Thrombosis in Systemic Lupus Erythematosus: Role of Impaired Fibrinolysis

Abstract

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can affect any part of the body, including the skin, liver, kidneys, and blood. Thrombosis is a frequent manifestation in SLE, contributing significantly to patient morbidity and mortality, although the precise mechanism(s) of how this occurs remains unclear. Fibrinolysis is the physiologic process of thrombus digestion and provides an important balance to hemostasis. This process is triggered upon vessel injury with the release of tissue-type plasminogen activator (t-PA) from endothelial cells. The central component of the fibrinolytic pathway is plasminogen, a zymogen that is converted to plasmin by t-PA. Plasminogen/plasmin is absorbed into the developing thrombus and digests fibrinogen and fibrin within the hemostatic plug to prevent excessive clot formation. Abnormalities of the fibrinolytic pathway are associated either with the development of thrombosis (impaired fibrinolysis) or, to a lesser extent, bleeding (excessive fibrinolysis). Indeed, impaired fibrinolysis has been reported in patients with SLE and may contribute to both the development of hypercoagulability and an increased risk of thrombosis. Here we discuss the role of impaired fibrinolysis and its contribution to hypercoagulability and thrombosis in SLE.

Keywords

plasmin - PAI-1 - t-PA - TAFI - lupus

• References

• 1 D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet 2007; 369 (9561) 587-596
• 2 Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003; 56 (7) 481-490
• 3 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112 (9) 682-698
• 4 Kluz J, Kopeć W, Jakobsche-Policht U, Adamiec R. Circulating endothelial cells, endothelial apoptosis and soluble markers of endothelial dysfunction in patients with systemic lupus erythematosus-related vasculitis. Int Angiol 2009; 28 (3) 192-201
• 5 Afeltra A, Vadacca M, Conti L , et al. Thrombosis in systemic lupus erythematosus: congenital and acquired risk factors. Arthritis Rheum 2005; 53 (3) 452-459
• 6 Widlansky ME, Gokce N, Keaney Jr JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42 (7) 1149-1160
• 7 Forastiero R, Martinuzzo M. Prothrombotic mechanisms based on the impairment of fibrinolysis in the antiphospholipid syndrome. Lupus 2008; 17 (10) 872-877
• 8 Palomo IG, Segovia FM, Alarcon ML , et al. An insight into the pathophysiology of thrombosis in antiphospholipid syndrome. Front Biosci 2007; 12: 3093-3103
• 9 Pierangeli SS, Colden-Stanfield M, Liu X, Barker JH, Anderson GL, Harris EN. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 1999; 99 (15) 1997-2002
• 10 Kernoff PB, McNicol GP. Normal and abnormal fibrinolysis. Br Med Bull 1977; 33 (3) 239-244
• 11 Alkjaersig N, Fletcher AP, Sherry S. The mechanism of clot dissolution by plasmin. J Clin Invest 1959; 38 (7) 1086-1095
• 12 Peters MJ, Nurmohamed MT, van Eijk IC, Verkleij CJ, Marx PF. Thrombin-activatable fibrinolysis inhibitor and its relation with inflammation in rheumatoid arthritis. Ann Rheum Dis 2009; 68 (7) 1232-1233
• 13 Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler CJ. Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod 2003; 18 (11) 2473-2477
• 14 Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med 2002; 126 (11) 1401-1404
• 15 Seguí R, Estellés A, Mira Y , et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol 2000; 111 (1) 122-128
• 16 Tàssies D, Espinosa G, Muñoz-Rodríguez FJ , et al. The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome. Arthritis Rheum 2000; 43 (10) 2349-2358
• 17 Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61 (5) 1186-1195
• 18 Brandt JT. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. Arch Pathol Lab Med 2002; 126 (11) 1376-1381
• 19 Schuster V, Zeitler P, Seregard S , et al. Homozygous and compound-heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis. Thromb Haemost 2001; 85 (6) 1004-1010
• 20 Tefs K, Tait CR, Walker ID, Pietzsch N, Ziegler M, Schuster V. A K19E missense mutation in the plasminogen gene is a common cause of familial hypoplasminogenaemia. Blood Coagul Fibrinolysis 2003; 14 (4) 411-416
• 21 Jørgensen M, Bonnevie-Nielsen V. Increased concentration of the fast-acting plasminogen activator inhibitor in plasma associated with familial venous thrombosis. Br J Haematol 1987; 65 (2) 175-180
• 22 Booth NA. Fibrinolysis and thrombosis. Best Pract Res Clin Haematol 1999; 12 (3) 423-433
• 23 Chu P, Russell NH, Powell RJ, Cater DR, Harris RJ. Abnormal fibrinolytic activity in systemic lupus erythematosus and possible mechanisms. Br J Rheumatol 1988; 27 (6) 436-439
