A Pilot Study of Pro-Urokinase in the Treatment of Deep Vein Thrombosis

Summary

Safety and efficacy of the thrombolytic agent pro-urokinase (pro-UK) in the treatment of deep vein thrombosis of the lower limbs (DVT) have been investigated in an open, uncontrolled, pilot study. Fifteen patients were infused with 800.000 IU (5 mg)/h of pro-UK over 24 h (120 mg), together with unfractionated heparin adjusted to maintain the activated partial thromboplastin time between 1.5 and 2.5 times the basal value. Efficacy was assessed comparing venographic changes in the 11 evaluable limbs before and after pro-UK infusion. The Marder score decreased from a median pre-thrombolysis value of 28 (range 4-40) to 16 (3-38) (p <0.05). One major hemorrhagic event (retroperitoneal bleeding 4 days after the end of the pro-UK infusion) occurred. Fibrinogen, alpha₂-antiplasmin and plasminogen significantly decreased from baseline values after 12 and 24 h, fibrin(ogen) degradation products significantly increased. Changes in hemostasis parameters were unrelated to thrombolytic efficacy. The results of this pilot study indicate that pro-UK is thrombolytic in DVT and that it can be administered simultaneously with conventional heparin treatment.

• References

• 1 Doyle DJ, Turpie AG, Hirsh J, Best C, Kinch D, Levine MN, Gent M. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med 1987; 107: 441-445
• 2 Prandoni P, Lensing AWA, Buller HR, Carta M, Cogo A, Vigo M, Casara D, Ruol A, ten Cate JW. Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-5
• 3 National Institutes of Health Consensus Development Conference. Thrombolytic therapy in thrombosis: A National Institutes of Health Consensus Development Conference. Ann Intern Med 1980; 93: 141-144
• d Francis CW, Marder VJ. Fibrinolytic therapy for venous thrombosis. Prog Cardiovasc Dis 1991; 34: 193-204
• Goldhabe rSZ, Buring JE, Lipnick RJ, Hennekens CH. Pooled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. Am J Med 1984; 76: 393-7
• 6 Van de Loo JCW, Kriessmann A, Trubenstein G, Knoch K, de Swart CAM, Asbeck F, Marbet GA, Schmitt HE, Sewell AF, Duckert F, Theiss W, Ritz R. Controlled multicenter pilot study of urokinase, heparin and streptokinase in deep vein thrombosis. Thromb Haemost 1983; 50: 660-663
• 7 D’Angelo A, Mannucci PM. Outcome of treatment of deep-vein thrombosis with urokinase: relationship to dosage, duration of therapy, age of the thrombus and laboratory changes. Thromb Haemost 1984; 51: 236-239
• 8 Bounameaux H, Banga JD, Bluhmki E, Coccheri S, Fiessinger J-N, Haar-mann W, Lockner D, Mahler F, Ninet J, Schneider P-A, de Torrente A, van der Meer J, Verhaeghe R. Double-blind, randomized comparison of systemic continuous infusion of 0.25 versus 0.50 mg/kg/24 h of Alteplase over 3 to 7 days for treatment of deep venous thrombosis in heparinized patients: results of the European Thrombolysis with rt-PA in Venous Thrombosis (ETTT) Trial. Thromb Haemost 1992; 67: 306-309
• 9 Verhaeghe R, Besse P, Bounameaux H, Marbet GA. Multicenter pilot study of the efficacy and safety of systemic rt-PA administration in the treatment of deep vein thrombosis of the lower extremities and/or pelvis. Thromb Res 1989; 55: 5-11
• 10 Goldhaber SZ, Meyerovitz MF, Green D, Vogelzang RL, Citrin P, Heit J, Sobel M, Wheeler HB, Plante D, Kim H, Hopkins A, Tufte M, Stump D, Braunwald E. Randomized controlled trial of tissue plasminogen activator in proximal deep vein thrombosis. Am J Med 1990; 88: 235-240
• 11 Marder VJ, Brenner B, Totterman S, Francis CW, Rubin R, KonetiRao A, Kessler CM, Kwaan HC, Sharma GVRK, Fong K-LL. Comparison of dosage schedules of rt-PA in the treatment of proximal deep vein thrombosis. J Lab Clin Med 1992; 119: 485-495
• 12 Gurewich V, Pannel R, Louie S, Kelley P, Suddith RL, Greenlee R. Effective and fibrin-specific clot lysis by a zymogen precursor form of urokinase (Pro-urokinase).A study in vitro and in two animal species. J Clin Invest 1984; 73: 1731-1739
• 13 Collen D, Stassen JM, Blaber M, Winkler M, Verstraete M. Biological and thrombolytic properties of proenzyme and active forms of human urokinase. Thrombolytic properties of natural and recombinant urokinase in rabbits with experimental jugular vein thrombosis. Thromb Haemost 1984; 52: 27-30
• 14 Van De Werf F, Vanhaecke J, De Geest H, Verstraete M, Collen D. Coronary thrombolysis with recombinant single-chain urokinase-type plasminogen activator in patients with acute myocardial infarction. Circulation 1986; 74: 1066-1070
• 15 Pannell R, Black J, Gurewich V. Complementary modes of action of tissue-type plasminogen activator and pro-urokinase by which their synergistic effect on clot lysis may be explained. J Clin Invest 1988; 81: 853-859
• 16 Marder VJ, Soulen RL, Atichartakam V, Budzynski AZ, Parulekar S, Kim JR, Edward N, Zahavi J, Algazy KM. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018--1029
• 17 Markel A, Manzo RA, Strandness DE. The potential role of thrombolytic therapy in venous thrombosis. Arch Intern Med 1992; 152: 1265-1267
• 18 Rogers LQ, Lutcher CL. Streptokinase therapy for deep vein thrombosis: a comprehensive review of the English literature. Am J Med 1990; 88: 389-395
• 19 Vaughan DE, Goldhaber SZ, Kim J, Loscalzo J. Recombinant tissue plasminogen activator in patients with pulmonary embolism: correlation of fibrinolytic specificity and efficacy. Circulation 1987; 75: 1200-1203
• 20 Turpie AGG, Levine NN, Hirsh J, Ginsberg JS, Cruickshank M, Jay R, Gent M. Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis. Chest 1990; 97: 172S-175S