Platelet CD40L Modulates Thrombus Growth Via Phosphatidylinositol 3-Kinase β, and Not Via CD40 and IκB Kinase α

Kuijpers, Marijke J. E.; Mattheij, Nadine J.A.; Cipolla, Lina; Geffen, Johanna P. van; Lawrence, Toby; Donners, Marjo M. P. C.; Boon, Louis; Lievens, Dirk; Torti, Mauro; Noels, Heidi; Gerdes, Norbert; Cosemans, Judith M.E.M.; Lutgens, Esther; Heemskerk, Johan W. M.

doi:10.1161/atvbaha.114.305127

Cited by 32 publications

(37 citation statements)

References 47 publications

(58 reference statements)

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“…26 Therefore, we hypothesize that TRAF3 expression may be higher in the vascular recurrence patients, which might increase the CD40 ligand signal transduction, thereby enhancing platelet-platelet interactions, secretion, and thrombus growth under artherogenic conditions. 27 In addition to the association with vascular recurrence in on-clopidogrel treatment patients, we also found that lower cg03548645 DNAm levels were correlated with higher platelet aggregation (ADP-induced platelet aggregation; P=0.0075). This association indicates that epigenetics might be involved in the vascular recurrence of stroke and in the pharmacodynamics of clopidogrel.…”

Section: Discussionsupporting

confidence: 53%

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke

Gallego-Fábrega

Carrera

Reny

et al. 2016

Stroke

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P atients with Ischemic stroke are at high risk of having a new stroke or developing other vascular diseases such as acute myocardial infarction, or vascular death, known as vascular recurrence. A study in the South London Stroke Register described a cumulative risk of vascular recurrence after a first stroke of 8.0% at 1 year and 16.6% at 5 years.1 To reduce vascular recurrence, the most prescribed treatment for secondary prevention of stroke is antiplatelet agents, 2 most widely used are acetylsalicylic acid, clopidogrel, or a combination of both. However 10% to 20% of patients treated with antiplatelet drugs have a new vascular event 3 ; in addition, serious vascular events are reduced only by <25% compared with placebo. 4 Pharmacogenetic studies have evaluated the relationship between genetic variants and high on-treatment platelet reactivity usually assessing platelet aggregation.5 Mega et al 5 found an association between the CYP2C19 reduced-function allele and lower levels of the clopidogrel active metabolite, diminished platelet inhibition, and higher rates of majorBackground and Purpose-Clopidogrel is one of the most used antiplatelet drugs in patients with cardiovascular disease. However, 16% to 50% of patients have a high on-clopidogrel platelet reactivity and an increased risk of ischemic events. The pathogenesis of high on-treatment platelet reactivity in patients with stroke is only partially explained by genetic variations. This study aims to find differentially methylated sites across the genome associated with vascular recurrence in ischemic stroke patients treated with clopidogrel. Methods-From a cohort of 1900 patients with ischemic stroke, we selected 42 patients treated with clopidogrel, including 21 with a recurrent vascular event and 21 without vascular recurrence during the first year of follow-up. Over 480 000 DNA methylation sites were analyzed across the genome. Differentially methylated CpG sites were identified by nonparametric testing using R. Replication analysis was performed in a new cohort of 191 subjects and results were correlated with platelet reactivity in a subset of 90 subjects using light transmission aggregometry. Results-A total of 73 differentially methylated CpG sites (P<1×10 −05) were identified; 3 of them were selected for further replication: cg03548645 (P=1.42×10 , XRCC1). The cg03548645 CpG remained significant in the replication study (P=0.034), a deep analysis of this region revealed another methylation site associated with vascular recurrence, P=0.037. Lower cg03548645 (TRAF3) DNA methylation levels were correlated with an increased platelet aggregation (ρ=−0.29, P=0.0075). observed that lower P2Y12 gene promoter DNA methylation (DNAm) was associated with an increased risk of clopidogrel high on-treatment platelet reactivity in patients with albumin ≤35 g/L, currently smoking, or abusing alcohol, suggesting a potential role for epigenetics in clopidogrel high on-treatment platelet reactivity and vascular events after clopidogrel treatment. Conclusions-Thi...

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Section: Discussionsupporting

confidence: 53%

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke

Gallego-Fábrega

Carrera

Reny

et al. 2016

Stroke

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“…Corroborating our previous studies, no differences in P-selectin or αIIbβ3 integrin activation were detected between Cd40 −/− Apoe −/− and Apoe −/− platelets in any of the experimental conditions ( Figure IA and IB in the online-only Data Supplement). 39 In addition, collagen-or ADP-induced platelet aggregation in whole blood was not affected by deficiency of CD40 ( Figure 1A and 1B). However, supernatants of thrombin-activated platelets displayed a significant decrease in chemokine (C-X-C motif) ligand 4, identifying platelet CD40 as a prominent mediator of inflammation rather than a regulator of thrombosis ( Figure 1C).…”

