Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets from nine patients with insulin-dependent diabetes before and 2 weeks after daily doses of 500 mg ticlopidine. Ticlopidine significantly prolonged bleeding time and reduced platelet reactivity to fixed, relatively high concentrations of aggregating agents, without interfering with thromboxane B2 formation. We used a rotating probe device at a relatively low shear rate (570 sec-1) to measure platelet adhesion to human subendothelium. This system was able to detect an impairment of platelet adhesion dependent on glycoprotein (GP) Ib defect (Bernard Soulier syndrome) or on low platelet von Willebrand factor content, but was insensitive to platelet GPIIb-IIIa defect (Glanzmann's thrombasthenia). In our patients, platelet adhesion was consistently reduced after the administration of ticlopidine. We conclude that ticlopidine is an inhibitor of platelet function that modulates the interaction between platelets. The drug also appears to interfere with mechanisms that modulate platelet-subendothelium interaction at relatively low shear rates. This double action could be relevant in the prevention of vasculopathy in patients with diabetes.
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PMID:Inhibition of ticlopidine of platelet adhesion to human venous subendothelium in patients with diabetes. 318 91

Vascular diseases and related complications still represent the main cause of death in diabetic patients. Neuropathy, nephropathy, retinopathy, and disturbed nutritive tissue perfusion may result from reduced capillary microcirculation. These disturbances are diabetes specific. Macroangiopathy does not differ structurally from atherosclerotic lesions of nondiabetic subjects, but leads to accelerated cerebral, coronary, and peripheral artery disease. Occurrence of life-terminating thrombotic events, which are superimposed on those vascular lesions, are increased. Thus, morbidity and mortality of diabetics depend mainly on vascular complications. Normal blood flow is a prerequisite of adequate organ perfusion and results from vasomotion, plasma components, corpuscular blood elements, vascular architecture, and the undisturbed interaction of these components at the endothelial interface. Functional thromboresistance of the endothelial layer is reduced in the diabetic state. Increased intravascular thrombin generation, reduced fibrinolytic potential, and hyperactive platelets lead to a prethrombotic state. This thrombotic diathesis increases the permanent danger of acute flow interruption. Activated platelets operate by three mechanisms: (1) Microembolization of the capillaries; (2) local progression of preexisting vascular lesions by secretion of constrictive, mitogenic, and oxidative substances; (3) trigger of the prognosis-limiting arterial thrombotic event. We were able to show that the increased functional properties of diabetic platelets result from the primary release of larger platelets with enhanced thromboxane formation capacity and increased numbers of functional glycoprotein receptors GPIb and GPIIb/IIIa, which are synthesized in the megakaryocytes. The megakaryocyte-platelet system is turned on in diabetes mellitus. It could be demonstrated with the Duesseldorf III method of flow cytometric activation marker testing (CD62, CD63, thrombospondin) that predominantly large platelets circulate in an activated state in diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelets in diabetes: the role in the hemostatic regulation in atherosclerosis. 835 57

Recently, the HPA-1b (PlA2) polymorphism of the platelet glycoprotein IIIa has been suggested as a genetic risk factor for coronary artery disease. We conducted two case-control studies of 103 patients with ischaemic cerebrovascular disease (CVD) and 101 patients with ischaemic heart disease (IHD). The groups were matched for age, race and sex. No significant differences regarding selected risk factors (hypertension, diabetes mellitus, hypercholesterolaemia and smoking) were found between case patients and controls. Moreover, we investigated 286 normal individuals from the Mediterranean area. Genotyping of HPA-1 was performed by PCR-allelic specific restriction and single-strand conformation polymorphism analysis. The prevalence of HPA-1b was similar among case patients and controls (29.2% vs. 25.3% and 26.7% vs. 34.6% for CVD and IHD case-control studies, respectively). The HPA-1b allele was found in 36.4% of the normal population. Finally, the analysis of platelet function in nine controls with the three possible HPA-1 genotypes (three a/a, three a/b and three b/b) indicates that HPA-1b genotype does not modify either the in vitro platelet aggregation and activation profile, nor the GP IIb/IIIa interaction with fibrinogen or von Willebrand factor. Our results do not support the role of HPA-1b polymorphism as an inherited risk factor for arterial thrombotic disease.
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PMID:HPA-1 genotype in arterial thrombosis--role of HPA-1b polymorphism in platelet function. 928 92

