A novel platelet-specific delivery system for fibrinolytic agents
Abstract number: OC360
Poncz* M., Kufrin* D., Eslin* D. E., Bdeir* K., Murciano J. C., Kuo A., Degen* J. L., Sachais B., Cines D. B.
*Children's Hospital of Philadelphia, USA; University of Pennsylvania, USA
Vascular occlusive disorders remain a leading cause of death despite the introduction of new antiplatelet drugs. We have been interested in whether ectopic expression of antithrombotic proteins in platelets would offer a novel therapeutic approach in such pathological settings. We examined whether the prothrombotic contribution of platelets could be diminished by genetically directing platelets to express and store urokinase-type plasminogen activator (uPA). This was accomplished by using 1.2 kb of the murine platelet factor 4 gene promoter to drive expression from a murine uPA mini-gene in transgenic mice. Positive transgenic lines expressed uPA message exclusively in marrow and platelets, and immunostains of marrow localized uPA to megakaryocytes. uPA protein and activity was demonstrated in platelets from transgenic animals, similar to the recent demonstration of ectopic uPA activity in the platelets of patients with Quebec Platelet Disorder (QPD). As in QPD patients, these mice had a mild bleeding diathesis, most prominent during the peripartum period. There was associated degradation of platelet alpha-granule proteins, including von Willebrand Factor, fibrinogen and Factor V, but there was no evidence of systemic fibrinolysis. Protection from thrombosis was documented using a FeCl3 carotid artery thrombosis model and was reversed using tranexamic acid, an anti-fibrinolytic drug. Transfusion of uPA-expressing platelets equivalent to 10% of the wildtype recipient's total platelets prevented occlusive thrombus formation. This effect was due to the released uPA, since pretreatment of recipient wildtype mice with tranexamic acid abrogated the antithrombotic effect of transfusion. In a murine model of pulmonary microemboli, the transgenic mice lysed injected nascent pulmonary emboli more effectively than wildtype mice, such that 10 min after the injection, >80% of the emboli were lysed compared to only 4% in the control. Thus, uPA ectopically expressed during megakaryopoiesis remains in the platelets, degrades alpha-granular proteins, prevents thrombus growth, and may lyse nascent thrombi, providing a murine model of QPD. More importantly, this animal model suggests that expression of uPA in platelets may be a potent antithrombotic strategy, and supports the concept of ectopic expression of diverse pro- and anticoagulant molecules in platelets, enabling their targeted release at sites of vascular injury or incipient thrombosis.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2003; 1 Supplement 1 July: abstract number
|Subject:||New anti-thrombotic agents and approaches|
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