Large Platelets Circulate in an Activated State in Diabetes Mellitus

Tschöepe, Diethelm; Roesen, P.; Esser, Jennifer S.; Schwippert, B.; Nieuwenhuis, H. K.; Kehrel, Beate E.; Gries, F. A.

doi:10.1055/s-2007-1002650

Cited by 251 publications

(174 citation statements)

References 33 publications

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“…Mechanisms, other than increased ADP exposure, may be involved in the reduced sensitivity of diabetic platelets to dual antiplatelet therapy observed in our study. Increased platelet turnover (36), cytosolic levels of calcium (37), oxidative stress resulting in aspirin-insensitive thromboxane biosynthesis (38), altered structure of platelet membrane due to impaired lipid metabolism, and enhanced protein glycation reducing interaction with drug target (39) all affect response to antiplatelet agents. The latter may explain why poor metabolic control may play a role in reduced platelet sensitivity to antiplatelet drugs (10).…”

Section: Diabetes and Dual Antiplatelet Treatmentmentioning

confidence: 99%

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

et al. 2005

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To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n ‫؍‬ 52) and 2) long-term effects of clopidogrel (group 2, n ‫؍‬ 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using wholeblood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n ‫؍‬ 16) compared with nondiabetic (n ‫؍‬ 36) patients at baseline and up to 24 h following a 300-mg loading dose (P ‫؍‬ 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n ‫؍‬ 60) compared with nondiabetic (n ‫؍‬ 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P ‫؍‬ 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients. Diabetes 54:2430 -2435, 2005 D iabetes is commonly associated with accelerated atherosclerosis, clinically resulting in premature coronary artery disease (CAD), increased risk of cerebrovascular disease, and severe peripheral vascular disease (1). Patients with type 2 diabetes have a two-to fourfold increase in the risk of CAD, and diabetic patients without prior myocardial infarction have the same risk for a subsequent acute coronary event as nondiabetic patients with a previous myocardial infarction (2,3). Recurrent ischemic events are also more frequent in patients with type 2 diabetes than in nondiabetic patients (4 -6). Platelet dysfunction, among other mechanisms, contribute to the increased risk of atherothrombotic complications in the diabetic population (7-9). Such altered platelet function is revealed by hypersensitivity to aggregants observed in in vitro studies.Platelets from diabetic subjects are also less sensitive to aspirin (10 -11). Importantly, reduced sensitivity, or "poor response," to aspirin has been associated with an increased risk of ischemic events (12-15). Combining clopidogrel to aspirin enhances platelet inhibition and has been associated with a reduction in ischemic events compared with the use of aspirin alone (16 -19). However, the magnitude of antiplatelet effects may be depressed in diabetic patients. The aim of this study was to compare platelet function profiles in diabetic and nondiabetic patients on combined aspirin and clopidogrel therapy. RESEARCH DESIGN AND METHODSTwo patient populations were included to investigate the 1) acute effects of a 300-mg loading dose of...

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Section: Diabetes and Dual Antiplatelet Treatmentmentioning

confidence: 99%

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

et al. 2005

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“…Type 2 diabetes is associated with increased plasma markers of platelet activation (3)(4)(5), and pharmacological intervention to reduce plasma triglycerides results in reduction in markers of platelet activation (6). Platelet activation plays an integral role in atherothrombosis (7), since platelet aggregation forms the scaffolding for the initiation of a platelet plug after damage to the vascular wall or rupture of atherosclerotic plaque.…”

