Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment
- 1 November 2008
- journal article
- review article
- Published by American Society of Hematology in Blood
- Vol. 112 (9), 3555-3562
- https://doi.org/10.1182/blood-2008-04-144758
Abstract
In ischemic stroke, treatment options are limited. Therapeutic thrombolysis is restricted to the first few hours after stroke, and the utility of current platelet aggregation inhibitors, including GPIIb/IIIa receptor antagonists, and anticoagulants is counterbalanced by the risk of intracerebral bleeding complications. Numerous attempts to establish neuroprotection in ischemic stroke have been unfruitful. Thus, there is strong demand for novel treatment strategies. Major advances have been made in understanding the molecular functions of platelet receptors such as glycoprotein Ib (GPIb) and GPVI and their downstream signaling pathways that allow interference with their function. Inhibition of these receptors in the mouse stroke model of transient middle cerebral artery occlusion prevented infarctions without increasing the risk of intracerebral bleeding. Similarly, it is now clear that the intrinsic coagulation factor XII (FXII) and FXI play a functional role in thrombus formation and stabilization during stroke: their deficiency or blockade protects from cerebral ischemia without overtly affecting hemostasis. Based on the accumulating evidence that thrombus formation and hemostasis are not inevitably linked, new concepts for prevention and treatment of ischemic stroke may eventually emerge without the hazard of severe bleeding complications. This review discusses recent advances related to antithrombotic strategies in experimental stroke research.This publication has 94 references indexed in Scilit:
- The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarctionThe Journal of Experimental Medicine, 2008
- Inflammation induces hemorrhage in thrombocytopeniaBlood, 2008
- Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivoThe Journal of Experimental Medicine, 2007
- Talin is required for integrin-mediated platelet function in hemostasis and thrombosisThe Journal of Experimental Medicine, 2007
- Platelet adhesion receptors do not modulate infarct volume after a photochemically induced stroke in miceBrain Research, 2007
- An EF hand mutation in Stim1 causes premature platelet activation and bleeding in miceJCI Insight, 2007
- Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulationProceedings of the National Academy of Sciences of the United States of America, 2007
- The role of platelet adhesion receptor GPIbα far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosisProceedings of the National Academy of Sciences of the United States of America, 2006
- 1,026 Experimental treatments in acute strokeAnnals of Neurology, 2006
- The Rapid Anticoagulation Prevents Ischemic Damage Study in Acute Stroke – Final Results from the Writing CommitteeCerebrovascular Diseases, 2005