Association of NETs Markers with Clinical and Radiological Outcomes in Patients with Acute Ischemic Stroke Undergoing Thrombectomy: Does Heparin Treatment Modify This?

Abstract

The aim of this study is to investigate the association of neutrophil extracellular traps (NETs) markers with clinical and radiological outcomes in acute ischemic stroke (AIS) patients undergoing endovascular thrombectomy (EVT) and assess the effect of periprocedural heparin during EVT on NETs markers and their association with outcomes. From 198 AIS patients included in the MRCLEAN-MED trial, randomized to receive EVT with (N = 104) or without (N = 94) low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h, n = 104), blood samples were collected at baseline, 1 h, and 24 h post-reperfusion. NETs markers (MPO-DNA, histone-DNA, citrullinated histone H3 [CitH3]) were measured in blood samples, and their associations with stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at 24 h post-reperfusion), long-term functional outcome (modified Rankin Scale [mRS] score at 90-day), and final infarct size (5-7 days) were assessed in EVT and heparin + EVT-treated patients using logistic regression, linear regression, and Pearson's correlation. Histone-DNA levels at 1 h post-heparin + EVT, but not EVT alone, were positively associated with final infarct size. Histone-DNA levels at 24 h post-heparin + EVT were negatively associated with infarct size mRS and NIHSS, while baseline CitH3 was positively correlated with NIHSS at 24 h post-EVT. Interaction analysis showed that the association between histone-DNA levels at 24 h and NIHSS at 24 h was different in the two treatment groups. No further associations were observed. At 1 h post-heparin + EVT, the histone-DNA levels were independently associated with larger infarct size, while at 24 h, histone-DNA linked to improved outcomes post-heparin + EVT and baseline-CitH3 to worse outcomes post-EVT, suggesting heparin may attenuate histone-DNA's effect on outcome.

Keywords: Coagulation; Endovascular thrombectomy; Functional outcome; Infarct size; Inflammation; Ischemic stroke; NETs markers; Stroke severity; Unfractionated heparin.