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1.
Introduction
Diadenosine 5',5'-P1,P4- tetraphosphate (Ap4A) is stored in platelet dense granules, but its effects on platelet function are not well understood.Methods and Results
We examined the effects of Ap4A on platelet purinergic receptors P2Y1, P2Y12 and P2X1. Flow cytometry was used to measure the effects of Ap4A in the presence or absence of ADP on: a) P2Y12-mediated decrease in intraplatelet phosphorylated vasodilator stimulated phosphoprotein (VASP), b) P2Y1-mediated increase in platelet cytosolic Ca2+, and c) P2X1-mediated intraplatelet entry of extracellular Ca2+. ADP-stimulated platelet shape change (P2Y1-mediated) and aggregation (P2Y1- and P2Y12-mediated) were measured optically. Ap4A inhibited 3 μM ADP-induced: a) platelet aggregation (IC50 9.8 ± 2.8 μM), b) P2Y1-mediated shape change, c) P2Y1-mediated increase in platelet cytosolic Ca2+ (IC50 40.8 ± 12.3 μM), and d) P2Y12-mediated decrease in VASP phosphorylation (IC50 > 250 μM). In the absence of added ADP, Ap4A had agonist effects on platelet P2X1 and P2Y12, but not P2Y1, receptors.Conclusion
Ap4A, a constituent of platelet dense granules, is a) an antagonist of platelet P2Y1 and P2Y12 receptors, where it inhibits the effects of ADP, and b) an agonist of platelet P2X1 and P2Y12 receptors. 相似文献2.
Kreutz RP Breall JA Kreutz Y Owens J Lu D Bolad I von der Lohe E Sinha A Flockhart DA 《Thrombosis research》2012,130(2):198-202
Introduction
Clopidogrel inhibits ADP mediated platelet aggregation through inhibition of the P2Y12 receptor by its active metabolite. Thrombin induces platelet aggregation by binding to protease activated receptor-1 (PAR-1), and inhibition of PAR-1 has been evaluated in patients treated with clopidogrel to reduce ischemic events after acute coronary syndromes. Residual PAR-1 mediated platelet aggregation may be dependent on extent of clopidogrel response.Material and Methods
Platelet aggregation was measured in 55 patients undergoing elective PCI at 16-24 hours after 600 mg clopidogrel loading dose by light transmittance aggregometry using ADP 20 μM and thrombin receptor agonist peptide (TRAP) at 15 μM and 25 μM as agonists. Genomic DNA was genotyped for common CYP2C19 variants.Results
Increasing quartiles of 20 μM ADP induced platelet aggregation after clopidogrel loading were associated with increasing levels of TRAP mediated platelet aggregation. Patients in the highest quartile (clopidogrel non-responders) of post treatment ADP aggregation had significantly higher TRAP mediated aggregation than the patients in the lowest quartile (clopidogrel responders) [TRAP 15 μM: 79.6 ± 5% vs. 69.5 ± 8%, p < 0.001].Conclusions
Non-responders to clopidogrel show increased residual platelet aggregation induced by TRAP, whereas clopidogrel responders exhibit attenuated response to TRAP. Addition of PAR-1 antiplatelet drugs may be most effective in patients with reduced clopidogrel response and high residual TRAP mediated platelet aggregation. 相似文献3.
