Download PDF
Thromb Haemost 1997; 78(04): 1178-1182
DOI: 10.1055/s-0038-1657711
Rapid Communication
Schattauer GmbH Stuttgart

High Antibody Levels to Prothrombin Imply a Risk of Deep Venous Thrombosis and Pulmonary Embolism in Middle-aged Men

A Nested Case-control Study
Timo Palosuo
1   The National Public Health Institute, Helsinki, Finland
,
Jarmo Virtamo
1   The National Public Health Institute, Helsinki, Finland
,
Jari Haukka
1   The National Public Health Institute, Helsinki, Finland
,
Philip R Taylor
2   The National Cancer Institute, Bethesda, MD, USA
,
Kimmo Aho
1   The National Public Health Institute, Helsinki, Finland
,
Marja Puurunen
1   The National Public Health Institute, Helsinki, Finland
,
Outi Vaarala
1   The National Public Health Institute, Helsinki, Finland
› Author Affiliations
Further Information

Publication History

Received 26 1997

Accepted after resubmission 19 June 1997

Publication Date:
12 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Antibodies against phospholipid-binding plasma proteins, such as β2-glycoprotein I (β2-GPI) and prothrombin, are associated with thromboembolic events in patients with systemic lupus erythematosus and also in subjects with no evident underlying diseases. We wanted to examine whether increased levels of antibodies to negatively-charged phospholipids (cardiolipin), to phospholipid-binding plasma proteins β2-GPI and prothrombin and to oxidised low-density lipoprotein (LDL) were associated with risk of deep venous thrombosis or pulmonary embolism in subjects with no previous thrombosis. The antibodies were measured in stored serum samples from 265 cases of deep venous thrombosis of the lower extremity or pulmonary embolism occurring during a median follow-up of about 7 years and from 265 individually matched controls. The study subjects were middle-aged men participating in a cancer prevention trial of alpha-tocopherol and beta-carotene and the cases of thromboembolic events were identified from nationwide Hospital Discharge Register.

The risk for thrombotic events was significantly increased only in relation to antiprothrombin antibodies. As adjusted for body mass index, number of daily cigarettes and history of chronic bronchitis, myocardial infarction and heart failure at baseline, the odds ratio per one unit of antibody was 6.56 (95% confidence interval 1.73-25.0). The seven highest individual optical density-unit values of antiprothrombin antibodies were all confined to subjects with thromboembolic episodes.

In conclusion, the present nested case-control study showed that high autoantibody levels against prothrombin implied a risk of deep venous thrombosis and pulmonary embolism and could be involved in the development of the thrombotic processes.

 

