QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.093450v1 316/3/1130    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ganguly, K. Articles by Murciano, J.-C. Search for Related Content PubMed PubMed Citation Articles by Ganguly, K. Articles by Murciano, J.-C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

CARDIOVASCULAR

Fibrin Affinity of Erythrocyte-Coupled Tissue-Type Plasminogen Activators Endures Hemodynamic Forces and Enhances Fibrinolysis in Vivo

Institute for Environmental Medicine (K.G., T.K., V.R.M., J.-C.M.), Institute for Medicine and Engineering (M.S.G., S.L.D.), and Departments of Laboratory Medicine (K.B., D.B.C.) and Pharmacology and Institute for Translational Medicine and Therapeutics (V.R.M.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Centro Nacional de Investigaciones Cardiovasculares (J.-C.M.), Madrid, Spain

Plasminogen activators (PAs; e.g., tissue-type, tPA) coupled to red blood cells (RBCs) display in vivo features useful for thromboprophylaxis: prolonged circulation, minimal extravasation, and preferential lysis of nascent versus 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/tPA variant with low fibrin affinity (rPA) bound to and lysed plasminogen-containing fibrin clots in vitro comparably. In contrast, when coinjected in mice with fibrin emboli lodging in pulmonary vasculature, only RBC/tPA accumulated in lungs, which resulted in a more extensive fibrinolysis versus 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 versus RBC/rPA (p < 0.001). These results indicate that because of high fibrin affinity, RBC/tPA binding to clots endures hemodynamic stress, which enhances fibrinolysis. Behavior of RBC/PAs under hemodynamic pressure is an important predictor of their performance in vivo.

Address correspondence to: Dr. Vladimir R. Muzykantov, Institute for Environmental Medicine, University of Pennsylvania School of Medicine, One John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068. E-mail: muzykant{at}mail.med.upenn.edu

This article has been cited by other articles:

				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]