Introduction
Sclerotherapy is associated with thromboembolic and ischemic neurological adverse events but the effects of sclerosants on platelet function are unknown. The aim of this study was to investigate the in vitro effects of detergent sclerosants Sodium Tetradecyl Sulphate (STS) and Polidocanol (POL) on platelet activation and aggregation.Materials and Methods
Whole blood and platelet rich plasma samples were incubated with sclerosants. Platelet and platelet microparticle (PMP) counts were measured by flow cytometry. Platelet activation was examined by ELISA for soluble factors (sP-selectin, von Willebrand factor, sCD40L and serotonin) and by flow cytometry for membrane-bound markers (CD62p, CD63) and cytoplasmic calcium. Platelet aggregation was assessed by PFA-100®, light transmission and impedance (Multiplate®) aggregometry, and by flow cytometry for glycoprotein (GP) Ib and GPIIb/IIIa subunits, heterodimer expression and activation (PAC-1 binding).Results
Both agents lysed platelets at high concentrations (≥ 0.1%) but induced platelet activation at lower concentrations as evident by a rise in membrane-bound and soluble markers, cytoplasmic calcium and release of phosphatidylserine + PMP. Agonist-stimulated platelet aggregation was inhibited by both sclerosants. Membrane expression of GPIb and GPIIb/IIIa individual subunits or heterodimer was not affected by sclerosants but the activation of GPIIb/IIIa was suppressed.Conclusion
Low concentration sclerosants activated platelets and released microparticles but inhibited platelet aggregation due to suppression of GPIIb/IIIa activation. 相似文献4.
Young-Hoon Jeong Jung-Hyun Cho Jin-Sin Koh Yongwhi Park Choong Hwan Kwak 《Thrombosis research》2010,126(4):e334
Background
Recent data suggest that cigarette smoking (CS) might decrease the risk of cardiovascular events in patients with ST-segment-elevation myocardial infarction (STEMI) or established cardiovascular disease. Although it may be related to the effect of CS on the metabolism of clopidogrel, the association between the extent of CS and clopidogrel-induced platelet inhibition has not been well defined.Patients and methods
We tested the association between smoking status and inhibition of platelet aggregation (IPA) in response to a clopidogrel loading of 600-mg in 20 healthy subjects. We then enrolled 138 consecutive STEMI patients treated with primary coronary stenting. On-clopidogrel platelet reactivity (PR) was assessed with conventional aggregometry and the VerifyNow P2Y12 assay, according to smoking status.Results
After 6 hours post-loading in healthy subjects, CS patients on ≥ 10 cigarettes/day showed a significantly higher value of 5 μmol/L ADP-stimulated IPA (P = 0.006), and had a trend toward a greater value of 20 μmol/L ADP-stimulated IPA (P = 0.093) compared with non-smokers. In STEMI patients, there was no difference in PR between non-smokers (n = 66) and CS patients < 10 cigarettes/day (n = 16). CS patients on ≥ 10 cigarettes/day (n = 56) demonstrated lower PR with 5 and 20 μmol/L ADP (40.9 ± 16.1% versus 46.6 ± 11.7%, P = 0.028, and 53.8 ± 16.6% versus 59.2 ± 12.2%, P = 0.040, respectively) and lower P2Y12 reaction units (204 ± 85 versus 270 ± 69, P < 0.001) than non-smokers. On multivariate analyses, CS ≥ 10 cigarettes/day was the only predictor of low on-clopidogrel PR (≤ 33%; the lowest quartile of 5 μmol/L ADP-induced PR; odds ratio 4.651, 95% confidence interval 1.181-18.519, P = 0.028).Conclusion: CS seems to increase antiplatelet response to clopidogrel in healthy volunteers and STEMI patients. Smoking 10 or more cigarettes/day can significantly decrease on-clopidogrel platelet reactivity in these populations. 相似文献5.
