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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 11, 2005; DOI: 10.1124/jpet.105.093450

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Received for publication July 29, 2005.
Revised November 10, 2005.
Accepted for publication November 10, 2005.

Fibrin affinity of erythrocyte-coupled tPA endures hemodynamic forces and enhances fibrinolysis in vivo

Kumkum Ganguly 1, Mukul S Goel 1, Tatyana Krasik 1, Khalil Bdeir 1, Scott Diamond 1, Douglas Cines 1, Vladimir R. Muzykantov 1*, Juan-Carlos Murciano 2

1 University of Pennsylvania 2 5Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

* Address correspondence to: E-mail: muzykant{at}mail.med.upenn.edu

Abstract

Plasminogen activators (PAs, e.g., tissue-type, tPA) coupled to red blood cells (RBC) display in vivo features useful for thromboprophylaxis: prolonged circulation, minimal extravasation, and preferential lysis of nascent vs. preexisting clots. Yet, factors controlling the activity of RBC-bound PAs in vivo are not defined and may not mirror the profile of soluble PAs. We tested the role of RBC/PA binding to fibrin in fibrinolysis. RBC/tPA and RBC/rPA (a tPA variant with low fibrin affinity) bound to and lysed plasminogen-containing fibrin clots in vitro comparably. In contrast, when co-injected in mice with fibrin emboli lodging in pulmonary vasculature, only RBC/tPA accumulated in lungs, which resulted in a more extensive fibrinolysis vs. RBC/rPA (p <0.01). Reconciling this apparent divergence between in vitro and in vivo behaviors, RBC/tPA, but not RBC/rPA perfused over fibrin in vitro at physiological shear stress bound to fibrin clots and caused greater fibrinolysis vs. RBC/rPA (p<0.001). These results indicate that due to high fibrin affinity, RBC/tPA binding to clots endure hemodynamic stress, which enhances fibrinolysis. RBC/PAs behavior under hemodynamic pressure is an important predictor of their performance in vivo.


Key words: drug delivery, fibrin, mouse, plasminogen activators, red blood cell, thrombosis


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K. Ganguly, J.-C. Murciano, R. Westrick, J. Leferovich, D. B. Cines, and V. R. Muzykantov
The Glycocalyx Protects Erythrocyte-Bound Tissue-Type Plasminogen Activator from Enzymatic Inhibition
J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 158 - 164.
[Abstract] [Full Text] [PDF]


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