A Study of the Use of the Thromboxane A2 Antagonist, Sulotroban, in Combination with Streptokinase for Local Thrombolysis in Patients with Recent Peripheral Arterial Occlusions: Clinical Effects, Platelet Function and Fibrinolytic Parameters

Robert J Lonsdale; Stan Heptinstall; John C Westby; David C Berridge; Peter W Wenham; Brian R Hopkinson; Geoffrey S Makin

doi:10.1055/s-0038-1651563

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1993; 69(02): 103-111
DOI: 10.1055/s-0038-1651563

Original Article

Clinical Studies

Schattauer GmbH Stuttgart

A Study of the Use of the Thromboxane A₂ Antagonist, Sulotroban, in Combination with Streptokinase for Local Thrombolysis in Patients with Recent Peripheral Arterial Occlusions: Clinical Effects, Platelet Function and Fibrinolytic Parameters

Robert J Lonsdale

¹The Department of Vascular Surgery, University Hospital, Nottingham, United Kingdom

,

Stan Heptinstall

²The Department of Medicine, University Hospital, Nottingham, United Kingdom

,

John C Westby

³The Department of Haematology, University Hospital, Nottingham, United Kingdom

,

David C Berridge

¹The Department of Vascular Surgery, University Hospital, Nottingham, United Kingdom

,

Peter W Wenham

¹The Department of Vascular Surgery, University Hospital, Nottingham, United Kingdom

,

Brian R Hopkinson

¹The Department of Vascular Surgery, University Hospital, Nottingham, United Kingdom

,

Geoffrey S Makin

¹The Department of Vascular Surgery, University Hospital, Nottingham, United Kingdom

› Institutsangaben

Abstract

als PDF herunterladen

Summary

In peripheral thrombolysis adjuvant anti-platelet therapy may help to lyse otherwise resistant thrombus, thereby increasing the number of patients successfully treated and reducing the “time to lysis”. If continued after lysis it may help to prevent early rethrombosis. In this pilot study 21 patients undergoing peripheral thrombolysis with streptokinase were randomised to receive the thromboxane receptor antagonist sulotroban or placebo. The dose of sulotroban given was 2 mg/min (four patients), 4 mg/min (five patients) or 8 mg/min (four patients), eight patients received placebo. The clinical and laboratory effects of the treatment were monitored.

Thrombolysis was achieved more quickly in patients receiving sulotroban, however, there was no difference between groups in the number of patients in whom recanalisation was achieved (six of eight receiving placebo and eight of 13 receiving sulotroban) or in the number of cases of early rethrombosis. During lysis there was an increase in plasma beta-thromboglobulin with similar levels being found in patients receiving sulotroban and streptokinase and those receiving streptokinase alone. No other major changes in platelet function during lysis were seen in patients receiving streptokinase alone. Sulotroban significantly reduced platelet aggregtion and ¹⁴C-5HT release in response to several platelet agonists. With the thromboxane mimetic U46619 the degree of inhibition of aggregation and ¹⁴C-5HT release depended on the dose of sulotroban used. High levels of inhibition were associated with an excess of haemorrhagic complications especially in combination with a low plasma fibrinogen level.

We conclude that the use of low dose sulotroban in combination with streptokinase merits further study and may have a role in accelerating lysis. However, the combination of high dose sulotroban with streptokinase causes an increased incidence of bleeding. Monitoring platelet function during such therapy may identify patients likely to bleed.

PDF (2020 kb)

