Biomarkers of Cardioembolic Stroke in Thrombus Composition: Diagnostic Value of DNA and Fibrin Content

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BACKGROUND AND PURPOSE: Cryptogenic strokes, accounting for 25%-40% of ischemic strokes, represent a major challenge in secondary prevention due to their uncertain etiology and high recurrence risk. Identifying biomarkers to reliably distinguish cardioembolic (CE) strokes among embolic strokes of undetermined source (ESUS) could help guide therapeutic decisions. Previous studies have indicated thrombus DNA content as a potential biomarker of CE stroke etiology, but direct quantification of fibrin, another key component, has not been adequately explored. METHODS: We analyzed thrombi collected from 186 ischemic stroke patients undergoing endovascular treatment between 2019 and 2023. Thrombi were processed using a quantitative method based on ex vivo tPA-mediated fibrinolysis followed by mechanical homogenization. Stroke etiology was classified according to TOAST criteria: 40% cardioembolic, 24% non-cardioembolic (large artery atherosclerosis or dissection), and 36% ESUS. Biomarker content was correlated with stroke etiology, and the diagnostic performance of DNA and fibrin (D-dimer) content was evaluated. RESULTS: Cardioembolic thrombi contained significantly higher levels of DNA (median [IQR]: 325.3 [177-484] ng/mg) and D-dimer (17.5 [9.1-23.8] μg/mg) compared to non-cardioembolic thrombi (DNA: 128 [76.4-263] ng/mg; D-dimer: 11.4 [6.8-13.2] μg/mg), with no significant differences observed in heme or GPVI content. The combined use of thrombus DNA and fibrin (D-dimer) content provided good discrimination between CE and non-CE thrombi, with an area under the ROC curve of 0.79 (95% CI, 0.70-0.87). CONCLUSION: DNA and fibrin content in thrombi are promising biomarkers for identifying cardioembolic stroke etiology. Prospective studies should evaluate their use in selecting ESUS patients who may benefit from anticoagulant therapy.

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