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A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation.

Authors :
Fuentes RE
Zaitsev S
Ahn HS
Hayes V
Kowalska MA
Lambert MP
Wang Y
Siegel DL
Bougie DW
Aster RH
Myers DD
Stepanova V
Cines DB
Muzykantov VR
Poncz M
Source :
The Journal of clinical investigation [J Clin Invest] 2016 Feb; Vol. 126 (2), pp. 483-94.
Publication Year :
2016

Abstract

The use of fibrinolytic agents to prevent new thrombus formation is limited by an increased risk of bleeding due to lysis of hemostatic clots that prevent hemorrhage in damaged blood vessels. We sought to develop an agent that provides thromboprophylaxis without carrying a significant risk of causing systemic fibrinolysis or disrupting hemostatic clots. We previously showed that platelet (PLT) α granule-delivered urokinase plasminogen activator (uPA) is highly effective in preventing thrombosis, while being associated with little systemic fibrinolysis or bleeding. Here, we generated a chimeric prodrug composed of a single-chain version of the variable region of an anti-αIIbβ3 mAb fused to a thrombin-activatable, low-molecular-weight pro-uPA (PLT/uPA-T). PLT/uPA-T recognizes human αIIbβ3 on both quiescent and activated platelets and is enzymatically activated specifically by thrombin. We found that this prodrug binds tightly to human platelets even after gel filtration, has a prolonged half-life in mice transgenic for human αIIb compared with that of uPA-T, and prevents clot formation in a microfluidic system. Importantly, in two murine injury models, PLT/uPA-T did not lyse preexisting clots, even when administration was delayed by as little as 10 minutes, while it concurrently prevented the development of nascent thrombi. Thus, PLT/uPA-T represents the prototype of a platelet-targeted thromboprophylactic agent that selectively targets nascent over preexisting thrombi.

Details

Language :
English
ISSN :
1558-8238
Volume :
126
Issue :
2
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
26690701
Full Text :
https://doi.org/10.1172/JCI81470