Defective Fibrinolytic Response in Atherosclerotic Patients – Effect of lloprost and Its Possible Mechanism of Action

Summary

Plasma fibrinolytic activity and tissue-type plasminogen activator (t-PA) were defective in response to venous stasis in five out of ten patients with peripheral occlusive artery disease. Discontinuous infusions of iloprost, a stable synthetic analogue of prostacyclin, restored a normal fibrinolytic response in all five patients but did not induce a parallel increase of plasma t-PA. These findings suggest that in addition to the possible benefits due to its vasodilatory and antiplatelet activity, iloprost may improve the fibrinolytic activity in patients with atherosclerotic disease, providing them with further antithrombotic protection. The profibrinolytic effect of iloprost seems not to depend on its ability to induce vascular t-PA release. Rather, it might be related to its inhibitory effect on PAI release from platelets, endothelial cells and/or hepatocytes. Venous occlusion test represents an easy diagnostic approach to fibrinolytic defects, even if related to arterial disease, and may help select patients who need therapeutic intervention.

Keywords

Peripheral artery disease - Fibrinolytic activity (response) - Prostacyclin analogues

• References

• 1 de Gaetano G, Cerletti C, Dejana E, Vermylen J. Current issues in thrombosis prevention with antiplatelet drugs. Drugs 1986; 31: 517-549
• 2 Erickson LA, Schleef RR, Ny T, Loskutoff DJ. The fibrinolytic system of the vascular wall. Clin Haematol 1985; 14: 513-530
• 3 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
• 4 Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
• 5 Nilsson IM, Ljungner H, Tengbom L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: Low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J 1985; 290: 1453-1456
• 6 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
• 7 D’Angelo V, Villa S, Mysliwiec M, Donati MB, de Gaetano G. Defective fibrinolytic and prostacyclin-like activity in human atheromatous plaques. Thromb Haemostas 1978; 39: 535-536
• 8 Mysliwiec M, Villa S, Kornblihtt L, de Gaetano G, Donati MB. Decreased plasminogen activator but normal prostacyclin activity in rat veins during development of experimental thrombosis. Thromb Res 1980; 18: 159-165
• 9 de Gaetano G, Carriero MR, Cerletti C, Mussoni L. Low dose aspirin does not prevent fibrinolytic response to venous occlusion. Biochem Pharmacol 1986; 35: 3147-3150
• 10 Guarini A, Mussoni L, Gugliotta L, Chetti L, Niewiarowski T, Catani L, Macchi S, Donati MB, Tura S. Depressed fibrinolysis in patients with acute leukaemia. Br J Haematol 1987; 66: 327-330
• 11 Winer BJ. Statistical Principles in Experimental Design. McGraw-Hill Kogakusha; London: 1971
• 12 Fitzgerald GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065-1068
• 13 Utsunomiva T, Krausz MM, Valeri CR, Shepro D, Hechtman HB. Treatment of pulmonary embolism with prostacyclin. Surgery 1980; 88: 25-30
• 14 Schneider J. Stimulation of the plasma fibrinolytic activity in rats by the prostacyclin analogue CG 4203. Thromb Res 1987; 48: 233-244
• 15 Dembiriska-Kiec A, Kostka-Trąbka E, Gryglewski RJ. Effect of prostacyclin on fibrinolytic activity in patients with arteriosclerosis obliterans. Thromb Haemostas 1982; 47: 190
• 16 Szczeklik A, Kopec M, Sladek K, Musial J, Chmielewska J, Teisseyre E, Dudek-Wojciechowska G, Palester-Chlebowczyk M. Prostacyclin and the fibrinolytic system in ischemic vascular disease. Thromb Res 1983; 29: 655-660
• 17 Musial J, Wilczynska M, Sladek K, Cierniewski CS, Nizankowski R, Szczeklik A. Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease. Prostaglandins 1986; 31: 61-70
• 18 Korbut R, Byrska-Danek A, Gryglewski RJ. Fibrinolytic activity of 6-keto-prostaglandin E₁ . Thromb Haemostas 1983; 50: 893
• 19 Krause W, Krais Th. Pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man. Eur J Clin Pharmacol 1986; 30: 61-68
• 20 Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 1984; 74: 1465-1472