Abstract 47: Proteomic Profiling of Acute Stroke Patients Highlights the Importance of vWF and vWF-Cleaving Protease (ADAMTS13) in Thrombolysis

Introduction: Recent animal studies show rADAMTS13 (vWF cleaving protease) to block tPA-induced BBB opening, reducing tPA-related hemorrhage and augmenting tPA’s thrombolytic effect. From proteomic screening, we found ADAMTS13/vWF to be an important pathway in tPA responders. Thus, the vWF/ADAMTS13 (vWF cleaving protease) axis may be an important modifier of tPA response in the clinical setting. But the effect of tPA on the ADAMTS13/vWF balance has not been studied directly in stroke patients post-tPA. Here we measured vWF and ADAMTS13 in acute ischemic stroke patients post IV tPA to investigate their clinical utility to follow tPA response. Methods: Quantitative Mass Spectrometry (MS), latex immuno-turbidimetric assay, and ELISA were performed in acute ischemic stroke plasma over time, with clinical outcome measured at 3 months. Response was defined per NINDS trial as mRankins= 4 points improvement on NIHSS. Results: Post tPA (up to 72 hours), ADAMTS13 is persistently and significantly higher in tPA responders than in non-responders (Figure 1A). Conversely, within 72 hrs post tPA, the ratio of vWF/ADAMTS13 (a measure of clot burden vs clot lysis) is significantly higher in tPA patients who did not improve compared to those who did. tPA patients also had lower vWF/ADAMTS13 ratios than non-tPA strokes (Figure 1B). Conclusion: Through dynamic changes detected in the vWF/ADAMTS13 pathway, our data suggest the balance of clot burden vs lysis is crucial in tPA response as measured in patient plasma in real time. More vWF degradation in tPA patients via ADAMTS13 is correlated to better clinical outcome within the first 72 hours, and conversely, increased clot burden was found in tPA non-responders. Studying endogenous ADAMTS13 activity in tPA response is an initial step to obtain evidence for its potential clinical utility. And vWF/ADAMTS13 ratio may be a biologically relevant and potentially clinically useful marker of clotting/lytic status in early thrombolysis.