Section: Deficiency Of Platelet Cd40 Does Not Impair Platelet Activationmentioning

confidence: 88%

“…38 In addition, we recently showed that CD40L-deficient platelets prevent GP VI-dependent dense thrombus formation on collagen or atherosclerotic plaque material. 39 Conversely, addition of CD40L enhanced GP VI-induced platelet aggregation via integrin αIIbβ3 and phosphatidylinositol-4,5-bisphosphate 3-kinase, but independent of inhibitor of nuclear factor κ-B kinase subunit α/nuclear factor κ-light-chain-enhancer of activated B cells. 39 Interestingly, platelets also express substantial levels of the alleged counter-receptor for CD40L, ie, CD40, 40,41 but its role has only been summarily described and suggests a role in thrombus formation.…”

mentioning

confidence: 97%

“…39 Conversely, addition of CD40L enhanced GP VI-induced platelet aggregation via integrin αIIbβ3 and phosphatidylinositol-4,5-bisphosphate 3-kinase, but independent of inhibitor of nuclear factor κ-B kinase subunit α/nuclear factor κ-light-chain-enhancer of activated B cells. 39 Interestingly, platelets also express substantial levels of the alleged counter-receptor for CD40L, ie, CD40, 40,41 but its role has only been summarily described and suggests a role in thrombus formation. 37,39 Here, we report the participation of platelet CD40 in inflammation mediating EC and leukocyte activation and driving atherosclerosis, whereas it plays a minor role in platelet-platelet interactions.…”

mentioning

confidence: 97%

“…39 Interestingly, platelets also express substantial levels of the alleged counter-receptor for CD40L, ie, CD40, 40,41 but its role has only been summarily described and suggests a role in thrombus formation. 37,39 Here, we report the participation of platelet CD40 in inflammation mediating EC and leukocyte activation and driving atherosclerosis, whereas it plays a minor role in platelet-platelet interactions.…”

mentioning

confidence: 99%

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Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

Gerdes

Seijkens

Lievens

et al. 2016

ATVB

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Objective— Beyond their eminent role in hemostasis and thrombosis, platelets are recognized as mediators of inflammation. Platelet cluster of differentiation 40 (CD40) ligand (CD40L and CD154) plays a key role in mediating platelet-induced inflammation in atherosclerosis. CD40, the receptor for CD40L, is present on platelets; however, the role of CD40 on this cell type is until now undefined. Approach and Results— We found that in both mice and humans, platelet CD40 mediates the formation of platelet–leukocyte aggregates and the release of chemokine (C-X-C motif) ligand 4. Leukocytes were also less prone to adhere to CD40-deficient thrombi. However, platelet CD40 was not involved in platelet aggregation. Activated platelets isolated from Cd40 −/− Apoe −/− mice adhered less to the endothelium upon injection into Apoe −/− mice when compared with CD40-sufficient platelets. Furthermore, lack of CD40 on injected platelets led to reduced leukocyte recruitment to the carotid artery as assayed by intravital microscopy. This was accompanied by a decrease in endothelial vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule, VE-cadherin, and P-selectin expression. To investigate the effect of platelet CD40 in atherosclerosis, Apoe −/− mice received thrombin-activated Apoe −/− or Cd40 −/− Apoe −/− platelets every 5 days for 12 weeks, starting at the age of 17 weeks, when atherosclerotic plaques had already formed. When compared with mice that received Apoe −/− platelets, those receiving Cd40 −/− Apoe −/− platelets exhibited a >2-fold reduction in atherosclerosis. Plaques of mice receiving CD40-deficient platelets were less advanced, contained less macrophages, neutrophils, and collagen, and displayed smaller lipid cores. Conclusions— Platelet CD40 plays a crucial role in inflammation by stimulating leukocyte activation and recruitment and activation of endothelial cells, thereby promoting atherosclerosis.

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Platelet CD40 ligand and bleeding during P2Y12 inhibitor treatment in acute coronary syndrome

Grosdidier

Blanz

Deharo

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet‐associated CD40L levels and bleeding events (n = 71). Treatment with P2Y12 inhibitors in patients with ACS did not affect plasma‐soluble CD40L levels, but decreased platelet CD40L surface expression (pCD40L) and platelet‐released CD40L (rCD40L) levels in response to stimulation as compared to healthy controls. In vitro inhibition of the ADP pathway in healthy control platelets reduced both pCD40L and rCD40L levels. In a multivariable analysis, the reduced pCD40L level observed in ACS patients was significantly associated with the risk of bleeding occurrence (adjusted odds ratio = 0.15; 95% confidence interval = 0.034‐0.67). P2Y12 inhibitor‐treated (ticagrelor) mice exhibited a 2.5‐fold increase in tail bleeding duration compared with controls. A significant reduction in bleeding duration was observed on CD40L+/+ but not CD40L−/− platelet infusion. In addition, CD40L blockade in P2Y12 inhibitor–treated blood samples from a healthy human reduced thrombus growth over immobilized collagen under arterial flow. In conclusion, measurement of pCD40L may offer a novel approach to assessing bleeding risk in patients with ACS who are being treated with P2Y12 inhibitors.

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Platelet CD40L Modulates Thrombus Growth Via Phosphatidylinositol 3-Kinase β, and Not Via CD40 and IκB Kinase α

Cited by 32 publications

References 47 publications

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke

Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

Platelet CD40 ligand and bleeding during P2Y12 inhibitor treatment in acute coronary syndrome

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