Antiplatelet therapy has limited efficacy for acute stroke and is associated with intracranial bleeding. Thrombolytic therapy is the cornerstone of treatment of acute atherothrombotic ischemic stroke but is also associated with brain hemorrhage. 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 VWF binding to GPIb. We have assessed the effect of ALX-0081, alone and in combination with rtPA, and of tirofiban, a GPIIb/IIIa inhibitor, in a photochemical injury-induced middle cerebral artery (MCA) thrombosis model in the guinea pig. ALX-0081 (5 and 8.5 mg/kg total dose), rtPA (0.032mg/kg+0.576mg/kg/30min and: 0.1mg/kg+0.9mg/kg/30 min) and tirofiban (20µg/kg bolus + 20µg/kg/2hrs infusion) were administered before, immediately after, 15 min after and 60 mi after total occlusion of the MCA. ALX-0081 prevented MCA thrombosis and induced reperfusion when given immediately after and 15 min after complete occlusion; rtPA induced reperfusion also when given 60 min after occlusion. Brain damage area was strikingly reduced in ALX-0081-treated but not in rtPA-treated guinea pigs; hemorrhage in the damaged hemisphere was markedly enhanced in rtPA-treated and in tirofiban-treated but not in ALX-0081-treated animals. Skin bleeding time was not modified or was moderately prolonged by ALX-0081 while tirofiban and rtPA prolonged it more strikingly . The inhibition of the VWF-GPIb axis in guinea pigs prevents cerebral artery thrombosis and induces early reperfusion without provoking intracerebral bleeding thus reducing brain infarct area.
Reperfusion of cerebral artery thrombosis by the GPIb-VWF blockade with the Nanobody ALX-0081 reduces brain infarct size in guinea pigs.
MOMI, Stefania;TANTUCCI, Michela;RICCI, Giovanni;GRESELE, Paolo
2013
Abstract
Antiplatelet therapy has limited efficacy for acute stroke and is associated with intracranial bleeding. Thrombolytic therapy is the cornerstone of treatment of acute atherothrombotic ischemic stroke but is also associated with brain hemorrhage. 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 VWF binding to GPIb. We have assessed the effect of ALX-0081, alone and in combination with rtPA, and of tirofiban, a GPIIb/IIIa inhibitor, in a photochemical injury-induced middle cerebral artery (MCA) thrombosis model in the guinea pig. ALX-0081 (5 and 8.5 mg/kg total dose), rtPA (0.032mg/kg+0.576mg/kg/30min and: 0.1mg/kg+0.9mg/kg/30 min) and tirofiban (20µg/kg bolus + 20µg/kg/2hrs infusion) were administered before, immediately after, 15 min after and 60 mi after total occlusion of the MCA. ALX-0081 prevented MCA thrombosis and induced reperfusion when given immediately after and 15 min after complete occlusion; rtPA induced reperfusion also when given 60 min after occlusion. Brain damage area was strikingly reduced in ALX-0081-treated but not in rtPA-treated guinea pigs; hemorrhage in the damaged hemisphere was markedly enhanced in rtPA-treated and in tirofiban-treated but not in ALX-0081-treated animals. Skin bleeding time was not modified or was moderately prolonged by ALX-0081 while tirofiban and rtPA prolonged it more strikingly . The inhibition of the VWF-GPIb axis in guinea pigs prevents cerebral artery thrombosis and induces early reperfusion without provoking intracerebral bleeding thus reducing brain infarct area.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
