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(Circulation. 2008;118:1442-1449.)
© 2008 American Heart Association, Inc.

Stroke

Cerebrovascular Thromboprophylaxis in Mice by Erythrocyte-Coupled Tissue-Type Plasminogen Activator

Kristina Danielyan, PhD; Kumkum Ganguly, PhD; Bi-Sen Ding, BS; Dmitriy Atochin, MD, PhD; Sergei Zaitsev, PhD; Juan-Carlos Murciano, PhD; Paul L. Huang, MD, PhD; Scott E. Kasner, MD; Douglas B. Cines, MD; Vladimir R. Muzykantov, MD, PhD

From the Pharmacology Department (K.D., B.-S.D., S.Z., V.R.M.), Neurology Department (S.E.K.), and Pathology Department (D.B.C.), University of Pennsylvania, Philadelphia; Los Alamos National Laboratory, Los Alamos, NM (K.G.); Cardiovascular Research Center, Massachusetts General Hospital, Boston (D.A., P.L.H.); and Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.-C.M.).

Correspondence to V. Muzykantov, 1 John Morgan Bldg, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104–6068. E-mail muzykant{at}mail.med.upenn.edu

Received November 2, 2007; accepted July 15, 2008.

Background— Cerebrovascular thrombosis is a major source of morbidity and mortality after surgery, but thromboprophylaxis in this setting is limited because of the formidable risk of perioperative bleeding. Thrombolytics (eg, tissue-type plasminogen activator [tPA]) cannot be used prophylactically in this high-risk setting because of their short duration of action and risk of causing hemorrhage and central nervous system damage. We found that coupling tPA to carrier red blood cells (RBCs) prolongs and localizes tPA activity within the bloodstream and converts it into a thromboprophylactic agent, RBC/tPA. To evaluate the utility of this new approach for preventing cerebrovascular thrombosis, we examined the effect of RBC/tPA in animal models of cerebrovascular thromboembolism and ischemia.

Methods and Results— Preformed fibrin microemboli were injected into the middle carotid artery of mice, occluding downstream perfusion and causing severe infarction and 50% mortality within 48 hours. Preinjected RBC/tPA rapidly lysed nascent cerebral thromboemboli, providing rapid, durable reperfusion and reducing morbidity and mortality. These beneficial effects were not achieved by preinjection of tPA, even at a 10-fold higher dose, which increased mortality from 50% to 90% by 10 hours after embolization. RBC/tPA injected 10 minutes after tail amputation to simulate postsurgical hemostasis did not cause bleeding from the wound, whereas soluble tPA caused profuse bleeding. RBC/tPA neither aggravated brain damage caused by focal ischemia in a filament model of middle carotid artery occlusion nor caused postthrombotic hemorrhage in hypertensive rats.

Conclusions— These results suggest a potential RBC/tPA utility as thromboprophylaxis in patients who are at risk for acute cerebrovascular thromboembolism.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 1403-1404. [Extract] [Full Text]

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				D. J. Schneider and B. E. Sobel A Novel Role for Tissue-Type Plasminogen Activator: Prevention of Thromboembolic Occlusion Circulation, September 30, 2008; 118(14): 1408 - 1409. [Full Text] [PDF]