Background
Many markers of platelet activation have been described but their reproducibility and comparability in patient populations are poorly defined.Objectives
We sought to compare markers of platelet and monocyte activation with platelet-monocyte aggregates, a proposed gold standard of in vivo platelet activation, and assess their reproducibility in patients with peripheral arterial disease: a population with substantial platelet activation, inflammation and risk of thrombotic events.Patients/Methods
Thirty patients with peripheral vascular disease attended on two occasions to permit within-day and between-day comparisons. In vivo platelet and monocyte activation were determined by flow-cytometric quantification of platelet-monocyte aggregation, platelet surface expression of P-selectin and CD40L, platelet-derived microparticles, and monocyte surface expression of CD40 and CD11b. Plasma concentrations of platelet-derived microparticles, soluble P-selectin and CD40L were measured by enzyme-linked immunosorbant assays.Results
Platelet-monocyte aggregation (36.7 ± 7.86%), and platelet surface expression of P-selectin (5.8 ± 1.65%) and CD40L (3.3 ± 1.45%) demonstrated comparable within-day (mean difference ± co-efficient of reproducibility; 0.9 ± 15.4%, 0.21 ± 1.65% and 0.2 ± 2.8% respectively) and between-day reproducibility (2.0 ± 12.4%, 0.10 ± 2.25% and 0.9 ± 6.4% respectively). Platelet-monocyte aggregates correlated well with other platelet (r = 0.30-0.50, P < 0.02) and monocyte (r = 0.27-0.47, P < 0.03) activation markers. Flow cytometric and assay quantified platelet-derived microparticles showed poorer reproducibility (co-efficient of reproducibility > 40).Conclusions
In patients with peripheral arterial disease, measurements of platelet-monocyte aggregates have good reproducibility and consistently reflect other markers of platelet and monocyte activation. 相似文献6.
Ames PR Batuca JR Muncy IJ De La Torre IG Pascoe-Gonzales S Guyer K Matsuura E Lopez LR 《Thrombosis research》2012,130(3):350-354
Introduction
Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on platelet activation, thromboxane generation, oxidative stress and anti-oxidant biomarkers was studied in type 2 diabetes mellitus (DM).Material and methods
Baseline and post-ASA samples (100/325 mg x 7 days) were obtained from 75 DM patients and 86 healthy controls for urinary 11-dehydro-thromboxane B2 (11dhTxB2), 8-iso-prostaglandin-F2α (8-isoPGF2α) and serum sP-Selectin, nitrite (NO2-), nitrate (NO3-) and paraoxonase 1 (PON1) activity.Results
Compared to baseline controls, baseline DM had higher mean levels of 11dhTxB2 (3,665 ± 2,465 vs 2,450 ± 1,572 pg/mg creatinine, p = 0.002), 8-isoPGF2α (1,457 ± 543 vs 1,009 ± 412 pg/mg creatinine, p < 0.0001), NO2- (11.8 ± 7.3 vs 4.8 ± 5.3 μM, p < 0.0001), NO3- (50.4 ± 39.3 vs 20.9 ± 16.7 μM, p < 0.0001) and sP-Selectin (120.8 ± 56.7 vs 93.0 ± 26.1 ng/mL, p = 0.02), and the same held for post-ASA levels (p < 0.0001). ASA demonstrated no effect on 8-isoPGF2α, NO2-, NO3-, sP-Selectin or PON1 activity in either DM or controls. Post ASA inhibition of urinary 11dhTxB2 was 71.5% in DM and 75.1% in controls. There were twice as many ASA poor responders in DM than in controls (14.8% and 8.4%) based on systemic thromboxane reduction. Urinary 8-isoPGF2α excretion was greater in DM ASA poor responders than good responders (p < 0.009).Conclusions
This suggests that oxidative stress may maintain platelet function irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources. 相似文献7.
Siller-Matula JM Miller I Gemeiner M Plasenzotti R Bayer G Mesteri I Fabry A Petroczi K Nöbauer K Razzazi-Fazeli E Planchon S Renaut J Quehenberger P Selzer E Jilma B 《Thrombosis research》2012,130(2):226-236
Background
In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We aimed to establish an ovine model to study thrombin effects in vivo.Methods
Thrombin (0.0004-0.42 IU/kg/min) was continuously infused in Austrian Mountain Sheep over five hours in the dose escalation study (n = 5 animals; 15 experiments). In the dose verification study animals received 0.42 IU/kg/min of thrombin vs. saline solution in a cross-over design (n = 3 animals; 7 experiments).Results
Thrombin at an infusion rate of 0.42 IU/kg/min decreased fibrinogen levels by 75% (p < 0.001) and increased degradation products of the fibrinogen beta-chain as shown in a proteomic analysis. Thrombin decreased platelet counts by 36% (p = 0.006), prolonged thrombin time by 70% (p = 0.012) and activated partial thromboplastin time by 32%. Interestingly, thrombin infusion significantly increased the activity of coagulation factors V and X (p < 0.05) and decreased the activity of the coagulation factors VIII and XIII (p < 0.05). Accordingly, thrombin displayed predominantly anti-coagulant and anti-platelet effects: 1) thrombin prolonged clotting time/clot formation time 7-fold (p = 0.019) and induced a 65% decrease in maximal clot firmness (p < 0.001); 2) thrombin reduced collagen- induced platelet aggregation by 85% and prolonged collagen/adenosine diphosphate closure time 3-fold; and 3) thrombin caused lung haemorrhage but not thromboembolism.Conclusion
Protracted intravenous infusion of thrombin over a period of five hours offers a new experimental model to study thrombin effects in a large animal species. 相似文献8.
