Histone content, and thus DNA content, is associated with differential in vitro lysis of acute ischemic stroke clots

J Thromb Haemost. 2024 May;22(5):1410-1420. doi: 10.1016/j.jtha.2024.01.013. Epub 2024 Jan 29.


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.

Keywords: ADAMTS-13; DNase; acute ischemic stroke; tPA; thrombolysis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Comparative Study

MeSH terms

  • ADAMTS13 Protein / genetics
  • ADAMTS13 Protein / metabolism
  • Aged
  • Aged, 80 and over
  • DNA* / metabolism
  • Deoxyribonuclease I / metabolism
  • Deoxyribonuclease I / therapeutic use
  • Extracellular Traps / metabolism
  • Female
  • Fibrinolysis / drug effects
  • Fibrinolytic Agents* / pharmacology
  • Fibrinolytic Agents* / therapeutic use
  • Histones* / metabolism
  • Humans
  • Ischemic Stroke* / drug therapy
  • Male
  • Middle Aged
  • Proteomics / methods
  • Thrombolytic Therapy
  • Thrombosis / drug therapy
  • Tissue Plasminogen Activator*
  • von Willebrand Factor / metabolism


  • Tissue Plasminogen Activator
  • DNA
  • Histones
  • Fibrinolytic Agents
  • Deoxyribonuclease I
  • ADAMTS13 Protein
  • ADAMTS13 protein, human
  • von Willebrand Factor