Linking Neutrophil Extracellular Traps and Platelet Activation: A Composite Biomarker Score for Predicting Outcomes after Acute Myocardial Infarction

Abstract

Background Activation of both platelets and neutrophils can contribute to the risk of major adverse cardiovascular events (MACE) following acute myocardial infarction (AMI). Neutrophil extracellular traps (NETs) are an important product of the platelet–neutrophil axis and exaggerate vascular damage in cardiovascular disease. Additionally, activated platelets can drive NETosis and are directly linked to thromboembolic risk. Investigating the combined effect of biomarkers for NETosis and platelet activation represents a novel approach to risk prediction post-AMI. Here, we examined the utility of a composite biomarker score, inclusive of both pathways, for predicting MACE post-AMI. Methods and Results In a case–control design, 100 case patients who experienced MACE within 1 year of index admission were matched in a 1:2 ratio with control patients. Serum levels of myeloperoxidase–DNA, neutrophil elastase–DNA, and citrullinated histone H3 were assayed by enzyme-linked immunosorbent assay (ELISA) as markers of NET burden. To measure platelet activation, soluble P-selectin was assayed by ELISA in parallel. Platelet and neutrophil counts were also recorded. Composite biomarker scores, inclusive of biomarkers for NETosis and platelet activation, were assessed using multivariate regression modeling. These composite biomarker scores were independent predictors of 1-year MACE. The strongest association with MACE was observed using a composite of platelet count, soluble P-selectin, and all NET markers (odds ratio: 1.94; 1.16–3.25). Conclusion Here, we demonstrate the importance of combining biomarkers of NETosis and platelet activation for risk prediction in patients with AMI. Combining biomarkers from closely linked, but distinct, biological pathways was more effective than utilizing either type of biomarker alone.

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

“…of NETs are significantly reduced after treatment ( 40 ). The activation of platelets and neutrophils increases the risk of major adverse cardiovascular events (MACEs) after acute myocardial infarction ( 41 ). Moreover, NETs stimulate fibroblasts, affect heart remodeling after STEMI and are important mediators of fiber remodeling ( 19 ).…”

“…The components of various NETs in plasma have been suggested to be used to predict the severity of diseases such as CAD and ischemic stroke. For example, PAD4 levels are very high in carotid plaques ( 52 ), and citrullinated histone H3 (CitH3), double-stranded DNA (dsDNA), neutrophil elastase (NE) levels, the myocardial infarction area, and left ventricular dysfunction are related to the poor prognosis of patients with coronary atherosclerosis and myocardial infarction ( 19 , 21 , 41 ). The plasma levels of the MPO-DNA complex and cell-free DNA (cfDNA) are directly proportional to immune thrombosis in patients with COVID-19 complicated with acute respiratory distress syndrome ( 6 , 53 ).…”

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

“…Activated platelets and neutrophils may contribute to an increased risk of adverse cardiovascular events after acute myocardial infarction [78]. NETs are an important product of the platelet-neutrophil axis and contribute to vascular damage in cardiovascular disease [78].…”

“…Activated platelets and neutrophils may contribute to an increased risk of adverse cardiovascular events after acute myocardial infarction [78]. NETs are an important product of the platelet-neutrophil axis and contribute to vascular damage in cardiovascular disease [78]. During transmigration, endothelial cells interact with neutrophils and may stimulate the formation of the NETs within the microcirculation and generate an occlusion, leading to thrombotic diseases.…”

Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

“…A plethora of recent studies underlining the roles and functions of extracellular histones as biomarkers for predicting outcomes of several human diseases have also been published [ 22 , 23 ]. Recent evidence especially demonstrates that the levels of NETs and histones may predict the cardiovascular risk [ 7 ], wherein circulating histones may function as signaling scaffold at the culprit site of myocardial infarction and stroke [ 24 , 25 , 26 , 27 , 28 ], also in COVID-19 patients with cardiac manifestations.…”