[en] [en] BACKGROUND: Accumulating evidence indicates that neutrophil activation (NA) contributes to microvascular thromboinflammation in acute ischemic stroke (AIS) due to a large vessel occlusion. Preclinical data have suggested that intravenous thrombolysis (IVT) before endovascular therapy (EVT) could dampen microvascular thromboinflammation. In this study we investigated the association between NA dynamics and stroke outcome, and the impact of IVT on NA in patients with AIS treated with EVT.
METHODS: A single-center prospective study was carried out, including patients treated with EVT for whom three blood samples (before, within 1 hour, 24 hours post-EVT) were drawn to measure plasma myeloperoxidase (MPO) concentration as a marker of NA. Unfavorable outcome was defined as a modified Rankin score of 3-6 at 3 months.
RESULTS: Between 2016 and 2020, 179 patients were included. The plasma MPO concentration peaked significantly 1 hour post-EVT (median increase 21.0 ng/mL (IQR -2.1-150)) and returned to pre-EVT baseline values 24 hours after EVT (median change from baseline -0.8 ng/mL (IQR -7.6-6.7)). This peak was strongly associated with unfavorable outcomes at 3 months (aOR 0.53 (95% CI 0.34 to 0.84), P=0.007). IVT before EVT abolished this 1 hour post-EVT MPO peak. Changes in plasma MPO concentration (baseline to 1 hour post-EVT) were associated with unfavorable outcomes only in patients not treated with IVT before EVT (aOR 0.54 (95% CI 0.33 to 0.88, P=0.013). However, we found no significant heterogeneity in the associations between changes in plasma MPO concentration and outcomes.
CONCLUSIONS: A peak in plasma MPO concentration occurs early after EVT and is associated with unfavorable outcomes. IVT abolished the post-EVT MPO peak and may modulate the association between NA and outcomes.
Disciplines :
Neurology
Author, co-author :
Maïer, Benjamin ; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France ; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France ; Neurology Department, Hôpital Saint-Joseph, Paris, France ; FHU NeuroVasc, Paris, France
Di Meglio, Lucas ; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France ; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France
Desilles, Jean-Philippe; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France ; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France ; FHU NeuroVasc, Paris, France
Solo Nomenjanahary, Mialitiana; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France
Delvoye, François ; Université de Liège - ULiège > Département des sciences cliniques ; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France
Kyheng, Maeva; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France
Boursin, Perrine; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France
Ollivier, Véronique; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France
Dupont, Sébastien; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France
Rambaud, Thomas; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France
Hamdani, Mylène; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France
Labreuche, Julien; Department of Biostatistics, CHU Lille, 59000 Lille, France
Piotin, Michel; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France
Halimi, Jean-Michel; Nephrology Department, Tours Hospital, Tours, France ; EA4245-Transplantation, Immunology and Inflammation, University of Tours, Tours, France
Mazighi, Mikaël ; Interventional Neuroradiology Department, Fondation Rothschild Hospital, Paris, France ; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France ; FHU NeuroVasc, Paris, France ; Department of Neurology, Lariboisiere Hospital, Université Paris Cité, Paris, France
Ho-Tin-Noe, Benoit; UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France, Université de Paris Cité, Inserm, Paris, France benoit.ho-tin-noe@inserm.fr
This work was supported by INSERM and by public grants overseen by the French National Research Agency (ANR) as part of the Investments for the Future program (PIA) under grant agreement No. ANR-18-RHUS-0001 (RHU Booster), ANR-21-CE17-0023-02 (ETHERISCH), and ANR INFLAME.
Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387: 1723-31. doi:10.1016/S0140-6736(16)00163-X
Lapergue B, Blanc R, Costalat V, et al. Effect of thrombectomy with combined contact aspiration and stent retriever vs stent retriever alone on revascularization in patients with acute ischemic stroke and large vessel occlusion: the ASTER2 randomized clinical trial. JAMA 2021; 326: 1158-69. doi:10.1001/jama.2021.13827
LeCouffe NE, Kappelhof M, Treurniet KM, et al. A randomized trial of intravenous alteplase before endovascular treatment for stroke. N Engl J Med 2021; 385: 1833-44. doi:10.1056/NEJMoa2107727
Suzuki K, Matsumaru Y, Takeuchi M, et al. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: the SKIP randomized clinical trial. JAMA 2021; 325: 244-53. doi:10.1001/jama.2020.23522
Yang P, Zhang Y, Zhang L, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med 2020; 382: 1981-93. doi:10.1056/NEJMoa2001123
Zi W, Qiu Z, Li F, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke: the DEVT randomized clinical trial. JAMA 2021; 325: 234-43. doi:10.1001/jama.2020.23523
Seners P, Turc G, Maïer B, et al. Incidence and predictors of early recanalization after intravenous thrombolysis: a systematic review and meta-analysis. Stroke 2016; 47: 2409-12. doi:10.1161/STROKEAHA.116.014181
Ducroux C, Di Meglio L, Loyau S, et al. Thrombus neutrophil extracellular traps content impair TPA-induced thrombolysis in acute ischemic stroke. Stroke 2018; 49: 754-7. doi:10.1161/STROKEAHA.117.019896
Zhang S, Cao Y, Du J, et al. Neutrophil extracellular traps contribute to tissue plasminogen activator resistance in acute ischemic stroke. FASEB J 2021; 35: e21835. doi:10.1096/fj.202100471RR
Jickling GC, Dziedzic T. Neutrophil count is related to stroke outcome following endovascular therapy. Neurology 2019; 93: 194-5. doi:10.1212/WNL.0000000000007851
Maestrini I, Strbian D, Gautier S, et al. Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes. Neurology 2015; 85: 1408-16. doi:10.1212/WNL.0000000000002029
Maestrini I, Tagzirt M, Gautier S, et al. Analysis of the association of MPO and MMP-9 with stroke severity and outcome: cohort study. Neurology 2020; 95: e97-108. doi:10.1212/WNL.0000000000009179
Brooks SD, Spears C, Cummings C, et al. Admission neutrophil-lymphocyte ratio predicts 90 day outcome after endovascular stroke therapy. J Neurointerv Surg 2014; 6: 578-83. doi:10.1136/neurintsurg-2013-010780
Lux D, Alakbarzade V, Bridge L, et al. The association of neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio with 3-month clinical outcome after mechanical thrombectomy following stroke. J Neuroinflammation 2020; 17: 60. doi:10.1186/s12974-020-01739-y
Pikija S, Sztriha LK, Killer-Oberpfalzer M, et al. Neutrophil to lymphocyte ratio predicts intracranial hemorrhage after endovascular thrombectomy in acute ischemic stroke. J Neuroinflammation 2018; 15: 319. doi:10.1186/s12974-018-1359-2
Malhotra K, Goyal N, Chang JJ, et al. Differential leukocyte counts on admission predict outcomes in patients with acute ischaemic stroke treated with intravenous thrombolysis. Eur J Neurol 2018; 25: 1417-24. doi:10.1111/ene.13741
Goyal N, Tsivgoulis G, Chang JJ, et al. Admission neutrophil-to-lymphocyte ratio as a prognostic biomarker of outcomes in large vessel occlusion strokes. Stroke 2018; 49: 1985-7. doi:10.1161/STROKEAHA.118.021477
Tay A, Tamam Y, Yokus B, et al. Serum myeloperoxidase levels in predicting the severity of stroke and mortality in acute ischemic stroke patients. Eur Rev Med Pharmacol Sci 2015; 19: 1983-8.
del Zoppo GJ. Microvascular changes during cerebral ischemia and reperfusion. Cerebrovasc Brain Metab Rev 1994; 6: 47-96.
