Significant Reduction In Platelet Aggregation Research Articles

The role of Sphingomyelin synthase 2 (SMS2) in platelet activation and its clinical significance

BackgroundSphingomyelin (SM) is an essential component of biological lipid rafts, and it plays an indispensable role in maintaining plasma membrane stability and in mediating signal transduction. The ultimate biosynthesis of SM is catalyzed by two sphingomyelin synthases (SMSs) namely SMS1 and SMS2, which are selectively distributed in the trans-Golgi apparatus and the plasma membrane. It has been demonstrated that SMS2 acts as an irreplaceable molecule in the regulation of transmembrane signaling, and loss of SMS2 has been reported to worsen atherosclerosis and liver steatosis. However, the function of SMS2 in platelet activation and its association with the pathological process of thrombosis in acute coronary syndrome (ACS) and portal hypertension (PH) remain unclear.MethodsIn this study, we tested the role of SMS2 in platelet activation and thrombosis using SMS2 knockout (SMS2 –/–) mice and SMS2-specific inhibitor, D609. Furthermore, we detected SMS2 expression in patients with ACS and PH.ResultsSMS2 –/– platelets showed significant reduction in platelet aggregation, spreading, clot retraction and in vivo thrombosis. Similar inhibitory effects on platelet activation were detected in D609-treated wild-type platelets. PLCγ/PI3K/Akt signaling pathway was inhibited in SMS2 –/– platelets and D609-treated wild-type platelets. In addition, we discovered that platelet SMS2 expression was remarkably increased in patients with ACS and PH, compared with healthy subjects.ConclusionsOur study indicates that SMS2 acts as a positive regulator of platelet activation and thrombosis, and provides a theoretical basis for the potential use of D609 in anti-thrombosis treatment.

The effect of warfarin administration on platelet aggregation.

The aim of this study was to assess the effect of anticoagulation treatment on platelet aggregation. The study group consisted of 24 patients on long-term warfarin therapy without any antiaggregation therapy. Platelet aggregation was measured using VerifyNow with arachidonic acid (AA) as an inducer in 23 patients and with light transmission aggregometry (LTA) in 19 patients using four different agonists. All patients had their international normalized ratio (INR) checked regularly. The mean INR value was 2.07 (SD 0.6). The average aggregation measured by VerifyNow was found to be 637.5 (SD 36.6) aspirin reaction units. The values of average aggregability in LTA were 73.3 % (SD 4.5 %), 73.2 % (SD6 %) and 72.1 % (SD 4.8 %) in case of aggregation induced by AA, ADP, and collagen, respectively. Epinephrine‑induced aggregability was 65.3 % (SD 14.7 %). Regression analysis between INR and values of collagen- or epinephrine‑induced aggregability (r = 0.654 and 0.575) was found statistically significant (p = 0.004 and 0.016); every increase in INR by 0,1 brings about an increase in collagen- and epinephrine‑induced aggregation values by 1.5 and 4, respectively. Administration of warfarin does not produce a significant reduction in platelet aggregation. On the contrary, prolonged INR evokes a mild increase in aggregation induced by collagen or epinephrine (Tab. 2, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: platelet aggregation, anticoagulation, warfarin, platelet function tests, chronic ischemic heart disease.

