Elsevier

Atherosclerosis

Volume 202, Issue 1, January 2009, Pages 255-262
Atherosclerosis

The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients

https://doi.org/10.1016/j.atherosclerosis.2008.04.001Get rights and content

Abstract

Background

Residual platelet reactivity (RPR) on antiplatelet therapy in ischemic heart disease patients is associated with adverse events. Clinical, cellular and pharmacogenetic factors may account for the variable response to antiplatelet treatment.

Objective

We sought to explore the interplay of multiple pro-inflammatory and anti-inflammatory cytokines with platelet function in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) on dual antiplatelet therapy.

Methods

In 208 ACS patients undergoing PCI on dual antiplatelet therapy we measured platelet function by platelet aggregation with two agonists [1 mM arachidonic acid (AA) and 10 μM ADP]. IL-1β, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-12, IP-10, IFN-γ, MCP-1, MIP-1α, MIP-1β, TNF-α, and VEGF levels were determined by using the Bio-Plex cytokine assay (Bio-Rad Laboratories Inc., Hercules, CA, USA). We defined patients with RPR those with platelet aggregation by AA ≥20% and/or ADP (10 μmol) ≥70%.

Results

We documented a significant association between IP-10, IFN-γ, IL-4 and RPR by both AA- and ADP-induced platelet aggregation after adjustment for age, sex, cardiovascular risk factors, ejection fraction, BMI, vWF and CRP. Patients with pro-inflammatory cytokines not compensated by anti-inflammatory cytokines had higher risk of RPR by both AA and ADP (AA: OR = 3.85, 95% CI 1.52–9.74; ADP: OR = 2.49, 95% CI 1.33–4.68) with respect to patients with balanced anti-/pro-inflammatory cytokines. Patients with anti-inflammatory response overwhelming pro-inflammatory response have lower risk of RPR (AA: OR = 0.55, 95% CI 0.28–1.06; ADP: OR = 0.47, 95% CI 0.26–0.87).

Conclusion

Our study provides new insights into the interplay of anti-/pro-inflammatory cytokines with platelet hyper-reactivity in high-risk patients.

Introduction

Good evidence exists indicating that inflammation plays a crucial role in the processes influencing the development of ischemic events after percutaneous coronary intervention (PCI) [1]. Pro-inflammatory molecules are actively involved in the activation and migration of leukocytes to sites of vascular injury and inflammation, and may contribute to the release by activated cells of prothrombotic factors, which in turn may activate platelets and other cell types [2], [3]. Platelets represent an important linkage between inflammation, thrombosis, and atherogenesis, as they are able to interact with leukocytes and endothelial cells with the participation of Von Willebrand factor (vWF) [4]. When activated, platelets coaggregate with circulating leukocytes and after their adherence to the vascular wall, platelets also provide a sticky surface to recruit leukocytes on the vessel wall [5].

Clinical studies documented that a residual platelet reactivity (RPR) on antiplatelet therapy in patients with ischemic heart disease is associated with adverse clinical events [6], [7], [8], [9], [10].

Clinical, cellular and pharmacogenetic factors may account for the variable response to antiplatelet treatment [9], [11], [12], [13], [14].

The role of the inflammatory state in modulating the effect of antiplatelet therapy on platelet reactivity has been suggested by clinical studies demonstrating the high prevalence of RPR in the acute phase of disease [15], [16], and that RPR is independently associated with routinely inflammatory markers [erythrocyte sedimentation rate (ESR) and leukocyte number] in acute coronary syndrome (ACS) patients [9]. However, the precise mechanisms by which the inflammatory state may influence platelet hyper-reactivity in high-risk cardiac patients on dual antiplatelet therapy have not yet been elucidated. In particular, no information is available about the dynamic relationship between the various anti-inflammatory and pro-inflammatory molecules in relation to platelet activation.

Therefore, aim of the present study was to explore the interplay of multiple pro-inflammatory and anti-inflammatory cytokines with platelet function in patients with ACS undergoing PCI on dual antiplatelet therapy.

Section snippets

Study population

In the framework of an ongoing project aimed to investigate the prevalence and the clinical implications of a RPR in patients with ACS undergoing PCI on dual antiplatelet therapy, we investigated 208 patients in relation to the presence or the absence of RPR by AA defined as platelet aggregation ≥20% (92/208).

All patients undergoing primary PCI received a clopidogrel loading dose (73 received 600 mg and 135 received 300 mg) followed by a daily dose of 75 mg. All patients received unfractionated

Relationship between 1 mM AA-induced platelet aggregation and cyto-chemokine levels

The evaluation of the relationship between pro-, anti-inflammatory cytokines and platelet aggregation by 1 mM AA, performed by Pearson's correlation tests, showed that IP-10 and IL-6 serum levels, but not other pro-inflammatory cytokines (IL-1β, IL-8, IL-12, TNF-α, MCP-1, MIP-1α, MIP-1β, IFN-γ and VEGF), were mildly, but significantly, related with platelet aggregation (IP-10: r = 0.30, p < 0.001; IL-6: r = 0.28, p < 0.05). Serum levels of anti-inflammatory cytokines IL-4 and IL-10 were inversely

Discussion

This study provides new insights into the association between inflammation and residual platelet reactivity on antiplatelet treatment, which was previously found to be related to the occurrence of clinical events in high-risk patients such as ACS patients undergone PCI on dual antiplatelet agents [9], [15], [16].

In the present study, by using extensive array of cytokines and other inflammatory markers, we demonstrated a modulatory effect of the interplay between pro- and anti-inflammatory

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