Platelet Activation and Chemokine Release Are Related to Local Neutrophil-Dominant Inflammation During Hyperacute Human Stroke

Abstract

Experimental evidence has emerged that local platelet activation contributes to inflammation and infarct formation in acute ischemic stroke (AIS) which awaits confirmation in human studies. We conducted a prospective observational study on 258 consecutive patients undergoing mechanical thrombectomy (MT) due to large-vessel-occlusion stroke of the anterior circulation (08/2018–05/2020). Intraprocedural microcatheter aspiration of 1 ml of local (occlusion condition) and systemic arterial blood samples (self-control) was performed according to a prespecified protocol. The samples were analyzed for differential leukocyte counts, platelet counts, and plasma levels of the platelet-derived neutrophil-activating chemokine C-X-C-motif ligand (CXCL) 4 (PF-4), the neutrophil attractant CXCL7 (NAP-2), and myeloperoxidase (MPO). The clinical-biological relevance of these variables was corroborated by specific associations with molecular-cellular, structural-radiological, hemodynamic, and clinical-functional parameters. Seventy consecutive patients fulfilling all predefined criteria entered analysis. Mean local CXCL4 (+ 39%: 571 vs 410 ng/ml, P = .0095) and CXCL7 (+ 9%: 693 vs 636 ng/ml, P = .013) concentrations were higher compared with self-controls. Local platelet counts were lower (− 10%: 347,582 vs 383,284/µl, P = .0052), whereas neutrophil counts were elevated (+ 10%: 6022 vs 5485/µl, P = 0.0027). Correlation analyses revealed associations between local platelet and neutrophil counts (r = 0.27, P = .034), and between CXCL7 and MPO (r = 0.24, P = .048). Local CXCL4 was associated with the angiographic degree of reperfusion following recanalization (r = − 0.2523, P = .0479). Functional outcome at discharge correlated with local MPO concentrations (r = 0.3832, P = .0014) and platelet counts (r = 0.288, P = .0181). This study provides human evidence of cerebral platelet activation and platelet-neutrophil interactions during AIS and points to the relevance of per-ischemic thrombo-inflammatory mechanisms to impaired reperfusion and worse functional outcome following recanalization.

Plasma Lipid Mediators Associate With Clinical Outcome After Successful Endovascular Thrombectomy in Patients With Acute Ischemic Stroke

“…Innate immunity and acute inflammatory response within the penumbra play important roles in the pathological progression of cerebral I/R injury. The regulation and execution of neuroinflammatory responses are mediated by inflammatory mediators, including vasoactive amines and peptides, lipid mediators, cytokines, chemokines, and complements (8)(9)(10)(11). Novel biomarkers in neuroinflammation may therefore be of great value in predicting clinical outcomes in patients with AIS after EVT treatment.…”

Low-Molecular-Weight Heparin Versus Aspirin in Early Management of Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

“…There has been increasing evidence over the past decade that peripheral innate and adaptive immune cells, such as neutrophils and natural killer cells, may play an important role in the pathophysiology of ischemic stroke. The influx of neutrophils may cause increased vascular resistance due to increased blood viscosity and cellular obstruction, leading to cerebral infarction associated with collateral failure (42)(43)(44). A recent study showed that toll-like receptors (TLRs) are involved in the activation of inflammatory responses during the acute phase after ischemic stroke (45,46).…”

An intravascular perspective on hyper-acute neutrophil, T-cell and platelet responses: Similarities between human and experimental stroke

“… 27 As a strong indicator of local platelet activation we found increased concentrations of the platelet-derived neutrophil-activating chemokine CXC motif ligand (CXCL) 4 (platelet factor 4) and the neutrophil attractant CXCL7 (neutrophil-activating peptide 2) in local ischemic blood samples before recanalization which represent the most abundant platelet releasates from α-granules. 28 Interestingly, CXCL7 is a potent chemoattractant for neutrophils while CXCL4 induces neutrophil degranulation and increases their secretion of matrix metalloproteinase (MMP)-9 and myeloperoxidase (MPO). 29 MMP-9 has been implicated in breakdown of the blood-brain barrier (BBB) in cerebral ischemia 30 , while MPO is indispensable for the formation of neutrophil extracellular traps (NETs).…”