Age, cardiovascular risk factors and coronary heart disease as determinants of platelet function in men. A multivariate approach

Terres, Wolfram; Weber, Kirsten E.; Küpper, W.; Bleifeld, W.

doi:10.1016/0049-3848(91)90369-8

Cited by 40 publications

(24 citation statements)

References 31 publications

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“…Platelet hyperactivity plays an important role in the pathogenesis of cardio-vascular diseases (for reviews see: Bashour et al 1988;Terres et al 1991). In accordance with previous observations (Frishman et al 1974;Diodati et al 1992), we have recently demonstrated (Chirkov et al 1993a) increased platelet aggregability in patients with stable angina pectoris, as assessed in vitro in platelet-rich plasma.…”

Section: Introductionsupporting

confidence: 78%

Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris

Chirkov

Chirkova

Horowitz

1996

Naunyn-Schmiedeberg's Arch Pharmacol

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Platelet hyperactivity plays an important role in the pathogenesis of cardio-vascular diseases. In patients with stable angina pectoris, we have recently demonstrated that nitroglycerin suppressed the increased platelet aggregability. The anti-aggregating effect of NTG and other nitrovasodilators is mediated by platelet guanylate cyclase, which generates cyclic GMP (cGMP) in response to nitric oxide (NO) liberated from the nitrovasodilator molecule. In the current study we utilised a more "direct" NO donor, sodium nitroprusside (SNP), to examine reversal of ADP-induced platelet aggregation in comparison with intraplatelet cGMP elevation in platelets from normal subjects (n = 22) and patients with stable angina pectoris (n = 23). Concentrations of SNP associated with 50% reversal of aggregation were 2.7 +/- 0.4 x 10(-7) mol/L with normal subjects and 4.5 +/- 0.5 x 10(-6) mol/L with patients (P < 0.01). SNP produced a concentration-dependent elevation of intraplatelet cGMP content: with 10(-4) mol/L SNP this was 17-fold for normals and 5-fold for patients (P < 0.01). An increase in cAMP content was seen only with 10(-4) mol/L SNP, and was 157 +/- 11% of baseline in platelets from normal subjects and 138 +/- 14% in patients. There was a strong interrelationship between cGMP-stimulating and anti-aggregating effects of SNP. The decrease in cGMP responsiveness to SNP was not related to a dysfunction of platelet guanylate cyclase; neither basal nor SNP-stimulated activity of the enzyme varied significantly between normal subjects and patients. Lipophilic derivatives of cGMP (db-cGMP) and cAMP (db-cAMP) caused reversal of aggregation; there was a nonsignificant trend towards decreased responsiveness of platelets from patients to both db-cGMP and db-cAMP. The observed decrease in responsiveness of platelets from angina patients to anti-aggregating effects of the exogenous NO donor, SNP, can therefore be attributed to suppressed cGMP accumulation. These results imply reduced platelet sensitivity to endogenous NO (endothelium-derived relaxing factor): this might contribute to platelet hyperaggregability observed in angina pectoris.

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Section: Introductionsupporting

confidence: 78%

Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris

Chirkov

Chirkova

Horowitz

1996

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Different methodologies were used in the 2 studies: flow cytometry here compared with aggregometry by Fontana et al, 15 and as discussed earlier, the precise relationship between the results from the 2 assays remains to be established. An alternative explanation, especially given our finding of a significant effect of age on fibrinogen binding in response to ADP and the known effect of age on aggregometry responses, 24 is the difference in the demographics of the subjects studied. In contrast to our cohort, the subjects of Fontana et al were all males and significantly younger (18 to 35 years of age).…”

Section: Discussionmentioning

confidence: 93%

“…A positive correlation was found between platelet response and increasing age and also with the density of GPIIb-IIIa on platelets, whereas a negative correlation was found with current smokers. Increasing age has been recognized to be associated with increased platelet response to ADP by others, 24 although the underlying mechanism for this is poorly understood. As would be expected, fibrinogen binding was correlated with the expression levels of GPIIb-IIIa on each platelet.…”

Section: Discussionmentioning

confidence: 99%

Dimorphism in the P2Y1 ADP Receptor Gene Is Associated With Increased Platelet Activation Response to ADP

