Antithrombotic thrombocytes: ectopic expression of urokinase-type plasminogen activator in platelets.
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.
Kufrin
Dubravka
D
Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, ARC; Rm 317, Philadelphia, PA 19104, USA.
Eslin
Don E
DE
Bdeir
Khalil
K
Murciano
Juan-Carlos
JC
Kuo
Alice
A
Kowalska
M Anna
MA
Degen
Jay L
JL
Sachais
Bruce S
BS
Cines
Douglas B
DB
Poncz
Mortimer
M
D000818:Animals; D000933:Antifibrinolytic Agents / Q000008:administration & dosage; D001792:Blood Platelets / Q000378:metabolism*; D002339:Carotid Arteries / Q000473:pathology; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D017713:Platelet Transfusion; D011655:Pulmonary Embolism / Q000628:therapy; D013927:Thrombosis / Q000517:prevention & control* / Q000628:therapy; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*
D000933:Antifibrinolytic Agents; D014568:Urokinase-Type Plasminogen Activator