Impaired Fibrinolysis in the Antiphospholipid Syndrome

Abstract

The pathogenesis of the antiphospholipid syndrome (APS) is complex and involves the persistent presence of antiphospholipid antibodies (aPL) in the bloodstream causing a prothrombotic condition. aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation. Impaired fibrinolysis has been found in APS patients with thrombotic as well as obstetric manifestations. Increased levels of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, together with the presence of aPL against annexin-2, tissue-type plasminogen activator, and plasminogen contribute to the compromised fibrinolytic activity in these patients. Furthermore, unfavorably altered fibrin morphology, less amenable to fibrinolysis, has been proposed as a novel prothrombotic mechanism in APS. This review aims to summarize the present knowledge of the mechanisms involved in impaired fibrinolysis in APS patients. We also present a case from clinical practice as an illustration of fibrinolysis impairment in APS patients from a real-life setting.

Keywords

antiphospholipid syndrome - fibrinolysis - fibrin - plasmin - tissue plasminogen activator

Publikationsverlauf

Artikel online veröffentlicht:
20. April 2021

• References

• 1 Cervera R, Piette JC, Font J. et al; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46 (04) 1019-1027
• 2 Cervera R, Bucciarelli S, Plasín MA. et al; Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies). Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 2009; 32 (3-4): 240-245
• 3 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
• 4 Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72 (02) 512-519
• 5 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 Haemost 1991; 66 (06) 629-632
• 6 Oosting JD, Derksen RH, Bobbink IW, 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 (10) 2618-2625
• 7 Atsumi T, Ieko M, Bertolaccini ML. et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000; 43 (09) 1982-1993
• 8 Pengo V, Ruffatti A, Tonello M. et al. Antiphospholipid syndrome: antibodies to Domain 1 of β2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost 2015; 13 (05) 782-787
• 9 de Laat B, Pengo V, Pabinger I. et al. The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study. J Thromb Haemost 2009; 7 (11) 1767-1773
• 10 Celińska-Lowenhoff M, Iwaniec T, Padjas A, Musiał J, Undas A. Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation. Thromb Haemost 2014; 112 (02) 287-296
• 11 Vikerfors A, Svenungsson E, Ågren A. et al. Studies of fibrin formation and fibrinolytic function in patients with the antiphospholipid syndrome. Thromb Res 2014; 133 (05) 936-944
• 12 Wiman B, Collen D. Molecular mechanism of physiological fibrinolysis. Nature 1978; 272 (5653): 549-550
• 13 Weisel JW, Nagaswami C, Korsholm B, Petersen LC, Suenson E. Interactions of plasminogen with polymerizing fibrin and its derivatives, monitored with a photoaffinity cross-linker and electron microscopy. J Mol Biol 1994; 235 (03) 1117-1135
• 14 Hajjar KA. The biology of annexin A2: from vascular fibrinolysis to innate immunity. Trans Am Clin Climatol Assoc 2015; 126: 144-155
• 15 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem 1995; 270 (24) 14477-14484
• 16 Dudek-Wojciechowska GA, Kloczewiak M, Latallo ZS, Kopeć M. Characterisation of large fragments rich in disulphide bridges from CNBr-treated products of exhaustive proteolysis of fibrinogen by plasmin. Biochim Biophys Acta 1973; 295 (02) 536-542
• 17 Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost 2005; 93 (04) 647-654
• 18 Curnow JL, Morel-Kopp MC, Roddie C, Aboud M, Ward CM. Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay. J Thromb Haemost 2007; 5 (03) 528-534
• 19 Grosso G, Vikerfors A, Woodhams B. et al. Thrombin activatable fibrinolysis inhibitor (TAFI)—a possible link between coagulation and complement activation in the antiphospholipid syndrome (APS). Thromb Res 2017; 158: 168-173
• 20 Carr Jr ME, Shen LL, Hermans J. Mass-length ratio of fibrin fibers from gel permeation and light scattering. Biopolymers 1977; 16 (01) 1-15
• 21 Antovic A. The overall hemostasis potential: a laboratory tool for the investigation of global hemostasis. Semin Thromb Hemost 2010; 36 (07) 772-779
• 22 Siudut J, Świat M, Undas A. Altered fibrin clot properties in patients with cerebral venous sinus thrombosis: association with the risk of recurrence. Stroke 2015; 46 (09) 2665-2668
• 23 Martínez-Zamora MA, Tassies D, Carmona F. et al. Clot lysis time and thrombin activatable fibrinolysis inhibitor in severe preeclampsia with or without associated antiphospholipid antibodies. J Reprod Immunol 2010; 86 (02) 133-140
