Abstract 15828: Alx-0081, a Selective Inhibitor of the Interaction Between Platelet Gpib and Von Willebrand Factor, Prevents Ischemic Stroke in the Guinea Pig: Comparison With the Thrombolytic Rtpa.
The interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (VWF) triggers the initial step of platelet adhesion and arterial thrombus formation. Antiplatelet therapy is the cornerstone of treatment of acute cerebrovascular disease but is associated with risk of bleeding. New antiplatelet approaches with a better efficacy/safety ratio are therefore required. ALX-0081 is a Nanobody® against the A1 domain of VWF that specifically blocks the GPIb binding site of VWF. We have assessed the efficacy and safety of ALX-0081 in a photochemical injury-induced middle cerebral artery (MCA) thrombosis model in the guinea pig. End points were: continuous measurement of blood flow in the MCA; skin bleeding time; brain damage (including ischemia and hemorrhage) by TTC staining and image analysis; hemoglobin content in the damaged hemisphere, an index of hemorrhage, expressed as % increase in the damaged vs healthy hemisphere. ALX-0081 (5 and 8.5 mg/kg) and rtPA (low dose: 0.032mg/kg+0.576mg/kg/30min; high dose: 0.1mg/kg+0.9mg/kg/30 min) were administered immediately after the total occlusion of the MCA. ALX-0081 restored perfusion in the MCA at both doses while rtPA was effective only at the high dose. ALX-0081 did not modify the skin bleeding time at low dose (5 mg/kg:+39%, p=NS) while it prolonged it at the high dose (8.5mg/kg:+259% p<0.01); rtPA prolonged bleeding time at both doses (low dose:+289%, p<0.01;high dose:+572%, p<0.001). The brain damage area was strikingly reduced in ALX-0081-treated guinea pigs (5mg/kg: 3.64±2.15% of total, 8.5mg/kg: 5.3±0.9%; vs 14.6±.1.2% in controls, p<0.001) but not in rtPA-treated guinea pigs (low dose:14±1.3% of total; high dose: 15.7±4.5%). The haemoglobin content in the damaged hemisphere was markedly enhanced in rtPA-treated (controls: 13.8±4.3%; rtPA low dose: 40.4±7.2%; high dose: 64.5±17.3%, p<0.001 vs controls) but not in ALX-0081-treated animals (15.3±1.7%). The inhibition of the VWF-GPIb axis seems an effective and safe strategy for the treatment of thromboembolic disorders.
- © 2010 by American Heart Association, Inc.