ANTIPLATELET ADEQUACY OF CYCLOPENTYL TRIAZOLOPYRIMIDINE VERSUS CLOPIDOGREL IN-PATIENTS WITH CORONARY HEART DISEASE

Objective: Ticagrelor, cyclopentyl triazolopyrimidine drug, and Clopidogrel, second-generation thienopyridine drug are antiplatelet drugs indicated for the prevention of thrombotic events in patients with acute or chronic coronary syndromes. The aim of this study is to assess efficacy and safety outcomes of ticagrelor treatment versus Clopidogrel treatment in patients with stable coronary artery disease (stable angina) using maximal platelet aggregation percent (MPAP) method and platelet reactivity index percent (PRIP) method.Methods: A total of 42 patients (27 male and 15 female), their ages ranging (48±8) years with stable angina enrolled from Ibn Albitar Center for Cardiac Surgery for this crossover study. After satisfying, the properties of inclusion criteria they screened for clopidogrel treatment 75 mg daily for 2 weeks than after 2 weeks periods of wash off they treated with ticagrelor 90 mg twice daily for another 2 weeks. Platelet reactivity was tested at baseline (before treatment), after 2 weeks treatment with clopidogrel and after another 2 weeks treatment with ticagrelor. Platelet reactivity measured by light transmittance aggregometry test and by vasodilator-stimulated phosphoprotein (VASP) phosphorylation test.Results: The results of MPAP after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (30±6% vs. 44±8%). As well, the results of PRIP using VASP-phosphorylation after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (22±5% vs. 36±7%).Conclusion: Treatment with ticagrelor produced a reduction in platelet reactivity consistent with the reduction in major adverse cardiovascular events and improved survival without increasing major bleeding.

The absorption of aspirin is reduced after coronary artery bypass grafting

BackgroundDespite treatment with the antiplatelet drug aspirin, some patients who undergo coronary artery bypass grafting (CABG) experience a thromboembolic event in the early postoperative period. The etiology of a reduced aspirin effect after CABG is still unsolved. Hence, we investigated whether patients who undergo CABG have a reduced absorption of aspirin after surgery, measured as levels of plasma salicylic acid (SA). MethodsIn total, 53 patients were included between October 2015 and May 2018. Blood samples where obtained at the day before surgery, and at the first (day 1) and second (day 2) postoperative day. A subgroup of 10 patients had additional blood samples obtained on day 1. Plasma SA was measured using liquid chromatography-electrospray-ionization tandem-mass spectrometry. Multiplate Analyzer (Roche, Roche Diagnostics, Mannheim, Germany) and VerifyNow Aspirin Test (Accumetrics, San Diego, Calif) were used to assess platelet aggregation as a measurement of the antiplatelet effect of aspirin. ResultsA comparison of the difference in change of SA concentration between the day before surgery with day 1 and day 2 showed a significantly reduced increase in SA plasma levels after intake of aspirin at day 1 and day 2 after surgery (P < .0001), including a significantly reduced SA increase in the subgroup at 2, 3, and 4 hours after intake of aspirin. Corresponding with a reduced effect of aspirin, neither Multiplate Analyzer arachidonic acid, nor VerifyNow Aspirin Test showed a significant reduction in platelet aggregation 1 hour after intake of aspirin at day 1 (P < .0001). This also accounted for the subgroup 2, 3, and 4 hours after aspirin intake on day 1. At day 2 the same pattern as preoperatively was detected. ConclusionsAfter CABG, the SA level and the effect of aspirin were reduced in the immediate postoperative period.

Dabigatran affects thrombin-dependent platelet aggregation after a week-long therapy

Objective. Dabigatran is a direct thrombin inhibitor. As the main adverse event is bleeding, it is relevant whether dabigatran has additional effects on platelet function. If so, it could affect the bleeding risk. We aimed to assess in vitro aggregation in patients with atrial fibrillation (AF) receiving dabigatran. Design. We evaluated 32 AF patients treated with dabigatran (study group) and 18 non-anticoagulated non-AF blood donors (control group). We assessed light transmittance platelet aggregation (LTA) with 100 nmol/L γ-thrombin in both groups. The LTA was performed at two time-points in our dabigatran group of patients. Results. The thrombin-induced platelet aggregation was significantly lower two hours after dabigatran was taken compared to baseline measurement (9% ± 6% vs. 29% ± 21%) in our study group. Moreover, we observed that the baseline value of platelet aggregation in patients on dabigatran treatment was significantly lower compared to healthy volunteers (29% ± 21% vs. 89 ± 8). However, one subanalysis showed that this significant reduction in platelet aggregation at baseline was only observed in patients who received dabigatran for over a week. Conclusion. The thrombin-induced platelet aggregation is reduced in non-valvular AF patients receiving dabigatran after a week-long therapy.

