Antiphospholipid syndrome (APS) is a clinical autoimmune disorder characterised by thrombosis, venous or arterial, and recurrent pregnancy morbidity in association with the persistence of antiphospholipid antibodies (aPL). The clinical variety of aPL ranges from asymptomatic individuals to those with multiple organ thromboses and failure developing over a short period, also known as catastrophic APS. An increasing number of phospholipid-binding proteins with crucial functions in the regulation of blood coagulation and fibrinolysis are targeted by APS-related autoantibodies. Disruption of fibrinolysis is one of the proposed pathophysiological mechanisms for the APS. There are some experimental data for an association between impaired overall fibrinolytic activity and autoimmune aPL; however, evidence is still inconclusive and more studies are needed in this area. In this article, we review the evidence by which aPL may disturb fibrinolysis.
2 Miyakis S Lockshin MD Atsumi T . International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).J Thromb Haemost2006; 4: 295–306.
3.
3 Forastiero R Martinuzzo M . Antigen specificity and clinical relevance of antiphospholipid syndrome-related autoantibodies.Curr Rheumatol Rev2005; 1: 177–187.
4.
4 Galli M Borrelli G Jacobsen EM . Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the anti-phospholipid syndrome) study.Blood2007; 110: 1178–1183.
5.
5 Forastiero R Martinuzzo M Pombo G . A prospective study of antibodies to β2 glycoprotein I and prothrombin, and risk of thrombosis.J Thromb Haemost2005; 3: 1231–1238.
6.
6 Bizzaro N Ghirardello A Zampieri S . Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: a 15-year longitudinal study.J Thromb Haemost2007; 5: 1158–1164.
7.
7 Giannakopoulos B Passam F Rahgozar S Krilis SA . Current concepts on the pathogenesis of the antiphospholipid syndrome.Blood2007; 109: 422–430.
8.
8 Vega-Ostertag M Pierangeli SS . Mechanisms of aPL-mediated thrombosis: effects of aPL on endothelium and platelets.Curr Rheumatol Rep2007; 9: 190–197.
9.
9 Pierangeli SS Chen PP Gonzalez EB . Antiphospholipid antibodies and the antiphospholipid syndrome: an update on treatment and pathogenic mechanisms.Curr Opin Hematol2006; 13: 366–375.
10.
10 Koike T Bohgaki M Amengual O Atsumi T . Antiphospholipid antibodies: lessons from the bench.J Autoimmun2007; 28: 129–133.
11.
11 Nilsson TK Lofvenberg E . Decreased fibrinolytic capacity and increased von Willebrand factor levels as indicators of endothelial cell dysfunction in patients with lupus anticoagulants.Clin Rheumatol1989; 8: 58–63.
12.
12 Keeling DM Campbell SJ Mackie IJ . The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus.Br J Haematol1991; 77: 354–359.
13.
13 Ferro D Violi F Quintarelli C . Fibrinolytic balance and lupus anticoagulant in patients with repeated spontaneous fetal loss.Br Med J1992; 305: 504–505.
14.
14 Tsakiris DA Marbet GA Makris PE . Impaired fibrinolysis as an essential contribution to thrombosis in patients with lupus anticoagulant.Thromb Haemost1989; 61: 175–177.
15.
15 Violi F Ferro D Valesini G . Tissue plasminogen activator inhibitor in patients with systemic lupus erythematosus and thrombosis.Br Med J1990; 300: 1099–1102.
16.
16 Kordich LC Forastiero R Basilotta E . Natural inhibitors of blood coagulation and fibrinolysis in patients with lupus anticoagulant.Blood Coagul Fibrinolysis1992; 3: 765–771.
17.
17 Atsumi T Khamashta MA Andujar C . Elevated plasma lipoprotein(a) level and its association with impaired fibrinolysis in patients with antiphospholipid syndrome.J Rheumatol1998; 25: 69–73.
18.