Introduction
The antithrombotic effect of the glycopreotein IIb/IIIa (GP IIb/IIIa) receptor antagonist Z4A5, exert alone or combination with heparin, and/or aspirin, was examined in a rabbit arteriovenous shunt thrombosis model.Materials and Methods
Thrombosis was induced by the insertion of a silk thread (thrombogenic substrate) into an extracorporeal shunt. Before and after drug administration (0, 5, and 15 min), ex vivo adenosine diphosphate (ADP)-induced platelet aggregation and coagulation parameters (prothrombin time (PT) and activated partial thromboplastin time (APTT)) were determined in platelet-rich plasma (PRP) and platelet poor-plasma (PPP), respectively.Results
Our data demonstrated that, compared to the control, Z4A5 decreased the thrombus weight (31-65%) in a dose-dependent manner and inhibited ADP-induced platelet aggregation (47-98%) 5 min after Z4A5 administration (25-100 mg/kg). However, PT and APTT remained stable, even at the highest dose (100 mg/kg). Heparin (100 U/kg) and aspirin (15 mg/kg) also significantly reduced thrombus mass, but this effect was accompanied by an increase of APTT by heparin. Furthermore, the combination of heparin (100 U/kg) and a low dose of Z4A5 (25 mg/kg) failed to produce an additional benefit beyond that provided by heparin or Z4A5 alone, whereas Z4A5 (25 mg/kg) plus aspirin (15 mg/kg) potentiated the antithrombotic effects of both compounds without further increasing the values of coagulation.Conclusions
Our results indicate that Z4A5 is an effective antithrombotic agent with no significant effects on values of coagulation. Furthermore, Z4A5 can potentiate these antithrombotic effects when prescribed with aspirin. 相似文献9.
Platelet aggregometry in the presence of PGE(1) provides a reliable method for cilostazol monitoring
Satoh K Fukasawa I Kanemaru K Yoda S Kimura Y Inoue O Ohta M Kinouchi H Ozaki Y 《Thrombosis research》2012,130(4):616-621
Introduction
Cilostazol has been shown to be effective for prevention and treatment of cerebral infarction. However, there appears to be no widely accepted method appropriate for monitoring cilostazol. We attempted to establish an assay system for cilostazol monitoring, using platelet aggregation induced by arachidonic acid (AA) in the presence of PGE1 which upregulates intracellular cyclic AMP.Methods
Blood was drawn from stroke patients before and after cilostazol intake. AA-induced platelet aggregation after pretreatment with 0 ~ 30 nM PGE1 for 2 minutes was measured by light transmittance aggregometry.Results
AA-induced platelet aggregation was 73.1 ± 2.2% in the absence of PGE1, and pretreatment with 30 nM PGE1 had virtually no inhibitory effect on platelet aggregation prior to cilostazol intake. In contrast, after cilostazol intake, 30 nM PGE1 significantly inhibited platelet aggregation to 12.7 ± 4.5% (p = 7.8 × 10(− 11)) , while in the absence of PGE1 platelet aggregation remained similar to that of prior-to-cilostazol value (70.6 ± 3.5%). The plasma concentration of cilostazol ranged from 0.55 to 3.51 μM. In the presence of 30 nM PGE1, all the patients with cilostazol concentrations exceeding 1 μM had their platelet aggregation inhibited almost completely. ROC analysis suggests that AA-induced platelet aggregation in the presence of 30 nM PGE1 had the excellent sensitivity (90.5%) and specificity (88.4%) for monitoring cilostazol.Conclusions
AA-induced platelet aggregation in the presence of 30 nM PGE1 could give good estimate on plasma concentrations of cilostazol. It is suggested that this system is a good tool for monitoring cilostazol. 相似文献10.
