Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke.

Jean-Philippe Desilles Stephane Loyau Varouna Syvannarath Jaime Gonzalez-Valcarcel Marie Cantier Liliane Louedec Bertrand Lapergue Pierre Amarenco Nadine Ajzenberg Martine Jandrot-Perrus Jean-Baptiste Michel Benoit Ho-Tin-Noe Mikael Mazighi

Stroke

From the Univ Paris Diderot, Sorbonne Paris Cite, Laboratory of Vascular Translational Science, U1148 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France (J.-P.D., S.L., V.S., J.G.-V., M.C., L.L., P.A., N.A., M.J.-P., J.-B.M., B.H.-T.-N., M.M.); Division of Neurology, Stroke Center, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France (B.L.); Departments of Neurology and Stroke Center (P.A.) and Hematology (N.A.), AP-HP, Bichat Hospital, Paris, France; and Department of Neurology and Stroke Center, AP-HP, Lariboisière Hospital, DHU Neurovasc, Paris, France (M.M.).

Published: November 2015

The study investigated downstream microvascular thrombosis (DMT) and its role in incomplete blood flow restoration during acute ischemic strokes, using a rat model.
Alteplase, a thrombolytic drug, was administered after a temporary artery blockage, and real-time imaging was used to observe blood vessel behavior and thrombus formation.
Results indicated that alteplase reduced thrombosis and improved blood flow and stroke outcomes, suggesting early intervention targeting DMT could enhance recovery in stroke patients.

Background And Purpose: Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model.

Methods: Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion.

Results: Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment. Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen.

Conclusions: Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke.

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http://dx.doi.org/10.1161/STROKEAHA.115.010721	DOI Listing

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