Deletion of mPGES-1 affects platelet functions in mice.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) constitutes an essential player in inflammation and is involved in the pathogenesis of rheumatoid arthritis. Platelets participate in the regulation of inflammatory processes by the release of proinflammatory mediators and platelet-derived microparticles (PMPs). However, the role of the inducible mPGES-1/PGE2 pathway in platelet functions has not been investigated. In the present study we report a significant impact of mPGES-1 on platelet functions during inflammation. Wild-type (WT) and mPGES-1-/- knockout (KO) mice were stimulated with lipopolysaccharide (LPS) for 24h. Platelet counts and activation were assessed by flow cytometry analysing CD62P-CD154 expression, PMP numbers, platelet-leukocyte aggregates and platelet aggregation. The accumulation of platelets and fibrinogen in the liver was analysed by immunofluorescent staining. In native platelets from WT and mPGES-1 KO mice, there were no differences among the investigated functions. After LPS treatment, the number of platelets was significantly decreased in WT, but not in KO mice. Platelet activation, platelet-leukocyte aggregates and PMP numbers were all significantly lower in KO mice compared with WT mice after LPS treatment. In addition, KO mice displayed a significant reduction in platelet aggregation ex vivo In the liver of LPS-stimulated WT and KO mice, there were no differences in platelet accumulation, although the percentage of total vessel area in the KO liver was significantly lower compared with the WT one. Our results demonstrate that systemic inhibition of mPGES-1 prevents platelet activation, which should have important implications with regard to the cardiovascular safety of mPGES-1 inhibitors.

Inhibition of Platelet Aggregation by the Leaf Extract of Carica papaya During Dengue Infection: An In Vitro Study.

Dengue cases were reported to undergo platelet activation and thrombocytopenia by a poorly understood mechanism. Recent studies suggested that Carica papaya leaf extract could recover the platelet count in dengue cases. However, no studies have attempted to unravel the mechanism of the plant extract in platelet recovery. Since there are no available drugs to treat dengue and considering the significance of C. papaya in dengue treatment, the current study aimed to evaluate two research questions: First one is to study if the C. papaya leaf extract exerts its action directly on platelets and second one is to understand if the extract can specifically inhibit the platelet aggregation during dengue viral infection. Sixty subjects with dengue positive and 60 healthy subjects were recruited in the study. Platelet-rich plasma (PRP) and platelet-poor plasma were prepared from both the dengue-infected and healthy control blood samples. Effect of the leaf extract obtained from C. papaya leaves was assessed on plasma obtained as well as platelets collected from both healthy and dengue-infected individuals. Platelet aggregation was significantly reduced when leaf extract preincubated with dengue plasma was added into control PRP, whereas no change in aggregation when leaf extract incubated-control plasma was added into control PRP. Upon direct addition of C. papaya leaf extract, both dengue PRP and control PRP showed a significant reduction in platelet aggregation. Within the dengue group, PRP from severe and nonsevere cases showed a significant decrease in aggregation without any difference between them. From the study, it is evident that C. papaya leaf extract can directly act on platelet. The present study, the first of its kind, found that the leaf extract possesses a dengue-specific neutralizing effect on dengue viral-infected plasma that may exert a protective role on platelets.

Hydroxychloroquine's Efficacy as an Antiplatelet Agent Study in Healthy Volunteers: A Proof of Concept Study.

