinki
,
Timo Palosuo
1   The Department of Immunobiology, National Public Health Institute, Helsinki
› Author Affiliations
Further Information

Publication History

Received 24 August 1995

Accepted after revision 30 November 1995

Publication Date:
26 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Antiphospholipid antibodies in patients with “antiphospholipid syndrome” may be directed at least in part against plasma phospholipid-binding proteins, such as Β2-glycoprotein I or prothrombin, which are involved in the control of thrombosis and haemostasis. IgG-class antibodies against prothrombin and Β2-glycoprotein I were measured by enzyme-linked immunoassay in initially healthy middle-aged dyslipid-aemic men (non-high-density lipoprotein >5.2 mml/1). Serum samples had been drawn at entry to a 5-year coronary primary-prevention trial with gemfibrozil from 106 subjects who experienced either a non-fatal myocardial infarction or cardiac death during the follow-up and from 106 subjects without coronary episodes, matched for treatment group (gemfibrozil/placebo) and geographical area.

The antiprothrombin antibody level, as expressed in optical density units, was significantly higher in patients than in controls (0.26 ±0.17 versus 0.22 ±0.09; p<0.02). A high level of antiprothrombin antibodies (highest tertile of distribution) predicted a 2.5-fold increase in the risk (95% confidence interval 1.2-5.3) of myocardial infarction or cardiac death. The distribution of IgG-class antibodies against (Β2-glycoprotein I did not differ significantly between cases and controls. The joint effect of antiprothrombin antibodies and other factors associated with hypercoagulative state: triglyceride level, lipoprotein(a) and smoking, was multiplicative for the risk. Antiprothrombin antibodies are a new immunological predictor of myocardial infarction and the effect of these antibodies may be mediated by hypercoagulative mechanisms.

 