• 24 Martinez-Zamora MA, Tassies D, Carmona F. et al. Thrombin activatable fibrinolysis inhibitor and clot lysis time in pregnant patients with antiphospholipid syndrome: relationship with pregnancy outcome and thrombosis. Am J Reprod Immunol 2009; 62 (06) 381-389
• 25 Asztabski M, Wypasek E, Ząbczyk M, Undas A. Reduced plasma fibrin clot permeability and susceptibility to fibrinolysis are associated with increased intima-media thickness in patients with primary antiphospholipid syndrome. Thromb Res 2014; 134 (05) 945-951
• 26 Ferro D, Saliola M, Meroni PL. et al. Enhanced monocyte expression of tissue factor by oxidative stress in patients with antiphospholipid antibodies: effect of antioxidant treatment. J Thromb Haemost 2003; 1 (03) 523-531
• 27 Stachowicz A, Zabczyk M, Natorska J. et al. Differences in plasma fibrin clot composition in patients with thrombotic antiphospholipid syndrome compared with venous thromboembolism. Sci Rep 2018; 8 (01) 17301
• 28 Kolev K, Gombás J, Váradi B. et al. Immunoglobulin G from patients with antiphospholipid syndrome impairs the fibrin dissolution with plasmin. Thromb Haemost 2002; 87 (03) 502-508
• 29 Rikarni D, Dharma R, Tambunan KL. et al. Prothrombotic effect of anti-beta-2 glycoprotein-1 antibodies on the expression of tissue factor, thrombomodulin, and plasminogen activator inhibitor-1 in endothelial cells. Acta Med Indones 2015; 47 (01) 31-37
• 30 Jurado M, Páramo JA, Gutierrez-Pimentel M, Rocha E. Fibrinolytic potential and antiphospholipid antibodies in systemic lupus erythematosus and other connective tissue disorders. Thromb Haemost 1992; 68 (05) 516-520
• 31 Ames PR, 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 (02) 190-194
• 32 Singh NK, Gupta A, Behera DR, Dash D. Elevated plasminogen activator inhibitor type-1 (PAI-1) as contributing factor in pathogenesis of hypercoagulable state in antiphospholipid syndrome. Rheumatol Int 2013; 33 (09) 2331-2336
• 33 Atsumi T, Khamashta MA, Andujar C. et al. Elevated plasma lipoprotein(a) level and its association with impaired fibrinolysis in patients with antiphospholipid syndrome. J Rheumatol 1998; 25 (01) 69-73
• 34 Bu C, Gao L, Xie W. et al. beta2-glycoprotein i is a cofactor for tissue plasminogen activator-mediated plasminogen activation. Arthritis Rheum 2009; 60 (02) 559-568
• 35 López-Lira F, Rosales-León L, Martínez VM, Ruiz Ordaz BH. The role of beta2-glycoprotein I (beta2GPI) in the activation of plasminogen. Biochim Biophys Acta 2006; 1764 (04) 815-823
• 36 Cesarman-Maus G, Ríos-Luna NP, Deora AB. et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood 2006; 107 (11) 4375-4382
• 37 Cesarman-Maus G, Cantú-Brito C, Barinagarrementeria F. et al. Autoantibodies against the fibrinolytic receptor, annexin A2, in cerebral venous thrombosis. Stroke 2011; 42 (02) 501-503
• 38 Ao W, Zheng H, Chen XW, Shen Y, Yang CD. Anti-annexin II antibody is associated with thrombosis and/or pregnancy morbidity in antiphospholipid syndrome and systemic lupus erythematosus with thrombosis. Rheumatol Int 2011; 31 (07) 865-869
• 39 Chen PP, Giles I. Antibodies to serine proteases in the antiphospholipid syndrome. Curr Rheumatol Rep 2010; 12 (01) 45-52
• 40 Cugno M, Dominguez M, Cabibbe M. et al. Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome. Br J Haematol 2000; 108 (04) 871-875
• 41 Cugno M, Cabibbe M, Galli M. et al. Antibodies to tissue-type plasminogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in 2 patients. Blood 2004; 103 (06) 2121-2126
• 42 Lu CS, Horizon AA, Hwang KK. et al. Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome. Arthritis Rheum 2005; 52 (12) 4018-4027
• 43 Yang CD, Hwang KK, Yan W. et al. Identification of anti-plasmin antibodies in the antiphospholipid syndrome that inhibit degradation of fibrin. J Immunol 2004; 172 (09) 5765-5773
• 44 Simmelink MJA, De Groot PG, Derksen RHWM. A study on associations between antiprothrombin antibodies, antiplasminogen antibodies and thrombosis. J Thromb Haemost 2003; 1 (04) 735-739
• 45 Bu C, Li Z, Zhang C, Gao L, Cai G. IgG antibodies to plasminogen and their relationship to IgG anti-β(2)-glycoprotein 1 antibodies and thrombosis. Clin Rheumatol 2008; 27 (02) 171-178
• 46 Foley JH, Cook PF, Nesheim ME. Kinetics of activated thrombin-activatable fibrinolysis inhibitor (TAFIa)-catalyzed cleavage of C-terminal lysine residues of fibrin degradation products and removal of plasminogen-binding sites. J Biol Chem 2011; 286 (22) 19280-19286
• 47 Oku K, Nakamura H, Kono M. et al. Complement and thrombosis in the antiphospholipid syndrome. Autoimmun Rev 2016; 15 (10) 1001-1004
• 48 Ieko M, Yoshida M, Naito S. et al. Increase in plasma thrombin-activatable fibrinolysis inhibitor may not contribute to thrombotic tendency in antiphospholipid syndrome because of inhibitory potential of antiphospholipid antibodies toward TAFI activation. Int J Hematol 2010; 91 (05) 776-783