caADAMTS13 reduces neutrophil-mediated vascular inflammation without exacerbating bleeding in experimental intracerebral haemorrhage.

Targeting thromboinflammation through the von Willebrand factor (VWF)/ADAMTS13 axis is a promising therapeutic target for acute ischaemic stroke (AIS). Constitutively active ADAMTS13 (caADAMTS13) is a novel thrombolytic that improves outcomes in experimental AIS, with enhanced thrombolytic efficacy compared to current licensed AIS treatments. Current thrombolytics are limited by a narrow therapeutic window and the requirement for definitive imaging to exclude intracerebral haemorrhage (ICH). This study aimed to assess whether caADAMTS13 is safe in the context of ICH, evaluating its potential use when the stroke subtype is unknown, including pre-hospital settings. In zebrafish larval and murine ICH models, both hyperacute (1 h) and delayed (12 or 24 h) caADAMTS13 administration did not exacerbate haemorrhage. Early cerebrovascular VWF accumulation (4 h) and acute neutrophil recruitment (24 h) were unchanged, while vascular neutrophil deposition was reduced by 80% in mice 7 days post-ICH. Delayed caADAMTS13 treatment reduces brain neutrophil recruitment by 37% and injury by 32%, improving ICH outcomes in zebrafish larvae. Together, these findings support the development of caADAMTS13 as a thrombolytic suitable for use in suspected stroke prior to brain imaging to maximise benefit from ultra-early treatment or in regions where rapid access to brain imaging is not possible.