Among central Europeans polymorphisms of GPIIIa, GPIb, GPIIb, and GPIa named human platelet antigen-1 (HPA-1), -2, -3, and -5 are the clinically most relevant systems in which alloimmunization occurs. These genetically determined polymorphisms of glycoproteins may render platelets sensible for plaque formation and thus could increase risk for coronary artery disease (CAD). We therefore determined gene frequencies of HPA-1, -2, -3, and -5 in European patients suffering from CAD (n = 92; median age, 46 years) or CAD accompanied by diabetes mellitus (DM) (n = 30; median age, 60 years, DM I/II, 5/25) and compared the data obtained with those in DM patients without CAD (n = 80; median age, 43 years; DM I/II, 53/27) and a control group (newborns, n = 906). Triglyceride and cholesterin levels as well as the percentage of smokers was significantly higher in the CAD group compared with the diabetics without DM (p < 0.005). No significant difference of the frequencies of any HPA-type between CAD patients with or without DM, diabetics, or controls could be detected. This was also true when evaluating a subgroup of patients aged 45 years or younger. To include a mutual influence of the described HPA-polymorphisms, we condensed the four HPA genotypes to joint glycoprotein variants. Again the same frequencies were found in patient groups and controls, when analyzing the five most common condensed joint glycoprotein variants. The analysis of the combined published studies shows that the pooled HPA-1 allele frequencies are identical in controls and CAD patients. Thus, no significant association between the polymorphisms of any of the studied HPA systems and the development of CAD can be found in central Europeans.
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PMID:Inherited platelet glycoprotein polymorphisms and a risk for coronary heart disease in young central Europeans. 968 30

Acute coronary syndromes not associated with ST-segment elevation, i.e. unstable angina and non-Q wave myocardial infarction, represent a heterogeneous group of clinical disorders sharing similar pathogenic mechanisms, clinical presentation and medical management. Current guidelines recommended an early anti-thrombotic and anti-ischemic treatment in these patients, as well as their prompt risk evaluation based on easily available clinical and instrumental data, to identify those subjects at greater risk in whom a more aggressive management is warranted. Despite the association of aspirin, heparin and anti-ischemic drugs, the 30-day rate of death or myocardial infarction remains high (9-15%) in patients with markers of greater risk (i.e. Braunwald class III, ST-segment depression, abnormal creatine kinase or troponin values). Moreover, in patients with acute coronary syndromes undergoing percutaneous coronary interventions (PCI), complex coronary lesions increase the peri-procedural risk of thrombotic complications. Regardless of the agonist responsible for platelet activation and aggregation, platelet glycoprotein (GP) IIb/IIIa receptor activation is the key factor in thrombosis formation. Several clinical trials in the past few years have documented the beneficial value of GP IIb/IIIa inhibitors in patients treated with aspirin and heparin, with a significant reduction in the cumulative end-point of death and/or myocardial infarction at 48-96 hours (odds ratio--OR 0.81, 95% confidence interval--CI 0.71-0.92, p < 0.01). Such therapeutical benefit is still present at 30 days (OR 0.88, 95% CI 0.81-0.97, p < 0.001) and 6 months (OR 0.88, 95% CI 0.79-0.97, p < 0.001). In patients treated with abciximab, eptifibatide or tirofiban, undergoing early PCI, a remarkable relative reduction in the risk of death and non-fatal acute myocardial infarction was shown before PCI (-34%, p < 0.001). The pre-PCI administration of GP IIb/IIIa inhibitors is associated with a significant reduction in peri-procedural complications (-41% relative reduction of death or acute myocardial infarction in the 48 hours after PCI, p < 0.001). In this subset of patients the benefit correlates with abnormal pre-PCI values of troponin, a reliable surrogate marker of active thrombosis. The greatest clinical benefit from GP IIb/IIIa inhibitors is expected in patients presenting high-risk features (early post-infarction angina; older age with a history of left ventricular dysfunction or diabetes; heart failure symptoms, ST-segment depression, abnormal troponin, creatine kinase, and C-reactive protein values at admission) as well as in patients with recurrent ischemic attacks and those undergoing early PCI. Although the combination of GP IIb/IIIa inhibition and standard doses of unfractionated heparin is associated with an increased risk of major bleeding, such risk can be remarkably reduced adopting simple technical suggestions.
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PMID:[The clinical use of the GPIIb/IIIa inhibitors eptifibatide and tirofiban in the treatment of acute coronary syndromes of the "non-ST elevation" type]. 1093 49

