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Abstract

Antibodies to prothrombin have been associated with venous and arterial thrombosis, and they cross-react with a structurally closely related protein plasminogen. We immunised 16 mice with human prothrombin and 15 mice with human plasminogen. Mice immunised with prothrombin developed cross-reactive antibodies to plasminogen (12/16), b2-glycoprotein I (4/16), tissue-type plasminogen activator (6/16) and cardiolipin (11/16). Mice immunised with plasminogen developed cross-reactive antibodies to prothrombin (8/15), tissue-type plasminogen activator (2/12) and cardiolipin (5/12). Functional effects of antibodies were examined. Immunisation with prothrombin induced lupus anticoagulant activity in 9/14 mice. In mice immunised with plasminogen, radial fibrinolysis was inhibited in 8/10 and plasminogen activation in the chromogenic assay was inhibited in 9/11. No cross-functionality was observed. In conclusion, antibodies to prothrombin and plasminogen cross-react in vivo. Antibodies to prothrombin and plasminogen have different functional profiles, immunisation with prothrombin leads to prolonged blood clotting time, and immunisation with plasminogen induces antibodies interfering with fibrinolysis.

Keywords

antiprothrombin antibodies antiphospholipid antibodies antiplasminogen antibodies lupus anticoagulant fibrinolysis

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Vaarala O , Puurunen M , Mänttäri M , Manninen V , Aho K , Palosuo T . Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men . Thromb Haemostasis 1996; 75: 456-469 .

Sammaritano LR , Gharavi AE , Lockshin MD . Antiphospholipid antibody syndrome: immunologic and clinical aspects . Semin Arthritis Rheumatol 1990; 20: 81-96 .

McNeil HP , Chesterman CN , Krilis SA . Immunology and clinical importance of antiphospholipid antibodies . Adv Immunol 1991; 49: 193-280 .

Hughes GRV . The antiphospholipid syndrome: ten years on . Lancet 1993; 342: 341-344 .

Puurunen M , Vaarala O , Julkunen H , Aho K , Palosuo T . Antibodies to plasma phospholipid-binding proteins and occurrence of thrombosis in patients with systemic lupus erythematosus . Clin Immunol Immunopathol 1996; 80: 16-22 .

Horbach DA , v Oort E , Donders RCJM , Derksen RHMW , de Groot PhG . Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus . Thromb Haemostasis 1996; 76: 916-924 .

Bertolaccini ML , Atsumi T , Khamashta MA , Amengual O , Hughes GR . Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus . J Rheumatol 1998; 25: 1104-1108 .

Palosuo T , Virtamo J , Haukka J et al. High antibody levels to prothrombin imply a risk of deep venous thrombosis and pulmonary embolism in middle-aged men . Thromb Haemostasis 1997; 78: 1178-1182 .

Patthy L . Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules . Cell 1985; 41: 657-663 .

10.

Castellino FJ , Beals JM . The genetic relationships between the kringle domains of human plasminogen, prothrombin, tissue-type plasminogen activator, urokinase and coagulation factor XII . J Mol Evol 1987; 26: 358-369 .

11.

Ikeo K , Takahashi K , Gojobori T . Evolutionary origin of numerous kringles in human and simian apolipoprotein(a) . FEBS Lett 1991; 287: 146-148 .

12.

Gharavi AE , Sammaritano LR , Wen J , Elkon KB . Induction of antiphospholipid autoantibodies by immunisation with b2-glyco-protein I (apolipoprotein H) . J Clin Invest 1992; 90: 1105-1109 .

13.

Pierangeli SS , Harris EN . Induction of phospholipid-binding antibodies in mice and rabbits by immunisation with human b2 glycoprotein I or anticardiolipin antibodies alone . Clin Exp Immunol 1993; 93: 269-272 .

14.

Blank M , Faden D , Tincani A et al. Immunisation with anticardiolipin cofactor (beta 2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice . J Autoimmun 1994; 7: 441-455 .

15.

Rauch J . Lupus anticoagulant antibodies: recognition of phospholipidbinding protein complexes . Lupus 1998; 7(Suppl 2): S29-S31 .

