Endothelial-Dependent Fibrinolysis in Subjects with the Lupus Anticoagulant and Thrombosis

Summary

To investigate the hypothesis that diminished endothelial fibrinolytic activity contributes to the pathogenesis of thrombosis in patients with the lupus anticoagulant (LA), we assessed the ability of endothelium to release tissue-type plasminogen activator (t-PA) in response to standardized venous occlusion (VO) of the arm, and the extent of inhibition of t-PA, in 11 subjects with LA and a history of thrombosis and in 36 healthy normal subjects. The mean rise in plasma t-PA antigen after VO, the mean plasma free t-PA activity after VO, and the mean plasma t-PA inhibitor level prior to VO were not significantly different in subjects with LA and thrombosis and in normal subjects. Four subjects with LA and thrombosis (36%), and five of 36 healthy control subjects (14%) generated no detectable free t-PA activity after VO (“non-responders”); this difference was not statistically significant. All four “non-responders” with LA and thrombosis had normal t-PA antigen release after VO, indicating that the lack of detectable free t-PA activity after VO was due to increased inhibition of released t-PA. We conclude that abnormally reduced endothelial fibrinolytic activity is not present in the majority of subjects with LA and thrombosis. In the subset of subjects with LA and thrombosis who generate no detectable t-PA activity after VO, a stimulatory effect of LA on endothelial production of t-PA inhibitor cannot be excluded.

Keywords

Fibrinoly - Thrombosis - Lupus anticoagulant - Endothelium

• References

• 1 Boey M, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GR V. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J 1983; 287: 1021-1023
• 2 Bowie EJ W, Thompson JH, Pascuzzi CA, Owen CA. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med 1963; 3: 416-430
• 3 Elias M, Eldor A. Thromboembolism in patients with the “lupus”-type circulating anticoagulant. Arch Intern Med 1984; 144: 510-515
• 4 Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GR V. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2: 1211-1214
• 5 Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980; 92: 156-159
• 6 Carreras LO, Defreyn G, Machin SJ, Vermylen J, Deman R, Spitz B, Van Assche A. Arterial thrombosis, intrauterine death and “lupus” anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981; 1: 244-246
• 7 Comp PC, De Bault LE, Esmon NL, Esmon CT. Human thrombomodulin is inhibited by IgG from two patients with nonspecific anticoagulants. Blood 1983; 62: 299 a (Abstract)
• 8 Cariou R, Tobelem G, Soria C, Caen J. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314: 1193-1194
• 9 Freyssinet JM, Wiesel ML, Gauchy J, Boneu B, Cazenave JP. An IgM lupus anticoagulant that neutralizes the enhancing effect of phospholipid on purified endothelial thrombomodulin activity. A mechanism for thrombosis Thromb Haemostas 1986; 55: 309-313
• 10 Harris EN, Asherson A, Gharavi AE, Morgan SH, Derue G, Hughes GR V. Thrombocytopenia in SLE and related autoimmune disorders: association with anticardiolipin antibodies. Br J Haematol 1985; 59: 227-234
• 11 Busch C, Owen WG. Identification in vitro of an endothelial cell cofactor for antithrombin III. J Clin Invest 1982; 69: 726-729
• 12 Nawroth PP, Stern DM, Kisiel W, Dietrich M. A pathway of coagulation on bovine capillary endothelial cells. Br J Haematol 1986; 63: 309-320
• 13 Loskutoff DJ. The fibrinolytic system of cultured endothelial cells: deciphering the balance between plasminogen activation and inhibition. Prog Fibrin Thromb 1985; 7: 15-22
• 14 Angles-Cano E, Sultan Y, Clauvel JP. Predisposing factors to thrombosis in systemic lupus erythematosus. Possible relation to endothelial damage J Lab Clin Med 1979; 94: 312-323
• 15 Hamsten A, Wiman B, DeFaire U, Blomback M. Increased levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
• 16 Paramo JA, Colucci M, Collen D. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573-574
• 17 Stalder M, Hauert J, Kruithof EK O, Bachmann F. Release of vascular plasminogen activator (v-PA) after venous stasis: electrophoretic-zymographic analysis of free and complexed v-PA. Br J Haematol 1985; 61: 169-176
• 18 Wiman B, Ljungberg B, Chmielewska J, Urden G, Blomback M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med 1985; 105: 265-270
• 19 Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemostas 1987; 57: 67-72
• 20 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
• 21 Exner T, Richard KA, Kronenberg H. A sensitive test demonstrating the lupus anticoagulant and its behavioral patterns. Br J Haematol 1978; 40: 143-150
• 22 Loizou S, McCrea JD, Rudge AC, Reynold R, Boyle CC, Harris EN. Measurement of anticardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-745
• 23 Hersch S, Kunelis T, Francis Jr RB. Pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor. Blood 1987; 69: 1315-1319
• 24 Bergsdorf N, Nilsson T, Wallén P. An enzyme linked immunosorbent assay for determination of tissue plasminogen activator applied to patients with thromboembolic disease. Thromb Haemostas 1983; 50: 740-744
• 25 Mahmoud M, Gaffney PJ. Bioimmunoassay (BIA) of tissue plasminogen activator (t-PA) and its specific inhibitor (t-PA/INH). Thromb Haemostas 1985; 53: 356-359
• 26 Juhan-Vague I, Moerman B, De Cock F, Aillaud MF, Collen D. Plasma levels of a specific inhibitor of tissue-type plasminogen activator (and urokinase) in normal and pathological conditions. Thromb Res 1984; 33: 523-530