Referenzen

References
1 Earnshaw JJ, Shaw JFL. Survey of the use of thrombolysis for acute limb ischaemia in the UK and Ireland. Br J Surg 1990; 77: 1041-1042
2 Lonsdale RJ, Harrison JD, Berridge DC, Earnshaw JJ, Gregson RHS, Wenham PW, Hopkinson BR, Makin GS. Comparison of recombinant tissue plasminogen activator and streptokinase in peripheral arterial thrombolysis. Br J Surg 1991; 78: 739
3 Coller BS. Platelets and thrombolytic therapy. N Engl J Med 1990; 322: 33-42
4 Heptinstall S, Berridge DC, Judge H. Effects of streptokinase and recombinant tissue plasminogen activator on platelet aggregation in whole blood. Platelets 1990; 1: 177-188
5 Fitzgerald DJ, Catella F, Roy L, FitzGerald GA. Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation 1988; 77: 142-150
6 Ohlstein EH, Storer B, Fujita T, Shebuski RJ. Tissue-type plasminogen activator and streptokinase induce platelet hyperaggregability in the rabbit. Thromb Res 1987; 46: 575-585
7 Terres W, Beythien C, Kupper W, Bleifield W. Effects of aspirin and prostaglandin E₁ on in vitro thrombolysis with urokinase. Circulation 1989; 79: 1309-1314
8 Schumacher WA, Lee EC, Lucchesi BR. Augmentation of streptokinase-induced thrombolysis by heparin and prostacyclin. J Cardiovasc Pharm 1985; 7: 739-746
9 Shebuski RJ, Smith JM, Storer BL, Granett JR, Bugelski PJ. Influence of selective endoperoxide/thromboxane A₂ antagonism with sulotroban on lysis time and reocclusion rate after tissue plasminogen activator-induced coronary thrombolysis in the dog. J Pharm Exp Ther 1988; 246: 790-796
10 Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and sustained artery recanalisation with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation 1988; 77: 670-677
11 Mickelson JK, Simpson PJ, Cronin M, Homeister JW, Laywell E, Kitzen J, Lucchesi BR. Antiplatelet antibody [7E3 F(ab’)₂] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model. Circulation 1990; 81: 617-627
12 Yasuda T, Gold HK, Leinbach RC, Yaoita H, Fallon JT, Guerrero L, Napier MA, Bunting S, Collen D. Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary artery thrombolysis with tissue-type plasminogen activator in a canine preparation. Circulation 1991; 83: 1038-1047
13 ISIS-2 (Second International Study of Infarct Survival) Collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction. Lancet 1988; ii: 349-360
14 Humphrey WR, Schaub RG. Effect of intravenous prostaglandin E₁ on thrombolysis induced by human recombinant tissue-type plasminogen activator in feline peripheral arterial thrombosis. Fibrinolysis 1991; 5: 71-79
15 Hess H, Mietaschk A, Bruckl R. Peripheral arterial occlusions: A 6-year experience with local low-dose thrombolytic therapy. Radiology 1987; 163: 753-758
16 Berridge DC, Hopkinson BR, Makin GS. Local low dose intra-arterial thrombolytic therapy: the risk of stroke or major haemorrhage. Br J Surg 1989; 76: 1230-1233
17 Patscheke H, Steigmeier K. Investigations on a selective non-prostanoic thromboxane antagonist, BM 13.177 in human platelets. Thromb Res 1984; 33: 277-288
18 Gresele P, Deckmyn H, Arnout J, Lemmens J, Janssens W, Vermylen J. BM 13.177, A selective blocker of platelet and vessel wall thromboxane receptors, is active in man. Lancet 1984; i: 991-994
19 Fiddler GI, Lumley P. Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers. Circulation 1990; 81 (Suppl. 01) 69-78
20 Earnshaw JJ, Westby JC, Makin GS, Hopkinson BR. Low dose intra-arterial streptokinase and acylated plasminogen-streptokinase activator complex: A retrospective review of two thrombolytic regimes in recent peripheral arterial ischaemia. Eur J Vase Surg 1987; 1: 151-158
21 von Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fribrinogens. Acta Haematol 1957; 17: 237-246
22 Soria J, Soria C, Samama M. Dosage du plasminogene a l’aide d’un substrat chromogene tripeptidique. Pathol Biol (Paris) 1976; 24: 725-729
23 Teger-Nilsson AC, Friberger P, Gyzander E. Determination of a new rapid plasma inhibitor in human blood by means of a specific tripeptide substrate. Scand J Clin Lab Invest 1977; 37: 403-409
24 Bucknell M. The effect of citrate on euglobulin methods of measuring fibrinolytic activity. J Clin Pathol 1958; 11: 403-405
25 Rylatt DB, Blake AS, Cottis LE, Massingham DA, Fletcher WA, Masci PP, Whitaker AN, Elms M, Bunce I, Webber AJ, Wyatt D, Bundesen PF. An immunoassay for human D-dimer using monoclonal antibodies. Thromb Res 1983; 31: 767-778
26 Nilsson K, Rosen S, Friberger P. A new kit for the determination of tissue plasminogen activator and its inhibitor in blood. Fibrinolysis 1987; 1: 163-168
27 Wilson JE, Thornton RD. Comparison of a direct latex-agglutination technic with the tanned red cell hemagglutination inhibition immunoassay (TRCHII) for semiquantitation of fibrinogen/fibrin degradation products. Am J Clin Pathol 1976; 65: 528-532
28 Berridge DC, Earnshaw JJ, Westby JC, Makin GS, Hopkinson BR. Fibrinolytic profiles in local low-dose thrombolysis with streptokinase and recombinant tissue plasminogen activator. Thromb Haemostas 1989; 61: 275-278
29 Mikhailidis DP, Barradas MA, O’Donoghue S, Dandona P. Evidence for in vivo platelet activation following the injection of conventional, unfractionated heparin. Platelets 1990; 1: 189-192
30 Vaughan DE, Van Hautte E, Declerk PJ, Collen D. Streptokinase-induced platelet aggregation. Prevalence and mechanism. Circulation 1991; 84: 84-91