• 24 Doria A, Ghirardello A, Boscaro M , et al. Fibrinolysis and coagulation abnormalities in systemic lupus erythematosus. Relationship with Raynaud's phenomenon, disease activity, inflammatory indices, anticardiolipin antibodies and corticosteroid therapy. Rheumatol Int 1995; 14 (5) 207-211
• 25 Ruiz-Argüelles GJ, Ruiz-Argüelles A, Lobato-Mendizábal E , et al. Disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system in systemic lupus erythematosus. Am J Hematol 1991; 37 (1) 9-13
• 26 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 (6) 2121-2126
• 27 Salazar-Paramo M, Garcia de la Torre I, Fritzler MJ, Loyau S, Anglés-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 (4) 275-278
• 28 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 (4) 871-875
• 29 Fritzler MJ, Hart DA, Wilson D , et al. Antibodies to fibrin bound tissue type plasminogen activator in systemic sclerosis. J Rheumatol 1995; 22 (9) 1688-1693
• 30 Binder BR, Christ G, Gruber F , et al. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci 2002; 17: 56-61
• 31 Hori Y, Gabazza EC, Yano Y , et al. Insulin resistance is associated with increased circulating level of thrombin-activatable fibrinolysis inhibitor in type 2 diabetic patients. J Clin Endocrinol Metab 2002; 87 (2) 660-665
• 32 Małyszko J, Małyszko JS, Hryszko T, Myśliwiec M. Simvastain affects TAFI and thrombomodulin in CAPD patients. Thromb Haemost 2001; 86 (3) 930-931
• 33 Kluft C, Meijer P, Biasucci LM , et al. Plasma levels of TAFI are elevated in patients with unstable angina pectoris (UAP) compared to stable angina pectoris but show no relationship with outcome of UAP. Thromb Haemost 1999;
• 34 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95 (9) 2855-2859
• 35 Gresele P, Momi S, Berrettini M , et al. Activated human protein C prevents thrombin-induced thromboembolism in mice. Evidence that activated protein c reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation. J Clin Invest 1998; 101 (3) 667-676
• 36 Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006; 15 (5) 308-318
• 37 Ben-Menachem E. Review article: systemic lupus erythematosus: a review for anesthesiologists. Anesth Analg 2010; 111 (3) 665-676
• 38 Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurol Clin 2010; 28 (1) 61-73
• 39 Simard JF, Costenbader KH. What can epidemiology tell us about systemic lupus erythematosus?. Int J Clin Pract 2007; 61 (7) 1170-1180
• 40 Fukuyama H, Nimmerjahn F, Ravetch JV. The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 2005; 6 (1) 99-106
• 41 Mackay M, Stanevsky A, Wang T , et al. Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE. J Exp Med 2006; 203 (9) 2157-2164
• 42 McGaha TL, Sorrentino B, Ravetch JV. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 2005; 307 (5709) 590-593
• 43 Anolik JH. B cell biology and dysfunction in SLE. Bull NYU Hosp Jt Dis 2007; 65 (3) 182-186
• 44 Stohl W, Metyas S, Tan SM , et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum 2003; 48 (12) 3475-3486
• 45 Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 1999; 189 (10) 1639-1648
• 46 Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 1994; 180 (4) 1295-1306
• 47 Yurasov S, Wardemann H, Hammersen J , et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 2005; 201 (5) 703-711
• 48 Childs SG. The pathogenesis of systemic lupus erythematosus. Orthop Nurs 2006; 25 (2) 140-145 , quiz 146–147
• 49 Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 2002; 29 (12) 2531-2536
• 50 Adams MJ, Palatinus AA, Harvey AM, Khalafallah AA. Impaired control of the tissue factor pathway of blood coagulation in systemic lupus erythematosus. Lupus 2011; 20 (14) 1474-1483
• 51 Cervera R, Khamashta MA, Font J , et al; European Working Party on Systemic Lupus Erythematosus. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003; 82 (5) 299-308
• 52 Palatinus A, Adams M. Thrombosis in systemic lupus erythematosus. Semin Thromb Hemost 2009; 35 (7) 621-629
• 53 Chang ER, Pineau CA, Bernatsky S, Neville C, Clarke AE, Fortin PR. Risk for incident arterial or venous vascular events varies over the course of systemic lupus erythematosus. J Rheumatol 2006; 33 (9) 1780-1784
• 54 Sarabi ZS, Chang E, Bobba R , et al. Incidence rates of arterial and venous thrombosis after diagnosis of systemic lupus erythematosus. Arthritis Rheum 2005; 53 (4) 609-612
• 55 Wahl DG, Guillemin F, de Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus—a meta-analysis. Lupus 1997; 6 (5) 467-473
• 56 Keeling DM, Campbell SJ, Mackie IJ, Machin SJ, Isenberg DA. The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus. Br J Haematol 1991; 77 (3) 354-359
• 57 Tomás JF, Alberca I, Tabernero MD, Cordero M, Del Pino-Montes J, Vicente V. Natural anticoagulant proteins and antiphospholipid antibodies in systemic lupus erythematosus. J Rheumatol 1998; 25 (1) 57-62
