Inhibition of Arterial Thrombus Formation in Two Canine Models: Comparison of Ancrod, a Fibrinogen-Depleting Agent, the Thrombin-Inhibitor r-Hirudin, and the Glycoprotein IIb/IIIa-Receptor Antagonist Ro 43-8857

Abstract

SummaryInhibition of arterial thrombus formation by ancrod, a fibrinogen depleting agent isolated from a snake venom, r-hirudin, an inhibitor of thrombin-mediated fibrinogen cleavage, or the glycoprotein (GP)IIb/IIIa-receptor antagonist Ro 43-8857 interfering with fibrinogen binding to platelets, was evaluated in two canine models. As a marker of platelet-dependent thrombus formation, cyclic blood flow reductions (CFR) were induced in the left coronary artery (LAD) of mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. In the second model CFRs were induced by thrombolysis of a copper coil-induced thrombus in the carotid artery. Blood flow rate during the reocclusion phase was used as an additional parameter of efficacy.The frequency of CFRs used as indicator of platelet aggregation and adhesion was significantly diminished by all treatments in both the carotid artery- and the LAD-model. In the LAD-model, following ancrod treatment, CFRs were correlated with plasma fibrinogen concentrations. Carotid artery blood flow after reperfusion, used as indicator of occlusive thrombus formation, rapidly declined to zero in the control group but remained at a high level after treatment with ancrod or r-hirudin. Ro 43-8857 at the selected dose improved blood flow rate only to a minor degree but prolonged the bleeding time from a mean value of 87.2 ± 10.9 s (n = 24) to values >300 s in 50% of the animals.Our results indicate that CFRs as indicator of platelet aggregation and adhesion are inhibited by either treatments. Blood flow as indicator of occlusive thrombus formation, however, is effectively improved by ancrod and r-hirudin only. Inhibition of fibrinogen binding to platelet GPIIb/IIIa receptors alone was found to be a less potent antithrombotic principle in this model.

Description of the chemical and pharmacological characteristics of a new hemisynthetic ultra‐low‐molecular‐weight heparin, AVE5026

“…[22] and modified by Ruebsamen et al. [23] using a copper coil positioned into the carotid artery by aid of a balloon catheter introduced via the femoral artery. Vessel patency was detected by ultrasonic flow measurement and defined as the cumulative time of blood flow ≥2 mL min −1 during the duration of the experiment [parameter measured: cumulative patency/time (min)].…”

“…Blood samples anticoagulated with sodium citrate (3.1%, 1 + 9 volume blood) were obtained from a carotid artery catheter before and after s.c. administration of AVE5026, enoxaparin or vehicle.One milligram per kilogram AVE5026 and enoxaparin were administered s.c. to groups of 4-6 rabbits 30 min prior to anesthesia. Seventy-five minutes after administration, the template bleeding time was measured using the SIMPLATE device technique at the shaved inner ear.Arterial thrombosis was induced in anesthetized dogs (purpose-bred beagle or German shepherd) as described by Kordenat et al[22] and modified by Ruebsamen et al[23] using a copper coil positioned into the carotid artery by aid of a balloon catheter introduced via the femoral artery. Vessel patency was detected by ultrasonic flow measurement and defined as the cumulative time of blood flow ‡2 mL min )1 during the duration of the experiment [parameter measured: cumulative patency/time (min)].…”

Recent advances: Treatment of myocardial infarction

“…Animal work has shown that a number of drugs (such as the monoclonal antibody and others such as integrelin) are valuable in animal models of coronary occlusion 29 30. Given alone, 7E3 improves vessel patency.…”

Identifying Phenogroups in Patients with Subclinical Diastolic Dysfunction Using Unsupervised Statistical Learning

“…Patients with clinical heart failure were identified if their electronic health record contained an ICD-9 diagnosis of congestive heart failure along with clinical documentation of at least one of the following signs or symptoms of heart failure: shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, weight gain, or lower extremity edema. Patients in Group 1 diagnosed with HFpEF were optimally matched for age, gender, race, and body surface area (15) with Group 2 patients who remained in asymptomatic diastolic dysfunction. This ultimately yielded 77 matched pairs which were included in our study.…”