With the inflammatory model of atherosclerosis taking center stage, anti-inflammatory drugs hold a promising place in the therapy of cardiovascular disease (CVD). Recent studies showed that hydroxychloroquine (HCQ) was protective against thrombovascular events in lupus erythematosus and traditional cardiovascular risk factors in patients with rheumatoid arthritis. Some preliminary experimental data have shown that it may prevent platelet activation too. To evaluate the antiplatelet activity of HCQ when given alone and in combination with aspirin (ASA) and compare it with ASA alone and ASA plus clopidogrel (CLOP) in healthy human volunteers. In part 1 of the study, 8 volunteers were given HCQ for 7 days. In part 2, 12 volunteers were randomly assigned in a 1:1:1 ratio to the 3 groups in which 2 of the 3 treatments, ASA, ASA plus CLOP, and ASA plus HCQ, were given in the 2 treatment periods separated by a 14-day washout period using the incomplete block design. Inhibition of platelet aggregation (IPA) was measured by light transmission aggregometry. When arachidonic acid (AA) was used as agonist, HCQ given alone showed a significant reduction in platelet aggregation (11.0% ± 4.2%, P = .03). The IPA was significantly increased when ASA plus HCQ was compared with ASA alone (31.2% ± 8.1%, P = .002). This synergistic effect was not seen with adenosine diphosphate and collagen as agonists. Levels of serum 11-dehydrothromboxane B2, a stable marker of thromboxane A2 production, were not significantly different between the groups. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values when HCQ was used alone or in combination with ASA. This study suggests that HCQ has antiplatelet properties possibly through the AA pathway (downstream to thromboxane A2 production). With possible additional beneficial effects over the traditional CVD risk factors, larger studies in the future might explore HCQ's potential as an antiplatelet agent.

In vitro effects of the glycoprotein IIb/IIIa receptor antagonists abciximab and eptifibatide on platelet aggregation in healthy cats

To determine effects of the glycoprotein IIb/IIIa receptor antagonists abciximab and eptifibatide on in vitro inhibition of cat platelets. Venous blood samples from 10 healthy cats. Blood samples were anticoagulated with hirudin. Aliquots of whole blood from each cat were allocated to 5 treatments (baseline, 50 μg of abciximab/mL, abciximab volumetric control treatment, 4 μM eptifibatide, and eptifibatide volumetric control treatment). Impedance platelet aggregometry was performed with 6.5 μM ADP or 32 μM thrombin receptor activator peptide (TRAP). Magnitude of platelet aggregation was determined by measuring the area under the curve 15 minutes after addition of ADP or TRAP. Eptifibatide caused a significant reduction in platelet aggregation, compared with baseline values, for aggregometry with both ADP (median, 50.0; range, 8 to 122 [baseline median, 306.0; baseline range, 130 to 664]) and TRAP (median, 75.5; range, 3 to 148 [baseline median, 219.0; baseline range, 97 to 578]). There was no significant difference in platelet aggregation with abciximab, the abciximab volumetric control treatment, or the eptifibatide volumetric control treatment for aggregometry with ADP or TRAP. Eptifibatide caused a significant reduction in platelet aggregation in vitro, but there was no identifiable antiplatelet effect for abciximab. Eptifibatide and abciximab have different binding and inhibitory actions; therefore, it can be hypothesized that abciximab would be ineffective in cats because of a lack of receptor binding, reduced binding kinetics, or lack of downstream signaling. Eptifibatide may be useful in identifying hyperreactive platelets in cats in an in vitro platelet inhibitory assay.

Dose response of surfactants to attenuate gas embolism related platelet aggregation

Intravascular gas embolism promotes blood clot formation, cellular activation, and adhesion events, particularly with platelets. Populating the interface with surfactants is a chemical-based intervention to reduce injury from gas embolism. We studied platelet activation and platelet aggregation, prominent adverse responses to blood contact with bubbles. We examined dose–response relationships for two chemically distinct surfactants to attenuate the rise in platelet function stimulated by exposure to microbubbles. Significant reduction in platelet aggregation and platelet activation occurred with increasing concentration of the surfactants, indicating presence of a saturable system. A population balance model for platelet aggregation in the presence of embolism bubbles and surfactants was developed. Monte Carlo simulations for platelet aggregation were performed. Results agree qualitatively with experimental findings. Surfactant dose-dependent reductions in platelet activation and aggregation indicate inhibition of the gas/liquid interface’s ability to stimulate cellular activation mechanically.

