The Hemostatic System as a Modulator of Atherosclerosis

Borissoff, Julian Ilcheff; Spronk, Henri M. H.; Cate, Hugo Ten

doi:10.1056/nejmra1011670

Cited by 497 publications

(442 citation statements)

References 144 publications

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“…These studies, however, are prone to methodological limitations including small sample sizes. Importantly, it is well recognized that coagulation factors play a significant role in the process of inflammation and atherosclerosis 25. The attenuation of protein C has been reported to reduce anti‐apoptotic activity of the endothelial barrier and to promote local inflammation within the arterial wall,25 which is accompanied, at least to a certain degree, by calcification 26.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, it is well recognized that coagulation factors play a significant role in the process of inflammation and atherosclerosis 25. The attenuation of protein C has been reported to reduce anti‐apoptotic activity of the endothelial barrier and to promote local inflammation within the arterial wall,25 which is accompanied, at least to a certain degree, by calcification 26. In addition, infiltration of vascular tissue is characterized by increased oxidative stress and subsequently by endothelial dysfunction leading to increased vascular stiffness 27.…”

Section: Discussionmentioning

confidence: 99%

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Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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BackgroundPreclinical data have indicated a link between use of vitamin K antagonists (VKA) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population.Methods and ResultsClinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P=0.019), ankle‐brachial index (β=−0.03; [−0.04/−0.01]; P<0.0001), intima‐media thickness (β=+0.03 mm [0.01/0.05]; P=0.0098), left ventricular ejection fraction (β=−4.02% [−4.70/−3.33]; P<0.0001), E/E′ (β=+0.04 [0.01/0.08]; P=0.014) left ventricular mass (β=+5.34 g/m2.7 [4.26/6.44]; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro‐atrial natriuretic peptide: β=+0.58 pmol/L [0.50/0.65]; P<0.0001; midregional pro‐adrenomedullin: β=+0.18 nmol/L [0.14/0.22]; P<0.0001; N‐terminal pro B‐type natriuretic peptide: β=+1.90 pg/mL [1.63/2.17]; P<0.0001; fibrinogen: β=+143 mg/dL [132/153]; P<0.0001; C‐reactive protein: β=+0.31 mg/L [0.20/0.43]; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP2C9,CYP4F2, and VKORC1 were modulating effects of VKA on subclinical markers of cardiovascular disease.ConclusionsThese data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long‐term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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“…This is associated with increased circulating levels of prothrombotic/inflammatory mediators, such as thrombin and CD40L, 4,7 and enhanced protease activity. 13,21 In this study, we describe for the first time that thrombin and CD40L act synergistically to induce MMP-10 both in vitro and in vivo, and to generate MPs carrying active MMP-10.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Thrombin is a critical mediator in the coagulation/ inflammation vessel wall crosstalk and can amplify inflammation induced by other stimuli, directly via protease-activated receptors (PARs) or indirectly through generation of downstream mediators. 3,4 In addition, CD40, a type I transmembrane protein receptor of the tumor necrosis factor- superfamily, and its immunomodulating ligand (CD40L/CD154) elicit a series of inflammatory and prothrombotic responses involved in atherogenic and thrombotic mechanisms (eg, overexpression of adhesive proteins, chemokines, metalloproteinases [MMPs], and tissue factor). [5][6][7] In fact, we and others have reported elevated levels of CD40L in patients with both stable and unstable angina, acute myocardial infarction, and diabetes mellitus with coronary artery disease, as well as the presence of CD40L in microparticles (MPs) from human atherosclerotic plaques that trigger an inflammatory/proliferative response on endothelial cells (ECs).…”

mentioning

confidence: 99%

Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo

Lizarrondo

Roncal

Calvayrac

et al. 2012

ATVB

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Objective— Thrombin induces CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) under inflammatory/prothrombotic conditions. Thrombin and CD40L could modulate endothelial MMP-10 expression in vitro and in vivo. Methods and Results— Human endothelial cells were stimulated with thrombin (0.1–10 U/mL), CD40L (0.25–1 μg/mL), or their combination (thrombin/CD40L) to assess MMP-10 expression and microparticle generation. Thrombin/CD40L elicited higher MMP-10 mRNA (5-fold; P <0.001) and protein levels (4.5-fold; P <0.001) than either stimulus alone. This effect was mimicked by a protease-activated receptor-1 agonist and antagonized by hirudin, a-protease-activated receptor-1, α-CD40L, and α-CD40 antibodies. The synergistic effect was dependent on p38 mitogen-activated protein kinase and c-Jun N -terminal kinase-1 pathways. Thrombin also upregulated the expression of CD40 in endothelial cell surface increasing its availability, thereby favoring its synergistic effects with CD40L. In mice, thrombin/CD40L further increased the aortic MMP-10 expression. Septic patients with systemic inflammation and enhanced thrombin generation (n=60) exhibited increased MMP-10 and soluble CD40L levels associated with adverse clinical outcome. Endothelial and systemic activation by thrombin/CD40L and lipopolysaccharide also increased microparticles harboring MMP-10 and CD40L. Conclusion— Thrombin/CD40L elicited a strong synergistic effect on endothelial MMP-10 expression and microparticles containing MMP-10 in vitro and in vivo, which may represent a new link between inflammation/thrombosis with prognostic implications.

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“…According to the literature, prothrombin and factor Xa are strongly elevated in individuals suffering from MS (Bhat and Steinman, 2009). Prothrombin and other hemostasis factors have been described to potentially enhance inflammation in artherosclerotic plaques, sepsis, endotoxemia and encephalomyelitis (Borissoff et al, 2011;Schoenmakers et al, 2005;Strukova, 2001). We showed an effect of IgG on the activity of coagulation as well as anticoagulation factors.…”

Section: Discussionmentioning

confidence: 99%

Effect of IgG from multiple sclerosis patients on amidolytic activity of coagulation and anticoagulation factors of hemostasis

et al. 2017

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Background: Immunoglobulin G (IgG) is a major immunoglobulin (Ig) in blood that accumulates to a greater extent in the bloodstream of patients impacted by neuroimmunological disorders such as multiple sclerosis (MS). The aim of this study was to determine the effect of IgG obtained from MS patients on the amidolytic activity of coagulation and on anticoagulation factors, and to compare those effects to the effects of IgG from healthy donors. Methods: Spectrophotometric hydrolysis of specific chromogenic substrate by key haemostasis factors was examined. Results: Our study shows that unlike healthy individuals, patients suffering from MS express IgG which enhances the amidolytic activity of thrombin and protein C, but inhibits the activity of factor Xa. Conclusion: Our study shows that IgG and coagulation factors, indeed, interact with each other. IgG may be key mediators of neuroinflammation and, therefore, may serve as a potential target for therapeutic strategies for MS and other neuroimmunological diseases.

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The Hemostatic System as a Modulator of Atherosclerosis

Cited by 497 publications

References 144 publications

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo

Effect of IgG from multiple sclerosis patients on amidolytic activity of coagulation and anticoagulation factors of hemostasis

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