Objective
The aim of this study was to examine the relationships between glycogen synthase 3β gene polymorphisms and bipolar I disorder, manic in a Korean sample.Methods
Patients with bipolar disorder (n = 118) and a control group (n = 158) were assessed by genotyping for GSK3β single nucleotide polymorphisms (SNPs) − 1727A/T and − 50C/T. The patients were divided into two groups according to the presence of psychotic symptoms (psychotic mania, n = 92; non-psychotic mania, n = 26) and also divided based on gender and age of onset. The severity of symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).Results
There were no significant differences in the genotype distributions or allelic frequencies of GSK3β polymorphisms and gender between patients with bipolar disorder and a normal control group. According to haplotype analysis, there was no association between these two groups. However, analysis of the age of onset of bipolar disorder revealed significant differences in genotype and allele distributions among the patients. Patients who were homozygous for the wild-type variant (TT) had an older age of onset than carriers of the mutant allele (A/A: 27.4 ± 9.1; A/T: 30.1 ± 11.8; T/T: 42.3 ± 19.9; p = 0.034). We detected differences in allele frequencies of the GSK3β − 1727A/T polymorphism between the psychotic mania group and the non-psychotic mania group.Conclusion
This study suggests that GSK3β polymorphisms are not associated with bipolar disorder. However, the GSK3β SNP − 1727A/T is associated with age of onset and presence of psychotic symptoms in bipolar disorder. 相似文献11.
Anne Flöck Astrid Zobel Gerhard Bauriedel Christoph Hammerstingl Anna Schuhmacher Georg Nickenig 《Thrombosis research》2010,126(2):e83
Introduction
Depressive disorders have been identified as independent risk factors for coronary heart disease. The present study (i) compared platelet function of depressed patients with that of healthy controls, (ii) analysed possible aggregability changes during 3 months of treatment with antidepressants, and (iii) sought to assess different effects of escitalopram and nortriptyline on platelet aggregation.Methods
Blood samples of 91 major depressed patients and 91 healthy controls were analysed with whole blood aggregometry in a case-control setting. Depressed patients were randomized to two groups treated either with escitalopram (n = 47) or nortriptyline (n = 44). Platelet aggregation was studied on days 0, 1, 3, 7, 14, 21, 84 of continuing medication and was determined in response to adenosine diphosphate (ADP) and collagen.Results
Platelet aggregation induced by ADP was increased among depressive patients compared with that of healthy controls (26%, p = 0.006). With antidepressant treatment, changes in platelet aggregation remained comparable in both groups at early time points (d1 to 21). In contrast, at day 84, patients with antidepressive response revealed significant differences in both medication groups: Patients receiving escitalopram showed a 23% decrease of ADP induced aggregation (p = 0.03) and a 15% decrease of collagen induced aggregation (p = 0.03). With nortriptyline the increase in impedance was reduced by 29% after ADP induction (p = 0.046).Conclusion
Depressed patients have higher ex vivo platelet aggregation that may contribute to increased cardiovascular morbidity. After three months of antidepressant treatment with either escitalopram or nortriptyline, platelet aggregation was significantly reduced in antidepressant responders, irrespective of the antidepressant medication type. 相似文献12.