Diabetes mellitus (DM) type 2 is a very strong risk factor for atherosclerosis. The final event of atherosclerosis is the vessels occlusion by platelet riche thrombus. Platelets adhesion and aggregation is mediated by interaction between platelets glycoproteins: GPIb-IX, GPIIb-IIIa and adhesive proteins: von Willebrand factor or fibrinogen. The expression of platelets GPIb-IX, GPIIb-IIIa, plasma vWF, fibrinogen concentrations were evaluated in 40 patients with diabetes type 2 (22 patients with PAOD stage II and IV according to Fontain, 18 diabetics without paod) and 32 healthy individuals. The expression of platelets glycoproteins GPIIb-IIIa and GPIb-IX was estimated by ELISA using monoclonal antibody against GPIIb-IIIa (CD41a) and GPIb-IX (CD 42a Immunotech). Plasma vWf (189.7 +/- 53.6%), fibrinogen (4.5 +/- +/- 1.3 g/l) level and expression of platelets GPIb-IX (63.2 +/- 19.6% in platelets concentration 125,000/mm3, 104.5 +/- 28.1% in platelets concentrations 250,000/mm3) and GPIIb-IIIa 50.8 +/- 10.1% in platelets concentrations 125,000/mm3, 95.3 +/- 21.3% in platelets concentrations 250,000/mm3 were statistically higher in patients with diabetes type 2 than in controls (vWf: 94.9 +/- 27.1%, fibrinogen: 2.8 +/- 0.4 g/l, GPIb-IX in platelets concentration 125,000/mm3: 43.8 +/- 9.3%, in concentration 250,000/mm3: 83.9 +/- 18.3%, GPIIb-IIIa in platelets concentration 125,000/mm3: 33.7 +/- 10.1%, in platelets concentration 250,000/mm3: 63.2 +/- 15.4%). We found significant correlation between the expression of GPIIb-IIIa, GPIb-IIIa, GPIb-IX and plasma adhesive proteins: vWF, fibrinogen in controls and both subgroups of diabetic patients. The correlation between plasma vWF and fibrinogen level and degree of arterial insufficiency in diabetic patients was also found. We can assume that higher vWf, fibrinogen plasma level in diabetic patients with and without PAOD could account for high expression of platelets GPIIb-IIIa and GPIb-IX.
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PMID:[Chronic peripheral arterial occlusive disease, platelet glycoproteins GPIIb-IIIa and GP Ib-IX, plasma von Willebrand factor and plasma fibrinogen concentrations in patients with type 2 diabetes mellitus]. 1123 40

Platelet-derived microparticles (PMPs) are released from platelets through the platelet activation by high shear stress, collagen, or calcium ionophore (A23187). PMPs are observed in patients with acute myocardial infarction, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia and other thrombotic disorders, but the importance of circulating PMPs in the pathogenesis of these diseases is still debated. Numbers of PMPs are usually determined by flowcytometry (FCM), but easier and reproducible PMP assay systems are needed. To develop a better ELISA for PMPs, we used antibodies against the platelet antigens anti-GPIb (NNKY5-5), anti-GPIIb/IIIa (NNKY2-11, anti-CD41), anti-GPIX (KMP-9), and anti-CD9 (NNKY1-19). PMPs were detected with all combinations of these antibodies, but the ELISA having the highest and most specific absorbance was obtained with a combination of KMP-9 (capture antibody) and NNKY5-5 (detecting antibody). PMPs in blood samples were measured by ELISA and FCM. ELISA correlated with PMPs quantitated by FCM. By shaking ELISA plates during incubation, nonspecific binding of platelets was eliminated. The level of PMPs was not increased in diabetes mellitus, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, or sepsis. The concentration of PMP was elevated in hemolytic uremic syndrome. Activated PMPs were absorbed to 0.8 microm filter, but circulating PMPs were not absorbed. These results suggest that activated PMPs are likely to adhere to leukocytes or endothelial cells at the activation site and that the circulating form of PMPs are likely to be a residue of activated PMPs. To detect only the activated form of PMPs, a new ELISA needs to be developed, and it will likely use a combination of antibodies that detect platelet activation markers such as P-selectin (CD62P) or activated GPIIb/IIIa.
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PMID:Development and assessment of enzyme immunoassay for platelet-derived microparticles. 1124 56