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confidence: 99%

A Novel Role for CD36 in VLDL-Enhanced Platelet Activation

et al. 2003

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Type 2 diabetes is characterized by increased plasma triglyceride levels and a fourfold increase in ischemic heart disease, but the mechanism is unclear. CD36 is a receptor/transporter that binds fatty acids of lipoproteins. CD36 deficiency has been linked with insulin resistance. There is strong evidence of in vivo interaction between platelets and atherogenic lipoproteins suggesting that atherogenic triglyceride-rich lipoproteins, such as VLDL, that are increased in diabetic dyslipidemia are important in this process. This study demonstrates that VLDL binds to the platelet receptor CD36, enhances platelet thromboxane A2 production, and causes increased collagen-mediated platelet aggregation. VLDL enhanced collagen-induced platelet aggregation by 1) shortening the time taken for aggregation to begin (lag time) to 70% of control (P ‫؍‬ 0.001); 2) increasing maximum aggregation to 170% of control (P ‫؍‬ 0.008); and 3) increasing thromboxane production to 3,318% of control (P ‫؍‬ 0.004), where control represents platelets stimulated with collagen (100%). A monoclonal antibody against CD36 attenuated VLDLenhanced collagen-induced platelet aggregation by 1) inhibiting binding of VLDL to platelets by 75% (P ‫؍‬ 0.041); 2) lengthening lag time to 190% (P < 0.001); and 3) decreasing thromboxane production to 8% of control (P < 0.001). In support of this finding, platelets from Cd36-deficient rats showed no increase in aggregation, thromboxane production, and VLDL binding in contrast to platelets from rats expressing CD36. These data suggest that platelet Cd36 has a key role in VLDLinduced collagen-mediated platelet aggregation, possibly contributing to atherothrombosis associated with increased VLDL levels. Diabetes 52:1248 -1255, 2003 I ndividuals with type 2 diabetes have at least four times greater risk of developing ischemic heart disease (IHD) than the general population. Type 2 diabetes and the metabolic syndrome are also associated with the atherogenic lipoprotein phenotype (1), characterized by elevated plasma triglyceride, increased VLDL production, increased small dense LDL levels, as well as decreased HDL. Recent data provide convincing evidence that increased plasma triglyceride levels are an independent risk factor for IHD (2), but the mechanism linking increased plasma triglyceride-rich lipoproteins, such as VLDL, to IHD remains uncertain.Type 2 diabetes is associated with increased plasma markers of platelet activation (3-5), and pharmacological intervention to reduce plasma triglycerides results in reduction in markers of platelet activation (6). Platelet activation plays an integral role in atherothrombosis (7), since platelet aggregation forms the scaffolding for the initiation of a platelet plug after damage to the vascular wall or rupture of atherosclerotic plaque. It is increasingly apparent that atherogenic lipoproteins and platelets interact both in vivo and in vitro, producing a procoagulant phenotype (8 -11), but the molecular interaction between triglycerides and platelets has not been elucida...

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“…The clinical ischaemia cascade of acute coronary syndromes is clearly a platelet-driven phenomenon [4]. Consequently, increased numbers of platelets circulate in an activated state in diabetic patients [5,6]. Increases in the constitutive number of platelet surface fibrinogen receptors (GPIIb-IIIa) led us to assume a primary "diabetic" thrombocytopathy which renders the peripheral platelet pool more susceptible towards activation [7].…”

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confidence: 99%

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

et al. 2003

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Aims/hypothesis. The gene encoding the β 3 -subunit (GPIIIa) of the platelet α 2 β 3 -integrin (fibrinogen receptor) shows a polymorphism PlA1/A2 with the A2 allele putatively associated with an increased risk of acute ischaemic events. This study investigated whether Type 2 diabetes as a particular macrovascular risk factor associates with the thrombogenic PIA2 genotype. Methods. The PlA genotype was determined in 112 consecutive Type 2 diabetic patients additionally classified according to the presence of macrovascular disease. Forty-four non-diabetic patients with angiografically documented cardiovascular disease (CAD/ AMI) and a further 59 non-diabetic subjects with no angiografical signs of CAD were investigated as genomic background control (n=103). PIA-genotyping was carried out by standard restriction fragment length analysis (RFLA) of PCR amplified lymphocyte template DNA. Results. The overall allelic PlA2-prevalence accounted to 34.8% (39/112) in diabetic patients as compared to 14.6% (15/103) in non-diabetic patients [OR 3.1 (1.6-6.1), p<0.01].This odds ratio increased to 7.0 (2.5-19.7), (p<0.01) in subjects free of criteria of macrovascular disease. In non-diabetic control subjects without CAD there was an allelic PIA2 frequency of 10.2% (6/59) as compared to 20.5% (9/44) in patients with CAD and a history of AMI being less than either diabetes subgroup. The PIA2 prevalence in the subgroup of diabetes patients with macrovascular complications did not differ from the respective value in patients without macrovascular disease. [29.0% (20/69) vs. 44.2% (19/43)]. Conclusion/interpretation. This study confirms a trendwise association of PlA2 with severe coronary artery disease, but rather suggests an even stronger, highly significant association with the metabolic condition of Type 2 diabetes mellitus. This justifies the speculation that pathways dependent on the platelet α 2 β 3 integrin physiology could be implicated in the pathogenesis of Type 2 diabetes which lends further support to the "common soil" hypothesis of diabetes and vascular disease. [Diabetologia (2003) Abbreviations: AMI, acute myocardial infarction; CAD, coronary artery disease; GPIIIa, β 3 subunit of the platelet surface α 2 β 3 -integrin (GPIIb-IIIa, fibrinogen-receptor); PIA, platelet antigen; RGD, aminoacidsequence Arg-Gly-Asp; SNP, single nucleotide polymorphism. Diabetologia (2003) 46:984-989

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Large Platelets Circulate in an Activated State in Diabetes Mellitus

Cited by 251 publications

References 33 publications

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

A Novel Role for CD36 in VLDL-Enhanced Platelet Activation

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

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