• 58 Fusegawa H, Ichikawa Y, Tanaka Y , et al. [Regulation of coagulo-fibrinolytic activity and lupus anticoagulants in systemic lupus erythematosus]. Ryumachi 1990; 30 (2) 90-98
• 59 Byron MA, Allington MJ, Chapel HM, Mowat AG, Cederholm-Williams SA. Indications of vascular endothelial cell dysfunction in systemic lupus erythematosus. Ann Rheum Dis 1987; 46 (10) 741-745
• 60 Jenkins GR, Seiffert D, Parmer RJ, Miles LA. Regulation of plasminogen gene expression by interleukin-6. Blood 1997; 89 (7) 2394-2403
• 61 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 (5) 516-520
• 62 Violi F, Ferro D, Valesini G , et al. Tissue plasminogen activator inhibitor in patients with systemic lupus erythematosus and thrombosis. BMJ 1990; 300 (6732) 1099-1102
• 63 Glas-Greenwalt P, Kant KS, Allen C, Pollak VE. Fibrinolysis in health and disease: severe abnormalities in systemic lupus erythematosus. J Lab Clin Med 1984; 104 (6) 962-976
• 64 Matsuda J, Kawasugi K, Gohchi K , et al. Clinical significance of the venous occlusion test on systemic lupus erythematosus patients with a focus on changes in blood levels of tissue plasminogen activator, von Willebrand factor antigen, and thrombomodulin. Acta Haematol 1992; 88 (1) 22-26
• 65 Awada H, Barlowatz-Meimon G, Dougados M, Maisonneuve P, Sultan Y, Amor B. Fibrinolysis abnormalities in systemic lupus erythematosus and their relation to vasculitis. J Lab Clin Med 1988; 111 (2) 229-236
• 66 Jordan JM, Allen NB, Pizzo SV. Defective release of tissue plasminogen activator in systemic and cutaneous vasculitis. Am J Med 1987; 82 (3) 397-400
• 67 Somers EC, Marder W, Kaplan MJ, Brook RD, McCune WJ. Plasminogen activator inhibitor-1 is associated with impaired endothelial function in women with systemic lupus erythematosus. Ann N Y Acad Sci 2005; 1051: 271-280
• 68 Nguyen G, Horellou MH, Kruithof EK, Conard J, Samama MM. Residual plasminogen activator inhibitor activity after venous stasis as a criterion for hypofibrinolysis: a study in 83 patients with confirmed deep vein thrombosis. Blood 1988; 72 (2) 601-605
• 69 Ringwald J, Buettner S, Zimmermann R , et al. Thrombin-activatable fibrinolysis inhibitor and activated factor XII in patients with systemic lupus erythematosus. Thromb Res 2007; 119 (1) 129-131
• 70 Donmez A, Aksu K, Celik HA , et al. Thrombin activatable fibrinolysis inhibitor in Behçet's disease. Thromb Res 2005; 115 (4) 287-292
• 71 Bu C, Li Z, Zhang C, Gao L, Cai G. IgG antibodies to plasminogen and their relationship to IgG anti-beta(2)-glycoprotein 1 antibodies and thrombosis. Clin Rheumatol 2008; 27 (2) 171-178
• 72 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 (Berl) 1996; 74 (8) 463-469
• 73 Kozmin LD, Shirokova IE, Lisitsina TA , et al. Anti-plasminogen autoantibodies from plasma of patients with systemic lupus erythematosus having anti-phospholipid antibody syndrome: isolation and some immunochemical properties. Biochemistry (Mosc) 2003; 68 (3) 339-345
• 74 Stefănescu M, Szegli G, Cremer L , et al. The presence and significance of some anti-enzyme antibodies (anti-plasminogen, anti-trypsin, anti-phospholipase C) in rheumatoid arthritis (RA) and reactive arthritis (rA). Arch Roum Pathol Exp Microbiol 1989; 48 (1) 47-53
• 75 Simmelink MJ, De Groot PG, Derksen RH. A study on associations between antiprothrombin antibodies, antiplasminogen antibodies and thrombosis. J Thromb Haemost 2003; 1 (4) 735-739
• 76 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
• 77 Bates RL, Payne SJ, Drury SL , et al. The prevalence and clinical significance of autoantibodies to plasminogen activator inhibitor 1 in systemic lupus erythematosus. Lupus 2003; 12 (8) 617-622
• 78 Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78 (12) 3114-3124
• 79 Lindahl G, Gersdorf E, Menzel HJ , et al. The gene for the Lp(a)-specific glycoprotein is closely linked to the gene for plasminogen on chromosome 6. Hum Genet 1989; 81 (2) 149-152
• 80 Loskutoff DJ, Samad F. The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol 1998; 18 (1) 1-6
• 81 Rau JC, Beaulieu LM, Huntington JA, Church FC. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost 2007; 5 (Suppl. 01) 102-115
• 82 Sigurdardottir O, Wiman B. Identification of a PAI-1 binding site in vitronectin. Biochim Biophys Acta 1994; 1208 (1) 104-110
• 83 Antovic JP. Thrombin activatable fibrinolysis inhibitor (TAFI). A link between coagulation and fibrinolysis. Clin Lab 2003; 49 (9-10) 475-486
• 84 Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 2000; 20 (12) 2511-2518
• 85 Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood 1996; 88 (6) 2093-2100
• 86 Juhan-Vague I, Morange PE, Aubert H , et al; HIFMECH Study Group. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol 2002; 22 (5) 867-873