Comparison of hirudin and heparin as adjuncts to streptokinase thrombolysis in a canine model of coronary thrombosis.

Abstract

Recombinant desulfatohirudin (HI), a potent and specific thrombin inhibitor, was compared with heparin (HE) as an adjunct to streptokinase thrombolysis. In pentobarbital-anesthetized dogs, an occlusive thrombus (whole blood+thrombin) was introduced into the left anterior descending coronary artery (LAD) with superimposed endothelial damage and distal high-grade stenosis. Intravenous infusion of saline (vehicle), HI (0.3 mg/kg followed by 0.3 mg/kg per hour, 1 mg/kg followed by 1 mg/kg per hour, or 2 mg/kg followed by 2 mg/kg per hour), or HE (60 units/kg followed by 40 units/kg per hour or 100 units/kg followed by 60 units/kg per hour) was initiated 15 minutes before streptokinase (750,000 units for 60 minutes) administration. Vessel patency was monitored for 180 minutes after streptokinase administration with a volume flow probe on the proximal LAD. In dogs treated with no adjunctive agent (saline control), none of the vessels were recanalized with streptokinase. Both HI and HE promoted reperfusion, inhibited reocclusion, and reduced the residual thrombus mass in a dose-dependent fashion. However, at comparable levels of therapeutic anticoagulation (activated partial thromboplastin time [APTI] = 1.5-2.0 times baseline) HI exhibited a higher incidence of reperfusion (eight of eight dogs [100%] versus one of eight dogs [12%J), a shorter time to reperfusion (33±6 versus 59 minutes), a longer duration of initial reperfusion (106±21 versus 10 minutes), and a smaller residual thrombus mass than did HE. Likewise, the slope of the relation between the APTT prolongation and the total reperfusion time ("anticoagulation/ antithrombosis profile") was almost five times higher for the combined HI data than for the HE data. Our results indicate that HI is more effective than HE in enhancing and sustaining coronary recanalization with streptokinase at a HI dose that modestly prolongs coagulation time and does not alter bleeding times. (Circulation Research 1993;72:1091-1102

Construction and Functional Evaluation of a Single-Chain Antibody Fusion Protein With Fibrin Targeting and Thrombin Inhibition After Activation by Factor Xa

“…19 Several reports imply that direct thrombin inhibitors may be superior to heparin. [3][4][5][6][7][8] This could be explained by a number of distinct mechanisms. In contrast to heparin, which only inhibits thrombin as a soluble molecule, hirudin can also inhibit thrombin that is bound to the clot or to soluble fibrin degradation products.…”

Dissolution of Mural Thrombus by Specific Thrombin Inhibition With r-Hirudin

“…34 However, if r-hirudin is administered in combination with thrombolytic agents (rt-PA), residual platelet-rich thrombus may be eliminated at lower levels of anticoagulation (aPTT ratios, 2.5 times control). 10 In experimental studies of coronary thrombosis, hirudin was superior to heparin in facilitating thrombolysis with both t-PA and streptokinase 10,39,40 and almost completely eliminated residual platelet-rich thrombus. 10 Dissolution of mural thrombus by specific thrombin inhibiton with r-hirudin is of potential therapeutic benefit after acute coronary syndromes that could lead to improved vessel patency with reduced stenosis, thus decreasing the need for revascularization procedures in a significant proportion of patients.…”

Hirudin (desulfated, 54–65) contracts canine coronary arteries: Extracellular calcium influx mediates hirudin-induced contractions

“…The administration of hirudin is known to lead to a significant increase in left ventricular end-diastolic pressure, and it tends to increase mean arterial pressure [15]. In clinical trials of hirudin for acute coronary syndromes, no adverse effects have been attributed to vasoconstriction during the administration of hirudin, nor have adverse effects been correlated with preentry FIG.…”