Introduction
Bivalirudin is used as an alternative to heparin in cardiac surgery, and may be superior to heparin with regard to platelet function. Bivalirudin however, is prone to cleavage by thrombin resulting in coagulation in areas of stasis.Material and Methods
We compared the preservation of platelet function and the quality of anticoagulation in autologous blood of 26 cardiac surgical patients collected intraoperatively and anticoagulated ex vivo with either bivalirudin or heparin, with supplementation of bivalirudin over time and prevention of stasis.Results
We found in both preservatives a reduction in ADP-induced platelet aggregation response over a period of 105 minutes (median, IQR: 73-141) as measured by Multiplate®. Supplementation of additional bivalirudin (23 ± 1.1 μg/ml/hr) and prevention of stasis was not able to prevent thrombin generation. We found a 5-fold increase in levels of prothrombin fragment 1 + 2 in bivalirudin preserved autologous blood as compared to heparin preserved blood (F1+2 levels median 8.9 nM [quartile percentiles 4.2-12.4] vs 1.3 nM [0.6-2.1], P = 0.001 Mann-Whitney, n = 10).Conclusions
Our study suggests that preservation of platelet function in autologous blood anticoagulated with bivalirudin is not a suitable alternative to heparin. 相似文献13.
Andrew J. Lucking Rajesh Chelliah Thomas M. Connolly Keith A. Fox Juan J. Badimon 《Thrombosis research》2010,126(5):431-435
Background
The Badimon chamber is a clinical ex vivo model of thrombosis that mimics flow conditions within the coronary circulation of man. The aims of this study were to characterise thrombus formation in the chamber and evaluate its reproducibility.Methods
Using blood from 24 healthy human volunteers, thrombus formation was assessed at low and high shear rates with porcine aortic tunica media as the thrombogenic substrate. Thrombus area was measured histomorphometrically. Reproducibility was assessed by paired measurements made both within and between days. Platelet activation was assessed before and at selected points within the extracorporeal circuit using flow cytometry, and fibrin content and distribution within the thrombus were assessed by immunohistochemistry.Results
Total thrombus area was highly reproducible within and between days in the low shear ([mean thrombus area, mean difference ± SEM] 8,018 μm2, 58 ± 204 μm2 and 8,177 μm2, -154 ± 168 μm2 respectively) and high shear chambers (11,802 μm2, -52 ± 175 μm2 and 11,877 μm2, 220 ± 181 μm2 respectively). Total thrombus area was greater in the high compared to the low shear chamber (11,970 ± 285 μm2versus 7,892 ± 298 μm2; P < 0.0001). Transit through the extracorporeal circuit did not result in platelet activation which was only detected after blood passed across the perfusion chambers (P = 0.02 for platelet-monocyte aggregate formation and P = 0.05 for P-selectin expression). Thrombus in the low shear chamber contained a greater proportion of fibrin (25.0 ± 6.0% versus 8.3 ± 1.6%, P < 0.001).Conclusions
The Badimon chamber provides a highly reproducible technique for the assessment of ex vivo platelet-rich thrombus formation in man. 相似文献14.
Background
A precise approach to the diagnosis of von Willebrand disease (vWD) remains elusive. One important reason is that vWD is a blood flow‐related disorder: a vW Factor‐platelet GPIb binding defect exists in this condition under the high shear‐rate (> 1000 sec‐1 in whole blood; > 3000 sec‐1 in PRP) conditions of physiologic blood flow which exist in the arterioles of mucous membranes, from which most bleeding in vWD occurs.Methods
We therefore studied 28 patients (mean 18.9 yrs) with vWD, diagnosed according to the 2007 NHLBI clinical guidelines, and 26 healthy controls (mean 17.5 yrs). Blood was collected into a plastic tube containing 4 U/ml FC dalteparin, 1.75 μg/ml of the Tab (anti‐CD41) monoclonal antibody directed against platelet GPIIb, and 1.0 μg/ml of an ALEXA 555‐conjugated rabbit anti‐mouse second antibody. Within 30-90 min, the blood was then withdrawn at 667 and 1330 sec− 1 through a special flow chamber allowing for real-time epifluorescence digital videomicroscopy of platelets interacting with a microfibrillar collagen substrate. With MetaMorph software (Universal Imaging) we quantified the percent area (PA) covered by and total volume (TV) of adherent platelet aggregates within a 435 μm × 580 μm field of view.Results
At 667 sec− 1 after 1 min PA and TV were similar for patients and controls, but at 1330 sec− 1 PA was 9.32 ± 4.21 (mean ± SD) for patients, a value lower (p < 0.001) than the 12.8 ± 3.39 for controls. TV was (1.43 ± 0.91)x104 for patients, a value also lower (p < 0.001) than the (2.22 ± 0.77)x104 for controls. PA or TV was below the 2.5th percentile for controls in 10 patients (36%) and both PA and TV were below the 2.5th percentile in eight.Conclusions
The novel flow device found that PA and TV were significantly reduced under high shear stress in vWD patients compared to normal controls. However, there was some overlap between the vWD and the control group, suggesting that some vWD patients had normal platelet adhesion/aggregation under the conditions studied. Further study with a higher shear rate appears indicated. 相似文献15.