Hetherington

Singh

Lodwick

et al. 2005

ATVB

127

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Objective-The platelet ADP receptors P2Y1 and P2Y12 play a pivotal role in platelet aggregation. There is marked interindividual variation in platelet response to ADP. We studied whether genetic variants in the P2Y1 or P2Y12 genes affect platelet response to ADP. Methods and Results-The P2Y1 and P2Y12 genes were screened for polymorphisms. Associations between selected polymorphisms and the platelet response to ADP (0.1, 1.0, and 10 mol/L), assessed by whole blood flow cytometric measurement of fibrinogen binding to activated glycoprotein IIb-IIIa, were then determined in 200 subjects. Five polymorphisms were found in the P2Y1 gene and 11 in the P2Y12 gene. All polymorphisms were silent. A P2Y1 gene dimorphism, 1622A͘G, was associated with a significant (Pϭ0.007) effect on platelet ADP response, with a greater response in carriers of the G allele (frequency 0.15). The effect was seen at all concentrations of ADP but greatest at 0.1 mol/L ADP, where the response in GG homozygotes was on average 130% higher than that seen in AA homozygotes (Pϭ0.006). Key Words: platelets Ⅲ thrombosis Ⅲ genes Ⅲ receptors Ⅲ adenosine diphosphate P latelet activation and thrombus formation play an integral role in the hemostatic mechanism after vascular injury. After disruption of atherosclerotic plaques, platelet aggregation also plays an important role in development of myocardial infarction and other acute coronary syndromes. 1 Binding of platelets to von Willebrand factor and collagen is the initiating event in platelet activation. This leads to platelet degranulation and release of ADP. ADP, acting via specific receptors, causes further platelet activation and platelet aggregation. Therefore, ADP plays a key direct role in platelet activation. ADP-mediated activation also partly explains the platelet response to other agonists. 2 Two platelet ADP receptors, P2Y1 and P2Y12, have been shown to initiate platelet activation when stimulated in concert. 3 Both are heterotrimeric G-protein-coupled receptors: P2Y1 to Gq and P2Y12 to Gi. Stimulation at P2Y1 leads to intracellular calcium mobilization and platelet shape change, 4 whereas stimulation at P2Y12 leads to inhibition of adenylyl cyclase 5 and activation of phosphoinositide-3 kinase. 6 The end effect is affinity modulation of the glycoprotein IIb-IIIa (GPIIb-IIIa) receptor for fibrinogen, resulting in fibrinogen binding and platelet aggregation. 7 It is well recognized that there is substantial interindividual variation in platelet response to ADP. 8,9 The reasons for the interindividual variation are poorly defined, but the observation that the response is stable over time, in a given individual, 9 raises the possibility that at least in part, it may be genetically controlled because of variation in the P2Y1 and/or P2Y12 genes. Conclusions-P2Y1 and P2Y12 genes are located on chromosome 3. The P2Y1 gene spans Ϸ4 kb 10 and is made up of a single exon of 3122 base pairs encoding a 372-aa protein. 11 The P2Y12 gene spans 47 kb and is made up of 3 exons and 2 introns. 12 There are ...

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“…Because platelet activation increases with age and in atherosclerotic disease (21,22 ), we studied the presence of PMPs and PMP subpopulations in aging and in atherosclerotic disease in vivo. In our study, the majority of circulating MPs originated from platelets in all individuals.…”

Section: Discussionmentioning

confidence: 99%

P-Selectin- and CD63-Exposing Platelet Microparticles Reflect Platelet Activation in Peripheral Arterial Disease and Myocardial Infarction

et al. 2006

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Background: Platelet-derived microparticles (PMPs) are generally considered a marker of platelet activation in cardiovascular disease. We studied the extent to which PMP subpopulations parallel platelet activation in vitro and in vivo. Methods: Using flow cytometry, we analyzed PMP subpopulations from resting and activated platelets in vitro (n ‫؍‬ 6) as well as from plasma samples of patients with stable angina, peripheral arterial disease, or myocardial infarction [non-ST-elevation (NSTEMI) and ST-elevation (STEMI)] and from older, age-and sexmatched and young healthy individuals [n ‫؍‬ 10 for all groups except NSTEMI (n ‫؍‬ 11)]. Coagulation markers prothrombin fragment F 1 ؉ 2 and thrombin-antithrombin complexes were determined by ELISA. The PMPassociated fraction of soluble (s)P-selectin was estimated by ELISA. Results: In vitro, stimulation of platelets with thrombin receptor-activating peptide (15 mol/L) or the calcium ionophore A23187 (2.5 mol/L) increased fractions of both platelets and PMPs exposing P-selectin or CD63 (P <0.001 for all). Whereas the number of PMPs released by A23187-stimulated platelets increased significantly (P <0.001), the number of PMPs released from thrombin receptor-activating peptide-stimulated platelets remained constant (P >0.05). Ex vivo, numbers of circu-

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Age, cardiovascular risk factors and coronary heart disease as determinants of platelet function in men. A multivariate approach

Cited by 40 publications

References 31 publications

Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris

Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris

Dimorphism in the P2Y1 ADP Receptor Gene Is Associated With Increased Platelet Activation Response to ADP

P-Selectin- and CD63-Exposing Platelet Microparticles Reflect Platelet Activation in Peripheral Arterial Disease and Myocardial Infarction

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