The role of platelets in autoimmunity, vasculopathy, and fibrosis: Implications for systemic sclerosis

Ntelis, Konstantinos; Solomou, Elena E.; Sakkas, Lazaros I.; Liossis, Stamatis–Nick C.; Daoussis, Dimitrios

doi:10.1016/j.semarthrit.2017.05.004

Cited by 41 publications

(26 citation statements)

References 125 publications

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“…It might, therefore, be hypothesised that the associations detected between the reduction in the occurrence of distinct cardiac events and low-dose ASA do not depend on a potential protective effect on small intramyocardial coronary artery disease. Nevertheless, platelet activation has been reported to play a role of both vascular and fibrotic manifestations of SSc 30. Moreover, markers of platelet activation have long been known to be responsive to antiplatelet therapy 31.…”

Section: Discussionmentioning

confidence: 99%

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study

et al. 2019

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ObjectivesTo investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc).Methods601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5–4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed.ResultsDuring 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05).ConclusionsThe present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

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Section: Discussionmentioning

confidence: 99%

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study

et al. 2019

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“…Of note that half of the patients were on anti-platelet treatment, regardless the history of DU. This probably reflects the perceived importance of platelets' role in the pathogenesis of SSc-related vasculopathy [30], although no study has addressed the use of these drugs for DU or for other SSc manifestations.…”

Section: Discussionmentioning

confidence: 99%

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study

et al. 2019

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Introduction: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc) and its Observational Trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc related DU in the expert centres, by analysing the baseline data of the DeSScipher OT1 trial. Method: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. Results: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous Iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). 32.6% of patients with DU and 12.8% patients without DU received two drugs (p<0.001), while 11.5% patients with DU and 1.9% without DU were treated with combination of three or more agents (p<0.001). Sixty-five percent of the patients with recurrent DU were treated with Bosentan and/or Sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. Conclusions: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention.

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“…Concomitant to the changes in the SSc endothelial lining, platelets undergo activation (19)(20)(21) and release vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor-, and serotonin (15). Platelets are also a source of the high-mobility group box 1 (HMGB1) protein (22), a damage-associated molecular pattern (DAMP) (23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis

et al. 2018

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Endothelial cell damage and platelet activation contribute to sustained vasculopathy, which is a key clinical characteristic of systemic sclerosis (SSc), also known as scleroderma. Microparticles released from activated platelets in the blood of SSc patients (SSc-microparticles) are abundant and express the damage-associated molecular pattern (DAMP) HMGB1. SSc-microparticles interacted with neutrophils in vitro and in immunocompromised mice and promoted neutrophil autophagy, which was characterized by mobilization of their granule content, enhanced proteolytic activity, prolonged survival, and generation of neutrophil extracellular traps (NETs). Neutrophils migrated within the mouse lung, with collagen accumulation in the interstitial space and the release of soluble E-selectin by the vascular endothelium. Microparticle-neutrophil interaction, neutrophil autophagy and survival, and generation of NETs abated in the presence of BoxA, a competitive inhibitor of HMGB1. Consistent with these results, neutrophils in the blood of SSc patients were autophagic and NET by-products were abundant. Our findings implicate neutrophils in SSc vasculopathy and suggest that platelet-derived, microparticle-associated HMGB1 may be a potential indicator of disease and target for novel therapeutics.

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The role of platelets in autoimmunity, vasculopathy, and fibrosis: Implications for systemic sclerosis

Cited by 41 publications

References 125 publications

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study

Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis

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