16.

Puurunen M , Mänttäri M , Manninen V . Antibodies to Prothrombin crossreact with plasminogen in patients developing myocardial infarction . Br J Haematol 1998; 100: 374-379 .

17.

Puurunen M , Jokiranta S , Vaarala O , Meri S . Lack of functional similarity between complement factor H and anticardiolipin cofactor, b2-glycoprotein I (apolipoprotein H) . Scand J Immunol 1995; 42: 547-550 .

18.

Church W , Messier TL , Ouellette LA , Potts SE . A kringle-specific monoclonal antibody . Hybridoma 1994; 13: 423-429 .

19.

Hochschwender SM , Laursen RA . Immunochemical characterisation of the kringle 4 fragment of human plasminogen . J Biol Chem 1981; 256: 11166-11171 .

20.

Ruiz-Arguelles A , Angles-Cano E , Perez-Romano B et al. Serum antibodies to distinct epitopes of the tissue-type plasminogen activator (t-PA) in patients with systemic lupus erythematosus . Am J Hematol 1995; 49: 109-114 .

21.

Salazar-Paramo M , Garcia de la Torre I , Fritzler MJ , Loyau S , Angles-Cano E . Antibodies to fibrin-bound tissue-type plasminogen activator in systemic lupus erythematosus are associated with Raynaud's phenomenon and thrombosis . Lupus 1996; 5: 275-278 .

22.

Jones DW , Gallimore MJ , Harris S , Winter M . Antibodies to FXII in lupus anticoagulant positive patients . Lupus 1998; 7(Suppl 2): B025–B025 (abstract).

23.

Viard J-P , Amoura Z , Bach J-F . Association of anti-b2-Glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus . Am J Med 1992; 93: 181-186 .

24.

Matsuda J , Gohchi K , Tsukamoto M , Saitoh N , Asami K , Hashimoto M . Anticoagulant activity of an anti-b2-glycoprotein I antibody is dependent on the presence of b2-glycoprotein I . Am J Hematol 1993; 44: 187-191 .

25.

Permpikul P , Rao LV , Rapaport SI . Functional and binding studies of the roles of prothrombin and beta2-glycoprotein I in the expression of lupus anticoagulant activity . Blood 1994; 83: 2878-2892 .

26.

Bevers EM , Galli M , Barbui T , Comfurius P , Zwaal RF . Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin . Thromb Haemostasis 1991; 66: 629-632 .

27.

Horbach DA , van Oort E , Derksen RH , de Groot PG . The contribution of anti-prothrombin antibodies to lupus anticoagulant activity <Eth> discrimination between functional and non-functional anti-prothrombin antibodies . Thromb Haemostasis 1998; 79: 790-795 .

28.

Church W , Messier TL . Inhibition of plasminogen activation by monoclonal antibodies to the kringle 5-B chain segment of human plasminogen . Hybridoma 1991; 10: 659-672 .

29.

Kanalas JJ . Effect of the nephritogenic autoantibody of Heymann's nephritis on plasminogen binding to gp330 and activation by urokinase . Biochim Biophys Acta 1993; 1225: 101-106 .

30.

Stefanescu M , Szegli G , Cremer L et al The presence and significance of some anti-enzyme antibodies (anti-plasminogen, anti-trypsin, antiphospholipase C) in rheumatoid arthritis (rA) . Arch Roum Pathol Exp Microbiol 1989; 48: 47-53 .

31.

Gonzalez-Gronow M , Cuchacovich M , Grigg DM , Pizzo SV . Analysis of autoantibodies to plasminogen in the serum of patients with rheumatoid arthritis . J Mol Med 1996; 74: 463-469 .

32.

Roubey RAS , Eisenberg RA , Harper MF , Winfield JB . ‘Anticardiolipin’ autoantibodies recognise b2-glycoprotein I in the absence of phospholipid . J Immunol 1995; 154: 954-960 .

Immunologic and hematologic properties of antibodies to prothrombin and plasminogen in a mouse model

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