Next-generation antithrombotics in ischemic stroke: preclinical perspective on 'bleeding-free antithrombosis'.
The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.
Department of Neurology, University Clinic of Würzburg, Würzburg, Germany. kraft_p1@klink.uni-wuerzberg.de
Peter
P
Kraft
Simon F
SF
De Meyer
Christoph
C
Kleinschnitz
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001779:Blood Coagulation Factors / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D002545:Brain Ischemia / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005174:Factor XII / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D020521:Stroke / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013927:Thrombosis / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D005174:Factor XII