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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2003-01-0054.
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Blood, 1 August 2003, Vol. 102, No. 3, pp. 926-933
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Antithrombotic thrombocytes: ectopic expression of urokinase-type plasminogen activator in platelets
Dubravka Kufrin,
Don E. Eslin,
Khalil Bdeir,
Juan-Carlos Murciano,
Alice Kuo,
M. Anna Kowalska,
Jay L. Degen,
Bruce S. Sachais,
Douglas B. Cines, and
Mortimer Poncz
From the Children's Hospital of Philadelphia, PA; Departments of Pediatrics, Pathology, and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia; and Children's Hospital Research Foundation, University of Cincinnati College of Medicine, OH
Arterial occlusive disorders are a leading cause of human morbidity. We hypothesized that ectopic expression of fibrinolytic proteins in platelets could be used to favorably alter the hemostatic balance at sites of thrombosis. To test our hypothesis, we directed murine urokinase-type plasminogen activator transgene expression to platelets using a platelet factor 4 promoter. Urokinase was selectively expressed and stored in the platelets of these mice. These transgenic mice had altered platelet biology and a bleeding diathesis similar to that seen in patients with Quebec platelet disorder, affirming the role of ectopic urokinase expression as the etiology of this inherited disease. These mice were resistant to the development of occlusive carotid artery thrombosis in the absence of systemic fibrinolysis and displayed rapid resolution of pulmonary emboli. Moreover, transfusion of urokinase-expressing platelets into wild-type mice prevented formation of occlusive arterial thrombi. These studies show the feasibility of delivering fibrinolytic agents to sites of incipient thrombus formation through selective storage in platelets and offer a new strategy to prevent thrombosis and hemorrhage.
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