Inhibition of VWF Demonstrates Thrombolysis Following ex vivo Thrombus Formation in Patients with AIS LVO
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Date
2024-05
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The Ohio State University
Abstract
Acute ischemic stroke (AIS) is the leading cause of combined death and disability across the world. While recombinant tissue plasminogen activator (rTPA) and its analogs are the sole approved thrombolytic for AIS, its application is constrained by its strict administration window due to lack of reversibility, and potential for hemorrhage. Von Willebrand factor (VWF) is a glycoprotein pivotal in the adhesion, aggregation, and propagation of platelets. Most notably, VWF is responsible for tethering a thrombus to the collagen within a vessel wall through interaction with the platelet glycoprotein receptor, GP-Ib. This interaction also further activates surrounding platelets and leads to deceleration in cerebral blood flow, exacerbating ischemic injury. Thus, VWF is a crucial mediator in AIS pathophysiology. BB-031 is an RNA aptamer shown to inhibit VWF-platelet interaction in in vivo and in vitro settings. The objective of this study was to determine if BB-031 will be an effective therapeutic in AIS large vessel occlusion (LVO) patients using a kinetic ex vivo microfluidic model.
A microfluidic model of arterial thrombus was used to recapitulate the constant pressure and kinetic environment found with in vivo occlusion. After thrombus formation, BB-031 was introduced to the flow at a concentration of 1692 nM. A 2-hour perfusion period was observed following treatment administration of BB-031 or vehicle control (PBS). Patency and thrombus surface area were measured throughout the perfusion.
In the kinetic model, patency was achieved in 85% (6/7) of samples in the BB-031 samples compared to 0% (0/8) of the samples in the vehicle control group. Analysis of the surface area of the thrombi showed a decrease in pre-occlusion platelets throughout the perfusion in the BB-031 treatment group compared to PBS control. Interestingly, post-occlusion platelets initially increased in surface area as new platelets were deposited and eventually decreased in the BB-031 group. The control group showed decreased post-occlusion platelet deposition.
This study demonstrates the potential of BB-031 as a therapeutic intervention for large vessel occlusion acute ischemic stroke, exhibiting encouraging trends in enhancing patency and modulating thrombus formation. These results offer promising for those affected by this lethal disease and more work must be done to further strengthen the thrombolytic replacement of rTPA with BB-031 or at least, efficacy for those patients not eligible for therapeutic treatment.
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Keywords
Stroke, Aptamer, von Willebrand Factor, Thrombolysis