Blockade of platelet alpha2B-adrenergic receptors in patients with coronary artery disease: a novel antiaggregant mechanism

Purpose: Platelets play a vital role in hemostasis and thrombosis. Catecholamines have a profound effect on platelet aggregation and atherothrombosis but the exact mechanism involved is insufficiently understood. In this report, we demonstrate the existence and role of alpha2B–adrenergic receptors (α2B–ARs) in platelets from patients with Coronary Artery Disease (CAD) compared to normal individuals. Methods: Sixteen healthy individuals and 7 patients with CAD who were under dual antiplatelet therapy with clopidogrel 75mg and acetylsalicylic acid 100mg were included. Blood samples were obtained from which platelets were isolated. The presence of α2B-ARs in platelets was proven by Western blot analysis and real time PCR. In order to investigate their function, we performed light transmittance aggregometry by examining the inhibitory effects of specific α2B-AR antibodies. Results: Pretreatment of human platelets with agents that selectively block α2B-ARs showed a substantial inhibition in platelet aggregation that had been induced by adenosine diphosphate (ADP), by epinephrine and by arachidonic acid. The percent aggregation decreased from 81.5±1.7% to 35.8±5% for ADP with α2B-Abs, from 72.2±1.9% to 25.5±4.3% for epinephrine with α2B-Abs, and from 87±2.1% to 47.9±6.2% for arachidonic acid with α2B-Abs, p<0.05 for all. Patients with CAD showed a significantly reduced expression of the receptor in the platelets (149.6±100.8 in normals versus 32.1±17.7, p = 0.015). Notably, pretreatment with α2B –Abs resulted in a significant further reduction of platelet aggregation. The ADP-treated plasma showed a significant reduction in platelet aggregation after pre-treatment with α2B-Abs (42±5.8% for the control group versus 31.7±2.2% for the group with α2B-Abs pretreatment, p< 0.001). When arachidonic acid was used to induce aggregation, pre-treatment with α2B -Abs reduced platelet aggregation from 41.2±7.3% to 28.2±7.5%, p= 0.006). Similarly, the presence of α2B-Abs decreased platelet aggregation induced by epinephrine from 44.4±22.1% to 19.1±7.2% (p = 0.01). Conclusions: Our results reveal that contrary to previous knowledge, the α2B–AR subtype does exist in platelets and is an important regulator of aggregation. Inhibition of α2B-ARs in platelets may offer a novel therapeutic opportunity in the prevention of atherothrombotic events. Interestingly, even in patients with coronary artery disease who were receiving dual antiplatelet therapy with aspirin and clopidogrel, the inhibition of α2B-ARs had an additional antiaggregant effect.

Cardiovascular protective effects of nebivolol in Zucker diabetic fatty rats

Although effective in reducing blood pressure, therapy with a first-generation [beta]-blocker is currently controversial in metabolic syndrome due to its negative impact on carbohydrate and lipid metabolism. We evaluated the effects of nebivolol, a third-generation highly selective [beta]-blocker with additional vasodilating activity, versus the traditional [beta]-blocker atenolol in controlling functional and morphological cardiovascular damage in a rat model of metabolic syndrome. During 6 months, Zucker diabetic fatty (ZDF) rats and control lean Zucker rats (LZR) were studied. The experimental groups were: untreated ZDF, ZDF along with nebivolol, ZDF along with atenolol and LZR. Blood pressure, plasma insulin, triglycerides, cholesterol, glucose and platelet aggregation were evaluated. Malondialdehyde, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, CuZn superoxide dismutase, catalase and glutathione peroxidase were determined in heart homogenates and transforming growth factor [beta]1 and plasminogen activator inhibitor-1 (PAI-1) expression, by immunohistochemistry (IHC). Vascular reactivity, vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule-1, PAI-1, enhanced nitric oxide synthase and collagen expression were evaluated in aorta. Nebivolol and atenolol presented a similar reduction in blood pressure. However, nebivolol showed a better lipid profile, preserved left ventricular function, a significant control in left ventricular geometry and moderated left ventricular hypertrophy versus atenolol. Significant reduction in platelet aggregation and a substantial endothelium-dependent and endothelium-independent relaxation in vessels were also shown in the nebivolol group versus atenolol group. Antioxidant defenses were preserved by nebivolol with a reduction in oxidative stress parameters. Vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule-1, PAI-1 and eNOS were favorably modulated with nebivolol in vessel wall. TGF[beta]1, PAI-1 and accumulation of collagen-III and collagen-I were also diminished in heart with nebivolol. The present study provides substantial information supporting an actual protective role of nebivolol in comparison with atenolol in experimental metabolic syndrome.

