A Pilot Study on Bolus Administration of Recombinant Staphylokinase for Coronary Artery Thrombolysis

Summary

Recombinant staphylokinase (Sak) is a highly fibrin-specific thrombolytic agent but the optimal dose and mode of administration remain to be defined. Intravenous (i.v.) infusion over 5 min of 20 mg Sak in 12 patients with acute myocardial infarction induced complete coronary patency (TIMI perfusion grade 3) in 7 patients (58%) within 60 min. In 3 of the 5 patients with no or suboptimal flow (TIMI grade 0,1 or 2) at 60 min, an additional 10 mg i.v. bolus of Sak resulted in TIMI grade 3 flow at 90 min. No major treatment-related complication occurred. Residual fibrinogen and α₂-antiplasmin levels at 90 min were 110 ± 6.0% and 98 ±4.1% (mean ± SEM) of baseline, respectively. Median antibody-related Sak-neutralizing activity was low at baseline (0.0 μg/ml) and after 1 week (0.5 μg/ml) but increased from day 10 on (to 4.0 μg/ml).

Thus, bolus thrombolysis with Sak may induce efficient coronary artery recanalization while preserving circulating fibrinogen and α₂-antiplasmin. Comparative trials of coronary thrombolysis with double-bolus Sak appear to be warranted.

• References

• 1 Anderson HV, Willerson JT. Current concepts: thrombolysis in acute myocardial infarction. N Engl J Med 1993; 329: 703-709
• 2 Neuhaus KL, Feuerer W, Jeep-Tebbe S, Niederer W, Vogt A, Tebbe U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989; 14: 1566-1569
• 3 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682
• 4 The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615-1622
• 5 Agnelli G. Rationale for bolus t-PA therapy to improve efficacy and safety. Chest 1990; 97: 161S-167S
• 6 Purvis JA. Novel and innovative dosing regimens in thrombolytic therapy for acute myocardial infarction. J Thromb Thrombol 1995; 1: 145-151
• 7 Goldhaber SZ. Bolus and accelerated thrombolysis. Experimental observations and clinical management of myocardial infarction and pulmonary embolism. Chest 1995; 107: 889-892
• 8 Becker RC. Achieving optimal reperfusion without adjunctive antithrombotic therapy: novel thrombolytic dosing strategies. J Thromb Thrombol 1995; 1: 269-277
• 9 Eisert WG. Bolus treatment regimen of rt-PA determines the rate and extent of fibrinolysis of identical doses in infusion therapy. Blood 1987; 70 (Suppl. 01) 370A
• 10 Cercek B, Lew AS, Yano J, Reddy KNN, Ganz W. Thrombolytic effect of recombinant tissue-type plasminogen activator administered as a bolus. Clin Res 1987; 35: 102A
• 11 Clozel J-P, Tschopp T, Luedin E, Holvoet P. Time course of thrombolysis induced by intravenous bolus or infusion of tissue plasminogen activator in a rabbit jugular vein thrombolysis model. Circulation 1989; 79: 125-133
• 12 Purvis JA, McNeill AJ, Siddiqui RA, Roberts MJ, McClements BM, McEneaney D, Campbell NPS, Khan MM, Webb SW, Wilson CM, Adgey AAJ. Efficacy of 100 mg of double-bolus alteplase in achieving complete perfusion in the treatment of acute myocardial infarction. J Am Coll Cardiol 1994; 23: 6-10
• 13 Collen D, Lijnen HR. Staphylokinase, a fibrin-specific plasminogen activator with therapeutic potential?. Blood 1994; 84: 680-686
• 14 Collen D, Van de Werf F. Coronary thrombolysis with recombinant staphylokinase in patients with evolving myocardial infarction. Circulation 1993; 87: 1850-1853
• 15 Schlott B, Hartmann M, Gührs KH, Birch-Hirschfeld E, Pohl HD, Vanderschueren S, Van de Werf F, Michoel A, Collen D, Behnke D. High yield production and purification of recombinant staphylokinase for thrombolytic therapy. BioTechnology 1994; 12: 185-189
• 16 Vanderschueren S, Barrios L, Kerdsinchai P, Van den Heuvel P, Hermans L, Vrolix M, De Man F, Benit E, Muyldermans L, Collen D, Van de Werf F. A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. Circulation 1995; 92: 2044-2049
• 17 Vanderschueren S, Stockx L, Wilms G, Lacroix H, Verhaeghe R, Vermylen J, Collen D. Thrombolytic therapy of peripheral arterial occlusion with recombinant staphylokinase. Circulation 1995; 92: 2050-2057
• 18 Gase A, Birch-Hirschfeld E, Gührs K-H, Hartmann M, Vetterman S, Damaschun G, Damaschun H, Gast K, Misselwitz R, Zinver D, Collen D, Schlott B. The thermostability of natural variants of bacterial plasminogen-activator staphylokinase. Eur J Biochem 1994; 223: 303-308
• 19 Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobek BE, Willerson J, Williams DO, Zaret BK, Braunwald E. Thrombolysis in Myocardial Infarction (T1MI) trial, phase 1: a comparison between i.v. tissue plasminogen activator and i.v. streptokinase: clinical findings through hospital discharge. Circulation 1987; 76: 142-154
• 20 Declerck PJ, Vanderschueren S, Billiet J, Moreau H, Collen D. Prevalence and induction of circulating antibodies against recombinant staphylokinase. Thromb Haemost 1994; 71: 129-133
• 21 Sobel BE, Nachowiak DA, Fry ETA, Bergmann SR, Torr SR. Paradoxical attenuation of fibrinolysis attributable to “plasminogen steal” and its implications for coronary thrombolysis. Coron Art Dis 1990; 1: 111-119
• 22 Eisenberg PR. Procoagulant effects of fibrinolytic agents. In: Coronary Thrombolysis in Perspective. Principles Underlying Conjunctive and Adjunctive Therapy Sobel BE, Collen D. (eds) Marcel Dekker Inc; Basel: 1993: 77-99
• 23 Vanderschueren SMF, Stassen JM, Collen D. On the immunogenicity of recombinant staphylokinase in patients and in animal models. Thromb Haemost 1994; 72: 297-301
• 24 Dehmer GJ, Gresalfi N, Daly D, Oberhardt B, Tate DA. Impairment of fibrinolysis by streptokinase, urokinase and recombinant tissue-type plasminogen activator in the presence of radiographic contrast agents. J Am Coll Cardiol 1995; 25: 1069-1075