The aim of the study was to explore the feasibility of same-day outpatient stent placement using a short course of intravenous antiplatelet therapy. Patients (n = 26) had stent placement and 6 hr of eptifibatide therapy. Demographics, procedural information, CPK data, and length of stay were recorded along with postdischarge outcomes. Twenty-one men and five women with median age of 60 years (49, 69) underwent transradial stenting. Baseline characteristics included diabetes 62%, hyperlipidemia 77%, prior coronary bypass surgery 19%, and unstable angina 35%. There were no CPK elevations (> 2 x normal) or ECG changes. Discharge occurred after 6.5 hr (5.8, 7.0). Neither vascular site complications nor readmission for procedure-related problems occurred. One patient later expressed concerns about discharge education. Outpatient stent placement with 6-hr infusion of GP IIb/IIIa inhibitor appears feasible and efficient in select patients. There may be challenges to meet with regard to patient education. Further studies with larger populations are needed to evaluate and optimize this approach.
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PMID:Same-day transradial outpatient stenting with a 6-hr course of glycoprotein IIb/IIIa receptor blockade: a feasibility study. 1197 25

Antagonists of the platelet fibrinogen receptor glycoprotein IIb/IIIa are potent inhibitors of platelet function and provide marked protection from ischemic events in patients undergoing PCI. These agents are also of benefit in patients with unstable angina or non-ST segment elevation myocardial infarction (MI) and provide a 9% reduction in the combined endpoint of 30-day death or MI. This benefit is most marked in patients undergoing early PCI or those at increased risk due to history of diabetes or elevation of the cardiac marker troponin. Based on these findings, the combined American Heart Association and American College of Cardiology guidelines on the management of unstable angina and non-ST segment elevation MI recommend intravenous GPIIb/IIIa in patients in whom PCI is planned particularly those with elevated troponin or diabetes. The use of these agents is associated with a slight increase in major bleeding and in rare instances thrombocytopenia that usually resolves quickly after therapy is discontinued.
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PMID:Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. 1238 36

Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI). In large trials, the GP IIb/IIIa inhibitors tirofiban and eptifibatide were each found to reduce the risk of death or myocardial infarction (MI) in these patients at 30 days. These agents appear to be of greatest benefit in patients with a positive troponin at baseline, diabetes or ST-segment depression, recurrent angina, prior aspirin use, or a Thrombolysis In Myocardial Infarction (TIMI) risk score > or = 4. The Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) TIMI-18 trial was designed to compare the benefits of an early invasive versus a conservative strategy in high-risk UA/NSTEMI patients treated with GP IIb/IIIa inhibition. Patients were treated with tirofiban (for 48 h) plus aspirin and heparin and randomized to either invasive therapy (coronary angiography and revascularization when feasible) or conservative treatment (angiography only for patients with recurrent ischemia at rest or a positive stress test). A significant reduction in death or MI was demonstrated at 30 days (p = 0.02) and at 6 months (p = 0.0498). Death, MI, or rehospitalization for an acute coronary syndrome was also reduced with the invasive therapy at six months (p = 0.025). These results provide evidence to physicians that early GP IIb/IIIa inhibition in combination with a prompt invasive approach should be used more widely in UA/NSTEMI patients, particularly those at high risk.
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PMID:Small molecule glycoprotein IIb/IIIa receptor inhibitors as upstream therapy in acute coronary syndromes: insights from the TACTICS TIMI-18 trial. 1264 40


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