  • References

  • 1 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344
    CrossrefPubMedSearch in Google Scholar
  • 2 Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA. A phospholipid (Β2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1992; 1: 75-81
    CrossrefPubMedSearch in Google Scholar
  • 3 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Suzuki T, Sumida T, Yasuda T, Koike T. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885-3891
    PubMedSearch in Google Scholar
  • 4 Galli M, Comfurius P, Maassen C, Hemker HC, De Baets MH, van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-1547
    CrossrefPubMedSearch in Google Scholar
  • 5 McNeil HP, Simpson RJ, Chesterman CM, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: (2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124
    CrossrefPubMedSearch in Google Scholar
  • 6 Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512
    PubMedSearch in Google Scholar
  • 7 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-32
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Oosting JD, Derksen RHWM, Bobbink IWG, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: An explanation for their pathogenic mechanism?. Blood 1993; 81: 2618-2625
    PubMedSearch in Google Scholar
  • 9 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-462
    CrossrefPubMedSearch in Google Scholar
  • 10 Roubey RAS, Eisenberg RA, Winfield JB. “Anticardiolipin” autoantibodies recognize (Β2-glycoprotein I in the absence of phospholipid. Importance of antigen density and bivalent binding. J Immunol 1995; 154: 954-960
    PubMedSearch in Google Scholar
  • 11 Baker WF, Bick RL. Antiphospholipid antibodies in coronary artery disease: a review. Semin Thromb Hemost 1994; 20: 27-34
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Vaarala O, Mänttäri M, Manninen V, Tenkanen L, Puurunen M, Aho K, Palosuo T. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91: 23-27
    CrossrefPubMedSearch in Google Scholar
  • 13 Frick HM, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237-1245
    CrossrefPubMedSearch in Google Scholar
  • 14 Puurunen M, Mänttäri M, Manninen V, Tenkanen L, Alfthan G, Ehnholm C, Vaarala O, Aho K, Palosuo T. Antibody against oxidized low-density lipoprotein predicting myocardial infarction. Arch Intern Med 1994; 154: 2605-2609
    CrossrefPubMedSearch in Google Scholar
  • 15 Viard JP, Amoura Z, Bach JF. Association of anti-beta 2 glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992; 93: 181-186
    CrossrefPubMedSearch in Google Scholar
  • 16 Martinuzzo ME, Forastiero RR, Carreras LO. Anti (Β2-glycoprotein I antibodies: detection and association with thrombosis. Br J Haematol 1995; 89: 397-402
    CrossrefPubMedSearch in Google Scholar
  • 17 Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo T. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993; 341: 923-925
    CrossrefPubMedSearch in Google Scholar
  • 18 Vaarala O, Lukka M, Alfthan G, Leirisalo-Repo M, Aho K, Palosuo T. Crossreactivity of anticardiolipin antibodies with oxidised low-density lipoprotein. Lupus 1994; 3: 359
    PubMedSearch in Google Scholar
  • 19 Arvieux J, Roussel B, Ponard D, Colomb MG. IgG2 subclass restriction of anti-beta 2 glycoprotein 1 antibodies in autoimmune patients. Clin Exp Immunol 1994; 95: 310-315
    PubMedSearch in Google Scholar
  • 20 Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: A new view of lupus anticoagulants and other “antiphospholipid” autoantibodies. Blood 1994; 84: 2854-2867
    PubMedSearch in Google Scholar
  • 21 Mussoni L, Mannucci L, Sirtori M, Camera M, Madema P, Sironi L, Tremoli E. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992; 12: 19-27
    CrossrefPubMedSearch in Google Scholar
  • 22 Hajjar KA, Gavish D, Breslow JL, Nachman RL. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-305
    CrossrefPubMedSearch in Google Scholar
  • 23 Miles LA, Fless GM, Levin EG, Scanu AM, Plowe EF. A potential basis for the thrombotic risks associated with lipoprotein(a). Nature 1989; 339: 301-303
    CrossrefPubMedSearch in Google Scholar
  • 24 Assmann G, Hunt BJ. Clinical chemistry and coagulation. Curr Opin Lipidol 1994; 5: 391-394
    CrossrefPubMedSearch in Google Scholar
  • 25 Yamazaki M, Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E, Aoshima K, Ikeda T, Matsuda T. Plasma levels of lipoprotein(a) are elevated in patients with the antiphospholipid antibody syndrome. Thromb Haemost 1994; 71: 424-427
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Jauhiainen M, Koskinen P, Ehnholm C, Frick MH, Mänttäri M, Manninen V, Huttunen J. Lipoprotein(a) and coronary heart disease risk: a nested case control study of the Helsinki Heart Study participants. Atherosclerosis 1991; 89: 59-67
    CrossrefPubMedSearch in Google Scholar
  • 27 Hanson SR, Griffith HJ, Harker LA, Kelly AB, Esmon CT, Gruber A. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest 1993; 92: 2003-2012
    CrossrefPubMedSearch in Google Scholar
  • 28 Ginsberg JS, Demers C, Brill-Edwards P, Johnston M, Bona R, Burrows RF, Weitz J, Denburg JA. Increased thrombin generation and activity in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state. Blood 1993; 81: 2958-2963
    PubMedSearch in Google Scholar
  • 29 Kienast J, Thompson SG, Raskino C, Pelzer H, Fechtrup C, Ostermann H, van de Loo J. Prothrombin activation fragment 1 + 2 and thrombin anti thrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atheriosclerosis. Thromb Haemost 1994; 72: 550-553
    PubMedSearch in Google Scholar
  • 30 Lassila R, Peltonen S, Lepäntalo M, Saarinen O, Kauhanen P, Manninen V. Severity of peripheral atherosclerosis is associated with fibrinogen and degradation of cross-linked fibrin. Arterioscler Thromb 1993; 13: 1738-1742
    CrossrefPubMedSearch in Google Scholar
  • 31 Wu JR, Lentz BR. Phospholipid-specific conformational changes in human prothrombin upon binding to procoagulant acidic lipid membranes. Thromb Haemost 1994; 71: 596-604
    Thieme ConnectPubMedSearch in Google Scholar