L-4F Alters Hyperlipidemic (But Not Healthy) Mouse Plasma to Reduce Platelet Aggregation

Background and Purpose- Hyperlipidemia is associated with platelet hyperreactivity. We hypothesized that L-4F, an apolipoprotein A-I mimetic peptide, would inhibit platelet aggregation in hyperlipidemic mice. Injecting L-4F into apolipoprotein E (apoE)-null and low-density lipoprotein receptor-null mice resulted in a significant reduction in platelet aggregation in response to agonists; however, there was no reduction in platelet aggregation after injection of L-4F into wild-type (WT) mice. Consistent with these results, injection of L-4F into apoE-null mice prolonged bleeding time; the same result was not found in WT mice. Incubating L-4F in vitro with apoE-null platelet-rich plasma also resulted in decreased platelet aggregation. However, incubating washed platelets from either apoE-null or WT mice with L-4F did not alter aggregation. Compared with WT mice, unstimulated platelets from apoE-null mice contained significantly more 12-hydroxy 5,8,10,14-eicosatetraenoic acid, thromboxane A(2), and prostaglandins D(2) and E(2). In response to agonists, platelets from L-4F-treated apoE-null mice formed significantly less thromboxane A(2), prostaglandins D(2) and E(2), and 12-hydroxy 5,8,10,14-eicosatetraenoic acid. By binding plasma-oxidized lipids that cause platelet hyperreactivity in hyperlipidemic mice, L-4F decreases platelet aggregation.

A randomised study comparing the antiplatelet and antinflammatory effect of clopidogrel 150 mg/day versus 75 mg/day in patients with ST-segment elevation acute myocardial infarction and poor responsiveness to clopidogrel: Results from the DOUBLE study

Introduction The antiplatelet effect of standard or increased clopidogrel doses in patients with ST- segment elevation acute myocardial infarction (STEMI) has never been studied. In this study we compared the antiplatelet effect of a 75 mg daily maintenance dose of clopidogrel with 150 mg in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Materials and methods Fifty-four patients with STEMI undergoing PCI were randomly allocated to receive either 75 mg/day clopidogrel (group 1) or 150 mg/day (group 2) for 1 month. Platelet function, measured by 5 different assays, was determined at 3 time points: 38 ± 8 hours after the procedure, 1 week and 1 month after randomization. Results In group 1, mean ± SD platelet reactivity index (PRI) measured with the VASP assay was 57.7 ± 15.7% and 46.9 ± 15.7% at 1 week and 1 month, respectively, compared to 38.8 ± 15.7% and 34.9 ± 12.6% in group 2 (p = 0.0001). Same results were observed for light transmittance aggregometry, whole blood aggregometry and VerifyNow, but not for thromboelastometry. In contrast to what may be expected, the 75 mg daily maintenance dose took longer than 1-week to provide the full clopidogrel antiplatelet effect. Furthermore, patients in group 2 had a nearly 50% reduction in C-reactive protein levels both at 1 week and 1 month. Conclusion In patients with STEMI and poor responsiveness to clopidogrel a 150 mg daily maintenance dose of clopidogrel is associated with a significant reduction of platelet aggregation and a trend towards reduced inflammation.

Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine

At the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. Since its approval in 1999, Vioxx, a selective cyclooxygenase-2 (COX-2) inhibitor, has been Merck & Co’s leading drug for control of acute pain and chronic pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year, worldwide sales of rofecoxib reached US $2.5 billion, and it is estimated that the drug was prescribed ≈10 million times per month in the United States.1 Thus, given the number of patients involved and the serious nature of the side effects, the withdrawal raised serious concerns about the safety of other selective COX-2 inhibitors, collectively called coxibs, that are on the market and those currently under development. Celecoxib (Celebrex) and rofecoxib were the first 2 coxibs approved by the US Food and Drug Administration (FDA) and launched in 1999 by Pfizer and Merck & Co, respectively. Since then, a second generation of these drugs has emerged onto the market. Valdecoxib (Bextra) was approved by the FDA and launched in 2002. In that same year, the European regulatory authority approved 2 other coxibs: etoricoxib (Arcoxia) and parecoxib sodium (Dynastat), the prodrug of valdecoxib. Today, etoricoxib and a fifth coxib, lumiracoxib (Prexige), are under consideration for FDA approval. In view of the rapid development in this area, the main concern is whether the reported cardiovascular effects of rofecoxib are a class effect applicable to all coxibs that were initially designed to reduce the gastric toxicity of nonselective COX inhibitors. Although most of the data accumulated so far would suggest a class effect related to the general mode of action of all coxibs and the physiological role of COX-2, recent in vitro data would theoretically support the hypothesis that the cardiovascular side …

Effect of Manidipine as Compared to Atenolol on Platelet Aggregation in Elderly Patients with Isolated Systolic Hypertension and Type II Diabetes Mellitus

This study was done to evaluate the effect of treatment with manidipine as compared with atenolol on thrombin-mediated platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. After a 2-week washout placebo period, 60 elderly patients (aged 65-80 years) with isolated systolic hypertension (SBP > 140 mm Hg and DBP < 90 mm Hg) were randomly assigned to manidipine 10 mg or atenolol 50 mg 6-week treatment according to a double-blind, crossover design. Thirty patients had a concomitant well-controlled type 2 diabetes mellitus (HbA1c < or = 6.5%). At the end of the washout and of each treatment period, blood pressure (BP) (by mercury sphygmomanometer) and platelet aggregation (by Born-type aggregometer) were evaluated. Blood samples were collected using sodium citrate as anticoagulant, and platelet aggregation was induced by 2 different concentrations of ADP and collagen. Manidipine and atenolol produced a significant BP reduction in both diabetic and nondiabetic patients, with no difference between treatments. Despite the similar BP effect, in diabetic patients manidipine produced a significant reduction in platelet aggregation induced by both doses of either ADP or collagen. In nondiabetic hypertensives, manidipine inhibited platelet aggregation only at the highest doses of both inducers. The difference in the platelet inhibitory effect of manidipine between diabetic and nondiabetic subjects was statistically significant (P < 0.05) at both inducer concentrations. No changes in platelet aggregation were observed in the atenolol group. These data indicate that, unlike atenolol, manidipine inhibits platelet aggregation in elderly hypertensive patients, expecially in those with associated type II diabetes mellitus. The clinical impact of this positive effect in terms of prevention of cardiovascular complications in these high-risk patients remains to be clarified.

Inhibition of platelet aggregation by nitric oxide donors improves with rest

It has been suggested that the platelets of patients with acute coronary syndromes (ACS) exist in a more activated state than those of patients with stable coronary heart disease (CHD) or healthy individuals. “Platelet nitrate responsiveness” (PNR) has been suggested as a measure of platelet activation, and has been shown to be reduced in both ACS and stable CHD. We examined the effect of a short period of undisturbed supine rest, an intervention aimed at reducing levels of “stress”, on PNR. In 8 healthy subjects we found that 45 minutes of rest led to a highly significant reduction in platelet aggregation and increase in PNR. Our finding supports the hypothesis that stress contributes to platelet activation as reflected in reduced PNR, which may contribute to the link between acute stress and cardiovascular events. It also emphasises that standardisation of sampling conditions in vitally important in studies utilizing PNR.

