title: Reperfusion of cerebral artery thrombosis by the GPIb-VWF blockade with the Nanobody ALX-0081 reduces brain infarct size in guinea pigs.
abstract: Thrombolytic therapy is the cornerstone of treatment of acute atherothrombotic ischemic stroke but is associated with brain hemorrhage; antiplatelet therapy has limited efficacy and is still associated with intracranial bleeding. Therefore, new antithrombotic approaches with a better efficacy/safety ratio are required. We have assessed the effect of ALX-0081, a Nanobody against the A1 domain of von Willebrand factor (VWF) that blocks VWF binding to GPIb, of the thrombolytic agent recombinant tissue plasminogen activator (rtPA), and of the GPIIb/IIIa antagonist tirofiban, in a middle cerebral artery (MCA) thrombosis model in guinea pigs. Drugs were administered before, immediately after, or 15 or 60 minutes after the total occlusion of the MCA. ALX-0081 prevented MCA thrombosis and induced reperfusion when given immediately after and 15 minutes after complete occlusion and reduced brain damage without inducing hemorrhage, whereas tirofiban prevented thrombosis but did not induce reperfusion and induced striking brain hemorrhage. rtPA also induced reperfusion when given 60 minutes after occlusion but provoked brain hemorrhage. Skin bleeding time was not modified or was moderately prolonged by ALX-0081, whereas tirofiban and rtPA prolonged it. The inhibition of the GPIb-VWF axis in guinea pigs prevents cerebral artery thrombosis and induces early reperfusion without provoking intracerebral bleeding thus reducing brain infarct area.
authors.affiliation: Section of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Momi
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.forename: Maarten
authors.initials: M
authors.lastname: Van Roy
authors.forename: Hans
authors.initials: H
authors.lastname: Ulrichts
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ricci
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000517:prevention & control*; D002536:Cerebral Arteries / Q000473:pathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D020767:Intracranial Thrombosis / Q000188:drug therapy*; D008297:Male; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D015424:Reperfusion / Q000379:methods; D061905:Single-Domain Antibodies / Q000494:pharmacology*; D015912:Thrombolytic Therapy / Q000379:methods*; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors
chemical_list: D005343:Fibrinolytic Agents; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D061905:Single-Domain Antibodies; D014841:von Willebrand Factor