Comparison of the novel thrombolytic constitutively active ADAMTS13 with clinical thrombolytics in a murine stroke model

Background
Recombinant tissue plasminogen activator (rtPA) and its variant, tenecteplase (TNK), are the currently approved thrombolytic drugs for the treatment of acute ischaemic stroke, but they are ineffective in a proportion of patients due to rtPA resistance of platelet-rich thrombi. A novel thrombolytic, constitutively active (ca)ADAMTS13 has been shown to improve experimental stroke outcomes where platelet-rich thrombi are present but has not been directly compared to rtPA or TNK.

Methods
We conducted a direct comparison of caADAMTS13 vs rtPA vs TNK vs vehicle control in the ferric chloride (FeCl3)-mediated distal middle cerebral artery occlusion model in mice, which features platelet and von Willebrand Factor (VWF)-rich thrombi that reproduce rtPA-resistant occlusion. Treatments were administered intravenously 1 h after FeCl3 application by bolus injection or bolus followed by infusion, as translationally applicable. Laser speckle contrast imaging measured early reperfusion over the hour following treatment and magnetic resonance imaging measured cerebral blood flow and lesion volume at 24 h.

Results
Reperfusion 1 h after treatment was greatest in caADAMTS13 treated animals. Later cerebral blood flow, 24 h post-treatment, within the stroke affected hypoperfused area was higher in caADAMTS13 and rtPA, but not TNK treated mice. Functionally, this led to the absence of an initial behavioural deficit in caADAMTS13 treated mice, alongside a smaller lesion volume at 24 h and reduced extent of bleeding.

Conclusions
These findings demonstrate an overall suggestion that caADAMTS13 has improved thrombolytic efficacy, compared to current stroke treatments, against platelet-rich thrombi, for which there is currently an unmet clinical need.