The Effect of Plasma Depletion of Platelet Concentrates on Platelet Aggregation and Phosphatidylserine Expression

Plasma-reduced platelet concentrates are commonly administered to prevent febrile transfusion reactions and to avoid fluid overload in neonates. Because little is known about the influence of centrifugation and resuspension on functional aspects of platelets, we examined the effects of plasma-reduction on platelet aggregation and platelet-dependent thrombin generation. Our results show that plasma reduction and resuspension of the platelet pellet in saline or plasma results in a significant reduction in platelet aggregation to a combination of the platelet agonists adenosine diphosphate and epinephrine (p < 0.001). In contrast, when a combination of the more potent agonists collagen and thrombin was used, platelet aggregation was maintained. Likewise, no decline was observed in platelet-dependent thrombin generation as measured by the functional prothrombinase assay or Annexin V binding. We conclude that centrifugation and resuspension of platelets to render the concentrate plasma-free, as a routine procedure in blood banking, variably affects in vitro platelet aggregability but does not significantly affect platelet-dependent thrombin generation.

Effects of alcohol ingestion post-exercise on platelet aggregation

The present study examined the influence of ingesting a moderate dose of alcohol on platelet count and platelet aggregation during recovery following exercise. Nineteen subjects (11 male and 8 female) were studied immediately after a standardised cycle ergometer test and during the 24-h period of recovery. In random order, alcohol (0.7 g/kg body mass) was given 1 h after exercise on one test occasion, while an equal volume of alcohol-free solution was administered on the other. Venous blood samples were obtained at baseline, post-exercise, and at 1, 5, and 22 h post-alcohol ingestion. Blood alcohol level increased significantly 1 h after the ingestion of alcohol, but decreased and returned to the resting baseline level at 5 h during recovery. Males and females subjects exhibited similar mean values of platelet count, platelet aggregation, and beta-thromboglobulin concentration at rest and following exercise and recovery. A significant increase in platelet count and a decrease in platelet aggregation using adenosine diphosphate (ADP) was found following exercise. Although plasma beta-thromboglobulin level (pooled data for males and females) showed an increase by 26.0% (from a mean pre-exercise value of 22.3–28.1 IU/ml), this rise was not significant ( P>.05). The post-exercise increase in platelet count was mainly due to exercise-induced plasma volume loss. During recovery, while the increase in platelet count post-exercise returned to the baseline level in control and alcohol trials, the optical density of platelet aggregation remained significantly depressed at 5-h during recovery in the alcohol trial but not in the normal control condition. It is concluded that exercise induces significant reduction in platelet aggregation and the consumption of alcohol after physical exercise delays the normal return of platelet aggregation to the resting baseline levels during recovery.

Platelet damage caused by the centrifugal pump: laser-light scattering analysis of aggregation patterns.

Platelets are damaged by shear force during centrifugal pumping; however, the mechanism of this damage has not been fully investigated. A new laser-light scattering (LS) assay method enables quantification of real-time changes in the number of platelet aggregates of different sizes. Using this method, we assessed the kinetics of platelet damage caused by the centrifugal pump from the standpoint of platelet aggregation capacity. Conventional optical density (OD) and LS methods were used to measure platelet aggregation with a Kowa AG-10 aggregometer. Platelet aggregation in fresh human blood was evaluated in a mock circuit for 3 h under a flow rate of 5.0 L/min and a pressure head of 100 mm Hg. Test samples were obtained before pumping for control, and at 1, 2, and 3 h after the start of pumping. The test series was begun 8 times. Aggregation after stimulation by 2.0 microg/ml collagen was determined; small (9 to 25 microm), medium (25 to 50 microm), and large (50 to 70 microm) aggregates were counted by the LS method. OD measurement at hourly intervals showed significant reduction in platelet aggregation. The LS method showed that generation of small and medium aggregates was not suppressed during pumping, but that generation of large aggregates was significantly reduced at 2 and 3 h of pumping. Platelet aggregation is significantly suppressed during centrifugal pumping, and the resulting platelet dysfunction is due mainly to inhibited development of small aggregates into larger aggregates.