  • References

  • 1 Harris EN, Gharavi AE, Boyey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GRV. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2: 1211-1214
    PubMedSearch in Google Scholar
  • 2 Galli M, Comfurius P, Maassen C, Hemker HC, De BaetsMH, van Breda-VriesmanPJC, 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
  • 3 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124
    CrossrefPubMedSearch in Google Scholar
  • 4 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measuremen of antiphospholipid antibodies by ELISA using β2-glycoprotein I as an antigen. J Immunol Methods 1991; 143: 223-229
    CrossrefPubMedSearch in Google Scholar
  • 5 Vermylen J, Amout J. Is the antiphospholipid syndrome caused by antibodies directed against physiologically relevant phospholipid-protein complexes?. J Lab Clin Med 1992; 120: 10-12
    PubMedSearch in Google Scholar
  • 6 Roubey RAS. Immunology of the antiphospholipid syndrome. Arthritis Rheum 1996; 39: 1444-1454
    CrossrefPubMedSearch in Google Scholar
  • 7 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA. Lupus anticoagulant are not directed to phospholipids only, but to a complex of lipid- bound human prothrombin. Thromb Haemost 1991; 66: 629-632
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Roubey RAS, Pratt CW, Buyon JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent on the presence of β2-glycoprotein I. J Clin Invest 1992; 90: 1100-1104
    CrossrefPubMedSearch in Google Scholar
  • 9 Permpikul P, Rao LVM, Rapaport SI. Functional and binding studies of prothrombin and β2-glycoprotein I in the expression of lupus anticoagulant activity. Blood 1994; 83: 2878-2879
    PubMedSearch in Google Scholar
  • 10 Arvieux J, Damige L, Caron C, Reber G, Bensa JC, Colomb MG. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 1120-1125
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Oosting JD, Derksen RHWM, Bobbink IWEG, Hackeng TM, Bouma BN, de GrootPG. 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
  • 12 Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo T. Cross-reaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993; 341: 923-925
    CrossrefPubMedSearch in Google Scholar
  • 13 Hӧrkkӧ S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, Terkeltaub R, Pierangeli SS, Branch DW, Palinski W, Witztum JL. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest 1996; 98: 815-825
    CrossrefPubMedSearch in Google Scholar
  • 14 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344
    CrossrefPubMedSearch in Google Scholar
  • 15 Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-3691
    PubMedSearch in Google Scholar
  • 16 Simioni P, Prandoni P, Zanon E, Saracino M, Scudeller A, Villata S, Scarano L, Girolami B, Beneditti L, Girolami A. Deep venous thrombosis and lupus anticoagulant. A case-control study. Thromb Haemost 1996; 76: 187-189
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Shur PH, Hennekens CH, Stampfer MJ. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117: 0997-1002
    CrossrefPubMedSearch in Google Scholar
  • 18 Bongard O, Reber G, Bounameux H, de MoerlooseP. Anticardiolipin antibodies in acute venous thromboembolism (letter). Thromb Haemost 1992; 67: 724
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 The ATBC Cancer Prevention Study Group. The alpha-tocopherol, beta- carotene lung cancer prevention study: Design, methods, participant characteristics and compliance. Ann Epidemiol 1994; 4: 01-10
    CrossrefPubMedSearch in Google Scholar
  • 20 Puurunen M, Vaarala O, Julkunen H, Aho K, Palosuo T. Antibodies to phospholipid-binding plasma proteins and occurrence of thrombosis in patients with systemic lupus erythematosus. Clin Immunol Immunopathol 1996; 80: 16-22
    CrossrefPubMedSearch in Google Scholar
  • 21 Clayton D, Hills M. Statistical methods in epidemiology. Chapter 33, Nested case-control studies. Oxford University Press; Oxford UK: 1993. pp 329-335
    Search in Google Scholar
  • 22 Vaarala O, Puurunen M, Mänttäri M, Manninen V, Aho K, Palosuo T. Antibodies to prothrombin imply a risk factor for myocardial infarction in middle-aged men. Thromb Haemost 1996; 75: 456-459
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Horbach DA, Oort E, Donders RCJM, Derksen RHWM, de GrootPG. Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Thromb Haemost 1996; 76: 916-924
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Bertolaccini ML, Atsumi T, Khamashta MA, Amengual O, Romero F, Hughes GRV. Clinical significance of antiprothrombin antibodies (aPT) in systemic lupus erythematosus (SLE) (abstract). Br J Rheumatol 1997; 36 (Suppl. 01) 9
    CrossrefPubMedSearch in Google Scholar
  • 25 Pengo V, Biasiolo A, Brocco T, Tonetto S, Ruffati A. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thromb Haemost 1996; 75: 721-724
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Craig WY, Poulin SE, Nelson CP, Ritchie RF. ELISA of IgG antibody to oxidized low-density lipoprotein: Effects of blocking buffer and method of data expression. Clin Chem 1994; 40: 882-888
    PubMedSearch in Google Scholar
  • 27 Salonen JT, Ylaä-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssӧnen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883-887
    CrossrefPubMedSearch in Google Scholar
  • 28 Maggi E, Chiesa R, Melissano G, Castellano R, Astore D, Grossi A, Finardi G, Bellomo G. LDL oxidation in patients with severe carotid atherosclerosis. A study of in vitro and in vivo oxidation markers. Arterio-scler Thromb 1994; 141892-141899
    PubMedSearch in Google Scholar
  • 29 Puurunen M, Mänttäri M, Manninen V, Vaarala O, Alfthan G, Ehnholm C, Aho K, Palosuo T. Antibodies against oxidised LDL predicting coronary infarction. Arch Int Med 1994; 154: 2605-2609
    CrossrefPubMedSearch in Google Scholar
  • 30 Amengual O, Atsumi T, Khamashta MA, Tinaones F, Cuandrajo MJ, Hughes GRV. Antibodies against oxidized low-density lipoprotein (ox-LDL) in 107 patients with antiphospholipid syndrome (APS). Arthritis Rheum 1996; 39 (Suppl. 09) S96
    PubMedSearch in Google Scholar
  • 31 Aho K, Vaarala O, Tenkanen L, Julkunen H, Jouhikainen T, Alfthan G, Palosuo T. Antibodies binding to anionic phospholipids but not to oxidized low-density lipoprotein are associated with thrombosis in patients with systemic lupus erythematosus. Clin Exp Rheumatol 1996; 14: 499-506
    PubMedSearch in Google Scholar
  • 32 Vaarala O. Antiphospholipid antibodies and atherosclerosis. Lupus 1996; 5: 442-447
    CrossrefPubMedSearch in Google Scholar
  • 33 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-462
    CrossrefPubMedSearch in Google Scholar
  • 34 Harley JB. Autoantibodies are central to the diagnosis and clinical manifestations of lupus. J Rheumatol 1994; 21: 1183-1185
    PubMedSearch in Google Scholar
  • 35 Van VenrooijWJ, van GelderCWG. B cell epitopes on nuclear autoantigens. What can they tell us?. Arthritis Rheum 1994; 37: 608-616
    CrossrefPubMedSearch in Google Scholar
  • 36 Lehman PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today 1993; 14: 203-208
    CrossrefPubMedSearch in Google Scholar
  • 37 Galli M, Beretta G, Daldossi M, Bevers EM, Barbui T. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1997; 77: 486-491
    Thieme ConnectPubMedSearch in Google Scholar