Histone content, and thus DNA content, is associated with differential in vitro lysis of acute ischemic stroke clots.
Publication/Presentation Date
5-1-2024
Abstract
BACKGROUND: Fibrin, von Willebrand factor, and extracellular DNA from neutrophil extracellular traps all contribute to acute ischemic stroke thrombus integrity.
OBJECTIVES: In this study, we explored how the proteomic composition of retrieved thromboemboli relates to susceptibility to lysis with distinct thrombolytics.
METHODS: Twenty-six retrieved stroke thromboemboli were portioned into 4 segments, with each subjected to 1 hour of in vitro lysis at 37 °C in 1 of 4 solutions: tissue plasminogen activator (tPA), tPA + von Willebrand factor-cleaving ADAMTS-13, tPA + DNA-cleaving deoxyribonuclease (DNase) I, and all 3 enzymes. Lysis, characterized by the percent change in prelysis and postlysis weight, was compared across the solutions and related to the corresponding abundance of proteins identified on mass spectrometry for each of the thromboemboli used in lysis.
RESULTS: Solutions containing DNase resulted in approximately 3-fold greater thrombolysis than that with the standard-of-care tPA solution (post hoc Tukey, P < .01 for all). DNA content was directly related to lysis in solutions containing DNase (Spearman's ρ > 0.39 and P < .05 for all significant histones) and inversely related to lysis in solutions without DNase (Spearman's ρ < -0.40 and P < .05 for all significant histones). Functional analysis suggests distinct pathways associated with susceptibility to thrombolysis with tPA (platelet-mediated) or DNase (innate immune system-mediated).
CONCLUSION: This study demonstrates synergy of DNase and tPA in thrombolysis of stroke emboli and points to DNase as a potential adjunct to our currently limited selection of thrombolytics in treating acute ischemic stroke.
Volume
22
Issue
5
First Page
1410
Last Page
1420
ISSN
1538-7836
Published In/Presented At
Akkipeddi, S. M. K., Rahmani, R., Ellens, N. R., Kohli, G. S., Houk, C., Schartz, D. A., Chittaranjan, S., Worley, L., Gunturi, A., Bhalla, T., Mattingly, T. K., Welle, K., Morrell, C. N., & Bender, M. T. (2024). Histone content, and thus DNA content, is associated with differential in vitro lysis of acute ischemic stroke clots. Journal of thrombosis and haemostasis : JTH, 22(5), 1410–1420. https://doi.org/10.1016/j.jtha.2024.01.013
Disciplines
Medicine and Health Sciences
PubMedID
38296159
Department(s)
Department of Surgery
Document Type
Article