Background
Recently several alternative forms of the original clopidogrel hydrogensulfate (CHS) were spread worldwide. A large amount of such drugs turned out to be clopidogrel besylate (CB). Only three studies, involving healthy volunteers, investigated the antiplatelet effect of CB, whereas its attribute remained unexplored in the case of patients with cardiovascular diseases. This retrospective study aimed to evaluate the difference between the antiplatelet effects of two clopidogrel formulas, CHS and CB, on patients with coronary artery diseases.Methods
Data of 150 patients with previous CHS treatment were investigated. According to the documentations, the CHS therapy was shifted to CB. 94 patients of the selected population received dual antiplatelet therapy, clopidogrel and aspirin. The antiplatelet effects of CHS and CB were compared by ADP induced platelet aggregation measurements using light transmission aggregometry.Results
Irrespective of the therapeutic combinations the performed statistical investigations failed to show significant difference (p = 0.30) between the effect of CB (AGGmaxCB: 27.6 ± 13.7%) or CHS (AGGmaxCHS: 29.0 ± 15.3%) on the ADP induced platelet aggregation. Insignificant deviations were found in both forms of clopidogrel salts, either in the lack (AGGmaxCB : 32.5 ± 14,2%; AGGmaxCHS: 34,0 ± 16,1%; p = 0,29) or in the presence of aspirin (AGGmaxCB: 24.7 ± 12,5%; AGGmaxCHS: 26,0 ± 14,1%; p = 0,31).Conclusion
Our results indicated that both CB and CHS had an identical inhibitory effect on ADP induced platelet aggregation in patients with cardiovascular diseases. Moreover their efficiency showed no overall significant difference in the case of dual antiplatelet therapy with aspirin as well. However there might be an inter- and intraindividual variability between the two clopidogrel formulas. 相似文献16.
Napoleone E Cutrone A Cugino D Amore C Di Santo A Iacoviello L de Gaetano G Donati MB Lorenzet R 《Thrombosis research》2012,129(6):736-742
Introduction
The renin-angiotensin system (RAS) promotes angiogenesis and growth of neoplastic cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer. Tissue factor (TF), for its involvement in tumor growth, angiogenesis, and metastasis is considered a hallmark of cancer progression.In this study we evaluated whether RAS blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB-231 cell line.Materials and Methods
Cell TF activity was assessed by one stage clotting time, TF and VEGF antigens and mRNA levels by ELISA and RT-PCR, respectively. AT1 was detected by flow-cytometry and angiotensin-II levels by EIA.Results
Captopril reduced in a concentration-dependent way both the strong constitutive TF activity (983.2 ± 55.2 vs. 686.7 ± 135.1 U/5 × 105 cells with 10 μg/ml captopril) and antigen (32.3 ± 5.9 vs. 13.2 ± 6.6 ng/ml) in MDA-MB-231. Similar results were observed with enalapril.AT1 was present on cell membrane and losartan, a competitive inhibitor of AT1, reduced TF expression to a degree similar as that exerted by ACE inhibitors. Moreover, captopril and losartan downregulated the constitutive mRNA TF expression by ~ 35%. Similar results were observed with anti-AT1 and angiotensin II antibodies. In addition, the constitutive VEGF antigen and mRNA levels were reduced in the presence of captopril or losartan, and an anti-VEGF antibody downregulated cell TF activity by ~ 40%.Conclusions
These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control. 相似文献17.