Denorme F, Manne BK, Portier I, et al. Platelet necrosis mediates ischemic stroke outcome in mice. Blood 2020; 135: 429-40. doi:10.1182/blood.2019002124
Desilles J-P, Syvannarath V, Di Meglio L, et al. Downstream microvascular thrombosis in cortical venules is an early response to proximal cerebral arterial occlusion. J Am Heart Assoc 2018; 7: e007804. doi:10.1161/JAHA.117.007804
Desilles J-P, Loyau S, Syvannarath V, et al. Alteplase reduces downstream microvascular thrombosis and improves the benefit of large artery recanalization in stroke. Stroke 2015; 46: 3241-8. doi:10.1161/STROKEAHA.115.010721
Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003; 108: 1440-5. doi:10.1161/01.CIR.0000090690.67322.51
Kolodziej AR, Abo-Aly M, Elsawalhy E, et al. Prognostic role of elevated myeloperoxidase in patients with acute coronary syndrome: a systemic review and meta-analysis. Mediators Inflamm 2019; 2019: 2872607. doi:10.1155/2019/2872607
Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 1102-11. doi:10.1161/01.ATV.0000163262.83456.6d
Zhang R, Brennan ML, Fu X, et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001; 286: 2136-42. doi:10.1001/jama.286.17.2136
Kollikowski AM, Schuhmann MK, Nieswandt B, et al. Local leukocyte invasion during hyperacute human ischemic stroke. Ann Neurol 2020; 87: 466-79. doi:10.1002/ana.25665
Desilles J-P, Syvannarath V, Ollivier V, et al. Exacerbation of thromboinflammation by hyperglycemia precipitates cerebral infarct growth and hemorrhagic transformation. Stroke 2017; 48: 1932-40. doi:10.1161/STROKEAHA.117.017080
Carbone F, Vuilleumier N, Bertolotto M, et al. Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways. Vascul Pharmacol 2015; 64: 16-27. doi:10.1016/j.vph.2014.11.007
Cuadrado E, Ortega L, Hernández-Guillamon M, et al. Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. J Leukoc Biol 2008; 84: 207-14. doi:10.1189/jlb.0907606
Liberale L, Bertolotto M, Minetti S, et al. Recombinant tissue plasminogen activator (r-tPA) induces in-vitro human neutrophil migration via low density lipoprotein receptor-related protein 1 (LRP-1). Int J Mol Sci 2020; 21: 7014. doi:10.3390/ijms21197014
Cooper JA, Lo SK, Malik AB. Fibrin is a determinant of neutrophil sequestration in the lung. Circ Res 1988; 63: 735-41. doi:10.1161/01.res.63.4.735
Kuijper PH, Gallardo Torres HI, van der Linden JA, et al. Neutrophil adhesion to fibrinogen and fibrin under flow conditions is diminished by activation and L-selectin shedding. Blood 1997; 89: 2131-8.
Silva LM, Doyle AD, Greenwell-Wild T, et al. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier. Science 2021; 374: eabl5450. doi:10.1126/science.abl5450
Fischer U, Kaesmacher J, Strbian D, et al. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial. Lancet 2022; 400: 104-15. doi:10.1016/S0140-6736(22)00537-2
Cho T-H, Nighoghossian N, Mikkelsen IK, et al. Reperfusion within 6 hours outperforms recanalization in predicting penumbra salvage, lesion growth, final infarct, and clinical outcome. Stroke 2015; 46: 1582-9. doi:10.1161/STROKEAHA.114.007964
Soares BP, Tong E, Hom J, et al. Reperfusion is a more accurate predictor of follow-up infarct volume than recanalization: a proof of concept using CT in acute ischemic stroke patients. Stroke 2010; 41: e34-40. doi:10.1161/STROKEAHA.109.568766
Renú A, Millán M, San Román L, et al. Effect of intra-arterial alteplase vs placebo following successful thrombectomy on functional outcomes in patients with large vessel occlusion acute ischemic stroke: the CHOICE randomized clinical trial. JAMA 2022; 327: 826-35. doi:10.1001/jama.2022.1645
Ames A, Wright RL, Kowada M, et al. The no-reflow phenomenon. Am J Pathol 1968; 52: 437-53.
Sommer CJ. Ischemic stroke: experimental models and reality. Acta Neuropathol 2017; 133: 245-61. doi:10.1007/s00401-017-1667-0
Chrysanthopoulou A, Gkaliagkousi E, Lazaridis A, et al. Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension. JCI Insight 2021; 6: e148668. doi:10.1172/jci.insight.148668
De Meyer SF, Langhauser F, Haupeltshofer S, et al. Thromboinflammation in brain ischemia: recent updates and future perspectives. Stroke 2022; 53: 1487-99. doi:10.1161/STROKEAHA.122.038733
