Reperfusion of cerebral artery thrombosis by the GPIb–VWF blockade with the Nanobody ALX-0081 reduces brain infarct size in guinea pigs

Abstract

Key Points Blockade of VWF-A1 by ALX-0081 induces reperfusion of a thrombus-occluded middle cerebral artery without provoking cerebral bleeding. The interaction between GPIb and VWF is not only essential for platelet adhesion but also for initial thrombus stabilization.

Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

“…20,21,[33][34][35][36] Taken together with our findings, these studies indicate that DMT targeting should be achieved as soon as possible following occlusion, even before recanalization, to be effective. In that regard, a recent EVT meta-analysis showed that the likelihood of a favorable outcome increased with the use of previous intravenous thrombolysis with alteplase.…”

GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

“…6 This model also provides an explanation for the thrombolytic effect of GpIba-VWF blockade after occlusive thrombosis in guinea pigs and confirms this finding in another model of MCA thrombosis. 10 In fact, our results demonstrate that each part of the occlusive thrombi is responsive to specific thrombolytic agents ( Figure 7B), suggesting that thrombolytic strategies should be adapted to thrombus subtype ( Figure 7C). Notably, our study further highlights the GpIba-VWF axis as a relevant therapeutic target for acute occlusive thrombosis.…”

“…We were not able to investigate the potential pro-hemorrhagic effect of GpIba-VWF blockade, because no hemorrhage was detected in our stroke model. However, in previous studies of ischemic stroke, blockade of GpIba-VWF interactions did not increase the rate of intracranial hemorrhage, 10,14 suggesting that this therapeutic strategy would be safer than current thrombolytic treatments. Because several inhibitors of GpIba-VWF interactions are currently under preclinical and clinical investigations as thromboprophylactic drugs, 32,33 they constitute promising candidates for the pharmacological treatment of acute occlusive thrombotic disorders.…”

“…1 However, during occlusive thrombus formation, the respective contributions of these shearspecific mechanisms remain unknown. In a recent study, Momi et al 10 demonstrated that blockade of the interaction between GpIba and von Willebrand Factor (VWF) leads to reperfusion after photothrombosis-induced stroke in guinea pigs, whereas GpIIb/IIIa inhibitors are ineffective. Although the beneficial effect of GpIba-VWF targeting through inhibition of the postreperfusion thrombo-inflammatory reaction is well established in transient mechanical stroke models, [11][12][13][14] the reason why GpIba-VWF blockade dissolves already-formed occlusive thrombi remains unclear.…”

(Dis)solving the stroke problem by vWF inhibition?

“…Remarkably, the GPIb-blocking antibodies were still protective when administered after ischemia, indicating that targeting of the GPIb-vWF interaction might be therapeutically beneficial in acute stroke. The current study by Momi et al 1 demonstrates that ALX-0081, a divalent humanized nanobody directed against the GPIb-binding site on vWF (A1 domain), effectively dissolved newly formed intracranial thrombi leading to reperfusion and reduced infarct size in guinea pigs (see figure). ALX-0081 treatment was as effective as tPA in re-establishing cerebral blood flow when given at early but not late time points after vessel occlusion, indicating that it only exerts its thrombolytic activity before the thrombus is stabilized by fibrin formation and possibly other interactions that are not established at early phases.…”