Encapsulation of a plasminogen activator speeds reperfusion, lessens infarct and reduces blood loss in a canine model of coronary artery thrombosis

SummaryIn the present study, a polymer-encapsulated plasminogen activator was investigated as an alternative to restore blood flow more effectively than free plasminogen activator. While current fibrinolytic agents have limited efficacy, attributable to delayed onset of sustained reperfusion and bleeding complications, encapsulated plasminogen activators have shown promise in addressing these shortcomings. A polymer-encapsulated plasminogen activator could offer an effective formulation with a prolonged shelf-life. In this study, coronary artery thrombosis was produced in the anesthetized dog by the injection of thrombin + whole blood, and then one of five randomly selected formulations was administered intravenously: saline, blank microcapsules, free streptokinase (FREE SK), streptokinase and blank microcapsules (FREE SK + BLANK), or streptokinase entrapped in polymer microcapsules (MESK). MESK significantly accelerated the time to reperfusion compared to FREE SK or FREE SK + BLANK. Additionally, substantial reductions were observed in residual clot mass, infarct mass, reocclusion episodes, fibrinogen depletion and blood loss with MESK compared to FREE SK. The results of this study demonstrate that MESK accelerates thrombolysis and the restoration of blood flow compared to identical dosages of FREE SK while also reducing systemic fibrinogenolysis and blood loss. Microencapsulation may produce an improved dosage form for restoring arterial blood flow and reducing bleeding complications with thrombolytic therapy.

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Pharmacologic inhibition of platelet vWF-GPIbα interaction prevents coronary artery thrombosis

Thrombosis and Haemostasis ◽

10.1160/th05-09-0640 ◽

2006 ◽

Vol 95 (03) ◽

pp. 469-475 ◽

Cited By ~ 27

Author(s):

Robert Swillo ◽

Gwen Morgan ◽

Courtney Leik ◽

Jonathan Brooks ◽

Gray Shaw ◽

...

Keyword(s):

Coronary Artery ◽

Canine Model ◽

Arterial Blood Flow ◽

Control Group ◽

Antithrombotic Agent ◽

Arterial Blood ◽

Artery Thrombosis ◽

Coronary Artery Thrombosis ◽

Platelet Receptor ◽

Dosing Regimens

SummaryUnder high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibα, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIbα interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 µg/kg, n=6; 500 µg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105±34 and 156±23 (p<0.05) min, respectively compared to the saline treated control group (32±6min, n=6). Patency of the injured vessel was sustained in 1/6 (100µg/kg) and 3/6 vessels (500 µg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 µg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day –2 followed by 1.1 mg/kg daily for2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure. The PTR and LDR clopidogrel treatments prolonged TTO to 98.2±30.0 min and 136.1±39.5 min (p<0.05), and sustained patency in 1/6 and 4/8 vessels, respectively. However, template bleeding time in the LDR clopidogrel group was sustained higher than the control group. The combination of PTR clopidogrel and GPG-290 (100 µg/kg) prolonged TTO equivalent to LDR clopidogrel alone (141.4±35.1 min) and sustained patency in 3/7 dogs, without increased bleeding while LDR clopidogrel combined with 100 µg/kg GPG-290 prevented occlusion in 5/8 dogs and further prolonged TTO (173.5±32.6 min) but was associated with increased bleeding compared to control. GPG-290 is an antithrombotic agent that may be combined with lower doses of clopidogrel to yield similar antithrombotic efficacy as higher loading doses.

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