Emmerechts J Vanassche T Loyen S Van Linthout I Cludts K Kauskot A Long C Jacquemin M Hoylaerts MF Verhamme P 《Thrombosis research》2012,129(4):514-519
Introduction
Partial inhibition of Factor VIII (FVIII) may provide antithrombotic efficacy whilst avoiding excessive anticoagulation.Materials and Methods
We studied the anticoagulant effects of a partial (TB-402) and a complete (BO2C11) FVIII-inhibiting monoclonal antibody (MAb) on FVIII, aPTT, thrombin generation and fibrin deposition in a flow chamber model. The antithrombotic efficacy of TB-402 and BO2C11 was compared in a mouse model of venous thrombosis.Results
Both in vitro and ex vivo, the maximally achievable FVIII inhibition by TB-402 was about 25 to 30%. The degree of inhibition reached a plateau in vitro at 0.316 μg/mL and ex vivo after administering 0.1 mg/kg and higher doses. BO2C11 strongly inhibited FVIII:C, up to 91% at 100 μg/mL in vitro, and by 88% ex vivo 1 hour after administering 1 mg/kg to the mice.Whereas BO2C11 also markedly prolonged the aPTT and completely inhibited thrombin generation in vitro and ex vivo, the effect of TB-402 on the aPTT and on thrombin generation was limited. Similarly, in a dynamic flow chamber model, TB-402 and BO2C11 inhibited tissue factor-induced human fibrin deposition by 40% and 76%, respectively.In a mouse model of FeCl3-induced venous thrombosis, TB-402 (1 mg/kg) inhibited thrombus formation to the same extent as BO2C11 (2 mg/kg) and enoxaparin (5 mg/kg), with a mean (± SD) occlusion time of 51 ± 13 minutes for TB-402, compared to 28 ± 6 minutes for the controls, 51 ± 13 minutes for BO2C11 and 55 ± 11 minutes for enoxaparin.Conclusions
In this mouse model of venular thrombosis, partial FVIII inhibition yielded similar antithrombotic effects as nearly complete FVIII inhibition. These preclinical data are indicative of a therapeutic potential of partial FVIII inhibition in the management of venous thromboembolism. 相似文献18.
Ruth F. Santos-Galduróz Orlando F.A. BuenoLilian I. Yamaga Fernanda ArmaniJosé Carlos F. Galduróz 《Clinical neurophysiology》2012,123(1):117-120
Objective
Since blood viscosity (BV) is one of the most important factors determining blood flow, this study aimed to investigate the possible correlation between increased blood viscosity and reduction of regional cerebral blood flow (rCBF) in healthy ageing.Methods
Male subjects were distributed in two groups: “young”, aged 20-30 (27 volunteers), or “elderly”, aged 60-70 (50 volunteers). Whole blood viscosity was obtained with a Wells-Brookfield Cone/Plate Viscometer. Cerebral blood flow was analysed by means of single photon emission computed tomography (SPECT).Results
The mean BV values were 3.28 ± 0.43 mPa in the group of young volunteers and 4.33 ± 0.73 mPa in the group of elderly volunteers (t = −6.9, p < 0.0001). The elderly had a lower blood flow than the young in the following regions: bilateral parietal; temporal-parietal and temporal of the left hemisphere. Pearson’s correlation between BV and rCBF showed a good inverse correlation when the BV was above 3.95 ± 0.83 mPa.Conclusions
Our results point to a close relationship between the two parameters analysed, BV and rCBF. The impairment in rCBF observed in the elderly volunteers might be due to an increase in BV, among other factors.Significance
These findings suggest interesting possibilities for the treatment/prevention of brain ageing. 相似文献19.
20.