Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity

Konstantinides, Stavros; Schäfer, Katrin; Koschnick, Stefan; Loskutoff, David J.

doi:10.1172/jci200113143

Cited by 118 publications

(181 citation statements)

References 37 publications

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“…At concentrations typically found in obesity but not in non-obese individuals, leptin markedly enhanced platelet aggregation 48 and in mouse models was associated with heightened thrombosis. 49 …”

Section: Obesitymentioning

confidence: 99%

Aspirin Resistance: Current Status and Role of Tailored Therapy

Grinstein

Cannon

2012

Clinical Cardiology

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Aspirin is integral in the primary and secondary prevention of coronary artery disease and acute coronary syndrome. Given the high clinical importance of aspirin in the management of coronary artery disease, much attention has been directed towards the concept of “aspirin resistance.” Unfortunately, the term aspirin resistance is ill‐defined in the literature, leading to a large variance in the reported prevalence of this phenomenon. In this review, the current understanding of aspirin resistance is discussed. Commonly used functional and diagnostic tests of platelet function, including their strengths and weakness, are reviewed. We next discuss several proposed mechanisms of aspirin resistance and special high‐risk groups at risk for aspirin treatment failure. We then discuss optimal dosing and diagnostic strategies for those populations at risk for aspirin resistance with a focus on tailored aspirin therapy for high‐risk groups. Finally, future topics of interest in the field of aspirin resistance are considered. Clin. Cardiol. 2012 doi: 10.1002/clc.22031Jonathan Grinstein has no funding, financial relationships, or conflicts of interest to disclose. Christopher P. Cannon receives research grants/support from the following companies: Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda. He is also on the advisory board (but funds donated to charity) for Alnylam, Bristol‐Myers Squibb, and Pfizer. He is a Clinical Advisor, equity in Automedics Medical Systems.

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Section: Obesitymentioning

confidence: 99%

Aspirin Resistance: Current Status and Role of Tailored Therapy

Grinstein

Cannon

2012

Clinical Cardiology

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“…7 Although leptin's major role seems to be in the regulation of body weight and energy metabolism, several evidences suggest that this hormone could be involved in other pathophysiological mechanisms, such as immune function, angiogenesis, bone formation and fertility, and the expression of leptin receptor has been demonstrated in a variety of tissues. [8][9][10][11][12][13] The long form of leptin receptor (ObRb) has been found on platelet membrane, 14 and it has been demonstrated that leptin-deficient ob/ob mice, 15,16 and wild-type mice treated with a leptin-neutralizing antibody, 17 develop unstable thrombi and an attenuated thrombotic response to arterial injury, and they exhibit a defective platelet aggregation. Leptin also promotes thrombosis in the mouse, and it potentiates the aggregation of murine platelets in vitro in a leptin receptor-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…Leptin also promotes thrombosis in the mouse, and it potentiates the aggregation of murine platelets in vitro in a leptin receptor-dependent manner. 15 Leptin also enhances the aggregation of human platelets, 14,[18][19][20] but it has recently been reported that the response varies significantly between donors, with platelets from some donors consistently responding to leptin (responders) and those from other donors never responding (non-responders). Although platelets from both responders and non-responders express the signaling form of the leptin receptor, platelets from responder donors express higher levels of this receptor than platelets from non-responders.…”

Section: Introductionmentioning

confidence: 99%

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

et al. 2006

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Objective: To verify whether platelet responsiveness to leptin is associated with metabolic syndrome risk factors. Design: Cross-sectional study. Subjects: We studied 169 consecutive patients, mean age ¼ 43.679.9 years, with overweight (N ¼ 57) or obesity (N ¼ 112). Measurements: Cluster analysis was used to generate three clusters based on platelet responsiveness to increasing doses of leptin. Profiles of metabolic syndrome risk factors of the three clusters were compared by discriminant analysis. Results: Platelet responsiveness to leptin was absent in cluster 1, whereas cluster 3 had the greatest platelet aggregation response to leptin pre-incubation. Plasma leptin levels significantly decreased from cluster 1 to cluster 3 in both gender. Patients in cluster 2 had an intermediate profile of leptin responsiveness. Highest body mass index (BMI) values were more frequent in non-responders, whereas the prevalence of high waist circumference, as well as hypertriglyceridemia and hypertension, increased with increasing responsiveness to leptin from cluster 1 to cluster 3. Pattern of metabolic syndrome risk factors qualified as group specific in 69.0% of the cluster 1, 54.9% of the cluster 2 and 55.8% of the cluster 3. Circulating leptin, waist circumference, plasma triglycerides and BMI defined distinctive patterns of metabolic syndrome risk factors in the clusters. Conclusions: In overweight and obese outpatients, metabolic syndrome risk factors parallel to some extent platelet responsiveness to leptin. Such a correlation involves plasma leptin levels, waist circumference, plasma triglycerides and BMI, and may contribute to the excess risk of cardiovascular events in overweight and obese patients.

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“…Resistin levels are associated with circulating levels of inflammatory markers including C-reactive protein, 92 whereas ghrelin appears to have anti-inflammatory effects by inhibiting the production of interleukin-8 and monocyte chemoattractant chemokine-1. 93 Leptin has prothrombotic effects, 94,95 and also increases oxidative stress. 96 Adiponectin has wide-ranging antiatherosclerotic effects including upregulating endothelial nitric oxide synthase, decreasing superoxide production by endothelial cells and inhibiting lipid accumulation in human monocyte-derived macrophages.…”

Section: Mechanisms Linking Obesity and Atherosclerosismentioning

confidence: 99%