Immunoglobulin G from Patients with Antiphospholipid Syndrome Impairs the Fibrin Dissolution with Plasmin
12. Juni 2001
Accepted after resubmission 28. November 2001
14. Dezember 2017 (online)
Immunoglobulin G (IgG) isolated from normal human blood plasma stabilizes the structure of perfused crosslinked fibrin and prolongs the time for its dissolution with plasmin, when the fibrin surface is exposed to 500 s-1 shear rate flow. The IgG from patients suffering in antiphospholipid syndrome with thrombotic complications exerts even stronger antifibrinolytic effect. A patient, whose IgG does not affect the fibrin dissolution with plasmin, displays a bleeding tendency. The shear stress-induced disassembly of the fibrin clots containing IgGs with antifibrinolytic potency occurs at a much more advanced stage of fibrin digestion, as evidenced by the electrophoretic pattern of the ureatreated samples. The antifibrinolytic effects are also produced under static conditions and these are caused by the variable portion of the IgG molecules (fragment Fab), whereas the constant part (fragment Fc) has no inhibitory effect. The IgGs with antifibrinolytic properties do not affect directly the plasmin activity in amidolytic assay, but the IgGs from APS patients obliterate the competition of the fibrin and the peptidyl-p-nitroanilide for the protease in the same assay system suggesting interference of the IgGs with the plasmin action on the fibrin substrate. Thus, the correlation of the clinical symptoms with the effect of the isolated IgG on the dissolution of perfused fibrin clots supports a physiological and a pathological role of IgG in the fibrinolytic process related to the variability of the cross-reactions of immunoglobulins with fibrin, fibrin degradation products or fibrin-plasmin complexes.
- 1 Shapiro SS. The lupus anticoagulant/antiphospholipid syndrome. Annu Rev Med 1996; 47: 533-53.
- 2 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149-57.
- 3 Rand JH, Wu XX. Antibody-mediated disruption of the annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome. Thromb Haemost 1999; 82: 649-55.
- 4 Roubey RAS. Immunology of the antiphospholipid syndrome: antibodies, antigens and autoimmune response. Thromb Haemost 1999; 82: 656-61.
- 5 Ieko M, Sawada K, Koike T, Notoya A, Mukai M, Kohno M, Wada N, Itoh T, Yoshioka N. The putative mechanism of thrombosis in antiphospholipid syndrome: impairment of the protein C and the fibrinolytic systems by monoclonal anticardiolipin antibodies. Semin Thromb Hemost 1999; 25: 503-7.
- 6 Cugno M, Dominguez M, Cabibbe M, Bisiani G, Galli M, Angles-Cano E, Agostoni A. Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome. Brit J Haematol 2000; 108: 871-5.
- 7 Ames PRJ, Tommasino C, Iannaccone L, Brillante M, Cimino R, Brancaccio V. Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies – a crucial role for acquired free protein S deficiency. Thromb Haemost 1996; 76: 190-4.
- 8 Scorer AE. Discordant effects on eicosanoids and fibrin degradation products in two murine models of antiphospholipid antibody. Thromb Res 1997; 85: 295-304.
- 9 Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486-9.
- 10 Harris EN. The Second International Anticardiolipin Standardization Workshop/The Kaps Group. Am J Clin Pathol 1990; 94: 476-84.
- 11 Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the second international workshop for identification of lupus anticoagulants. Thromb Haemost 1995; 74: 1597-603.
- 12 Steiner LA, Lowey S. Optical rotatory dispersion studies of rabbit )’Gimmunoglobulin and its papain fragments. J Biol Chem 1966; 241: 231-40.
- 13 Porter RR. The hydrolysis of rabbit )’-globulin and antibodies with crystalline papain. Biochem J 1959; 73: 119-26.
- 14 Kouki T, Inui T, Yamashiro K, Hachiya T, Ochi Y, Kaajita Y, Takasu N, Sato Y, Hagata A. Demonstration of fragments with thyroid stimulating activity from thyroid stimulation blocking antibodies-IgG molecules by papain digestion. Clin Endocrinol 1997; 47: 693-8.
- 15 Komorowicz E, Kolev K, Léránt I, Machovich R. Flow-rate modulated dissolution of fibrin with clot-embedded and circulating proteases. Circ Res 1998; 82: 1102-8.
- 16 Komorowicz E, Kolev K, Machovich R. Fibrinolysis with des-kringle derivatives of plasmin and its modulation by plasma protease inhibitors. Biochemistry 1998; 37: 9112-8.
- 17 Kolev K, Léránt I, Tenekejiev K, Machovich R. Regulation of the fibrinolytic activity of neutrophil leukocyte elastase, plasmin and miniplasmin by plasma protease inhibitors. J Biol Chem 1994; 269: 17030-4.
- 18 Kolev K, Komorowicz E, Owen WG, Machovich R. Quantitative comparison of fibrin degradation with plasmin, miniplasmin, neutrophil leukocyte elastase and cathepsin G. Thromb Haemost 1996; 75: 140-6.
- 19 Inglese J, Samama P, Patel S, Burbaum J, Stroke IL, Appel KC. Chemokine receptor-ligand interactions measured using time-resolved fluorescence. Biochemistry 1998; 37: 2372-7.
- 20 Laudano AP, Doolittle RF. Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization. Structural requirements, number of binding sites and species differences. Biochemistry 1980; 19: 1013-9.
- 21 Walker JB, Nesheim ME. The molecular weights, mass distribution, chain composition and structure of soluble fibrin degradation products released from a fibrin clot perfused with plasmin. J Biol Chem 1999; 274: 5201-12.
- 22 Dominguez M, Cacoub P, de la Torre IG, Piette JC, Salazar-Paramo M, vGodeau P, Angles-Cano E. Autoantibodies to receptor induced neoepitopes of fibrinolytic proteins in rheumatic and vascular diseases. J Rheumatol 2001; 28: 302-8.
- 23 Puurunen M, Palosuo T, Lassila R, Anttila M, Vaarala O. Immunological and hematological properties of antibodies to prothrombin and plasminogen in a mouse model. Lupus 2001; 10: 108-15.
- 24 Carr ME, Dent RM, Carr SL. Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma. J Lab Clin Med 1996; 128: 83-8.
- 25 Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267: 24259-63.
- 26 Gabriel DA, Smith LA, Folds JD, Davis L, Cancelosi SE. The influence of immunoglobulin (IgG) on the assembly of fibrin gels. J Lab Clin Med 1983; 01: 545-52.
- 27 O’Kane MJ, Wisdom GB, Desai ZR, Archbold GPR. Inhibition of fibrin monomer polymerization by myeloma immunoglobulin. J Clin Pathol 1994; 47: 266-8.
- 28 Kolev K, Tenekedjiev K, Komorowicz E, Machovich R. Functional evaluation of the structural features of proteases and their substrate in fibrin surface degradation. J Biol Chem 1997; 272: 13666-75.
- 29 Collet JP, Park D, Lesty C, Soria J, Soria C, Montalescot G, Weisel JW. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed. Dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000; 20: 1354-61.
- 30 Carr ME, Gabriel DA. The effect of dextran 70 on the structure of plasmaderived fibrin gels. J Lab Clin Med 1980; 96: 985-93.