18 Curnow JL Morel-Kopp MC Roddie C . Reduced fibrinolysis and increased fibrin generation in hypercoagulable patients using the overall hemostatic potential assay.J Thromb Haemost2007; 5: 528–534.
19.
19 Puurunen M Palosuo T Lassila R . Immunologic and hematologic properties of antibodies to prothrombin and plasminogen in a mouse model.Lupus2001; 10: 108–115.
20.
20 Simmelink MJA de Groot PG Derksen RHWM . A study on association between antiprothrombin antibodies, antiplasminogen antibodies and thrombosis.J Thromb Haemost2003; 1: 735–739.
21.
21 Bu C Li Z Zhang C . IgG antibodies to plasminogen and their relationship to IgG anti-β2-glycoprotein I antibodies and thrombosis.Clin Rheumatol2008; 27: 171–178.
22.
22 Cugno M Dominguez M Cabibbe M . Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome.Br J Haematol2000; 108: 871–875.
23.
23 Cugno M Cabibbe M Galli M . 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.Blood2004; 103: 2121–2126.
24.
24 Lu CS Horizon AA Hwang KK . Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome.Arthritis Rheum2005; 52: 4018–4027.
25.
25 Bates RL Payne SJ Drury SL . The prevalence and clinical significance of autoantibodies to plasminogen activator inhibitor 1 in systemic lupus erythematosus.Lupus2003; 12: 617–622.
26.
26 Cesarman-Maus G Rios-Luna NP Deora AB . Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome.Blood2006; 107: 4375–4382.
27.
27 Tassies D Espinosa G Munoz-Rodriguez F . The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome.Arthritis Rheum2000; 43: 2349–2358.
28.
28 Forastiero R Martinuzzo M Adamczuk Y . The combination of thrombophilic genotypes is associated with definite antiphospholipid syndrome.Haematologica2001; 86: 735–741.
29.
29 Yasuda S Tsutsumi A Atsumi T . Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with antiphospholipid antibodies.J Rheumatol2002; 29: 1192–1197.
30.
30 Ieko M Ichikawa K Atsumi T . Effects of β2-glycoprotein I and monoclonal anticardiolipin antibodies on extrinsic fibrinolysis.Semin Thromb Hemost2000; 26: 85–90.
31.
31 Takeuchi R Atsumi T Ieko M . Suppressed intrinsic fibrinolytic activity by monoclonal anti-β2-glycoprotein I autoantibodies: possible mechanism for thrombosis in patients with antiphospholipid syndrome.Br J Haematol2002; 119: 781–788.
32.
32 Patterson AM Ford I Graham A Booth NA Greaves M . The influence of anti-endothelial/antiphospholipid antibodies on fibrin formation and lysis on endothelial cells.Br J Haematol2006; 133: 323–330.
33.
33 Kolev K Gombas J Varadi B . Immunoglobulin G from patients with antiphospholipid syndrome impairs the fibrin dissolution with plasmin.Thromb Haemost2002; 87: 502–508.
34.
34 Yang CD Hwang KK Yan W . Identification of anti-plasmin antibodies in the antiphospholipid syndrome that inhibit degradation of fibrin.J Immunol2004; 172: 5765–5773.
35.
35 Chen XX Gu YY Li SJ . Some plasmin-induced antibodies bind to cardiolipin, display lupus anticoagulant activity and induce fetal loss in mice.J Immunol2007; 178: 5351–5356.
36.
36 Horbach DA van Oort E Lisman T . β2-glycoprotein I is proteolytically cleaved in vivo upon activation of fibrinolysis.Thromb Haemost1999; 81: 87–95.
37.
37 Yasuda S Atsumi T Ieko M . Nicked β2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis.Blood2004; 103: 3766–3772.
38.
38 Lopez-Lira F Rosales-Leon L Monroy Martinez V Ruiz Ordaz BH . The role of β2-glycoprotein I (β2GPI) in the activation of plasminogen.Biochim Biophys Acta2006; 1764: 815–823.
