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PubMedDate not supplied

The lack of correlation between experimental metastatic potential and platelet aggregating activity of B16 melanoma clones viewed in relation to tumor cell heterogeneity.

Two widely used B16 melanoma cell lines of low and high lung colonizing potential (B16-F1 and B16-F10) were compared in their ability to induce platelet aggregation. The results of these experiments showed a reproducible difference in platelet aggregating activity of these two cell lines which directly correlated with their lung colonizing potentials. However, when clones were derived from these heterogeneous cell lines and tested for experimental metastatic potential, platelet aggregating ability and Met-72 expression, no correlation could be attached to the platelet aggregating activity of the clones. Results of these experiments provide direct evidence that platelet aggregation is not an accurate index of experimental metastatic potential of tumor cell clones, nor is it an essential trait of all metastatic cells. The ability of tumor cells to induce platelet aggregation is examined and discussed in the context of cellular heterogeneity.

Animals↗
PubMed1987

Impaired platelet aggregation and thromboxane generation in essential fatty acid-deficient rats.

ADP-induced platelet aggregation and thrombin-induced thromboxane B2 generation in diluted whole blood from rats fed a fat-free diet supplemented with 10% (by weight) hydrogenated coconut oil [essential fatty acid (EFA) deficient] were significantly lower than that in animals fed 10% safflower oil [(SFO) rich in linoleic acid] or 10% marine oil (rich in eicosapentaenoic acid and docosahexaenoic acid). Plasma fibrinogen levels were significantly lower and liver function was impaired in the EFA-deficient group compared with the other two groups. Platelet responsiveness to ADP was restored when plasma from the EFA-deficient rats was replaced by plasma obtained from rats fed a nonpurified diet. ADP responsiveness and thrombin-stimulated thromboxane B2 production in diluted whole blood were also restored after 2 wk of injections of 100 mg ethyl linoleate every 48 h, and partially restored by injections of 100 mg ethyl alpha-linolenate. When ADP-induced platelet aggregation was examined in washed platelets, the impaired ADP aggregation (found when platelets of the EFA-deficient rats were suspended in their own plasma) was not observed at either high (9.5 microM) or low (1.0 microM) ADP concentrations. Although thrombin-stimulated thromboxane B2 production in washed platelets in the EFA-deficient rats was lower than that in the SFO-fed rats, the magnitude of aggregation was not different. In addition, inhibition of thrombin-induced platelet aggregation by apyrase (0.06 U/mL) was identical in the two groups. These results suggest that impaired platelet aggregation in EFA deficiency is related more to plasma factors than to inherent platelet properties and that restoration of normal liver function is associated with normal platelet function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1984

[Inhibition of platelet aggregation and cyclic nucleotide phosphodiesterase (specifically cyclAMP) by 3-hydroxypyridine derivatives].

The effects of 3-hydroxypyridine (3-HP) derivatives on platelet aggregation and platelet phosphodiesterase (PDE) of cyclic nucleotides (cAMP-dependent) were studied. It was shown that some derivatives of 3-HP inhibit platelet aggregation (the most pronounced effect was exerted by 2-benzyl-3- oxypyridine ). Several derivatives o 3-HP given in a concentration 10(-3) M were discovered to inhibit PDE by 40 to 75%. No correlation was found between the efficacy of 3-HP as antiaggregation agents and PDE inhibitors.

1-Methyl-3-isobutylxanthine↗
PubMed1986

[Dynamics of the level of acylhydroperoxides and platelet aggregation in chronic ischemic heart disease and essential hypertension during treatment].

Platelet aggregation has been found to be increased in chronic coronary disease of any type, whereas the acylhydroperoxide level was only increased in anginal patients. Conventional therapy normalizes platelet aggregation in patients with angina or angina plus essential hypertension, yet it has no effect on acylhydroperoxides. In essential hypertension, platelet aggregation and acylhydroperoxides increase near the time of discharge.

Adult↗
PubMed1986

Inhibition of platelet aggregation in whole blood by dipyridamole and aspirin.

We have examined the effects of dipyridamole on platelet aggregation in whole blood both in vitro and after administration to man. The effects of dipyridamole ex vivo were compared with those of aspirin and a combination of dipyridamole and aspirin. In vitro dipyridamole was most effective as an inhibitor of platelet aggregation induced by platelet activating factor (PAF) and low concentrations of arachidonic acid (AA). Its inhibitory effect was always potentiated by adenosine suggesting that its effect on aggregation may be via inhibition of adenosine uptake into blood cells. Ex vivo, dipyridamole, aspirin and the combination of these drugs inhibited the platelet aggregation induced by PAF and AA. Again, adenosine increased the degree of inhibition. These results stress the importance of measuring platelet aggregation in the natural whole blood environment for detection of the inhibitory effects of dipyridamole and suggest a mode of action for the drug.

Aspirin↗
PubMed2006

Pump-induced platelet aggregation with subsequent hypotension: Its mechanism and prevention with clopidogrel.

OBJECTIVES: Use of extracorporeal circuits in cardiopulmonary bypass and hemodialysis often causes bleeding problems and hypotension. As shown previously, this might be caused by activation of blood platelets due to pumping. The present study investigates the mechanism of pump-induced platelet aggregation and its possible prevention. METHODS AND RESULTS: Continuous measurement of platelet aggregation in an extracorporeal shunt from a carotid to a femoral artery in rats showed that aggregation during the first 10 minutes of pumping was not reduced by coating the tube with albumin or heparin nor by using dalteparin instead of unfractionated heparin as anticoagulant. Also, pump characteristics seemed unimportant because aggregation could already be elicited by single tube compression with one pump roller. It was calculated that during compression wall shear stress in the tube rises far beyond the values known to induce platelet aggregation, occurring also in clinically used roller pumps. A crucial role for adenosine diphosphate was demonstrated by blockade of platelet adenosine diphosphate-P2Y12 receptors with the clinically used drug clopidogrel (50 mg/kg intravenously, n = 8). This prevented platelet aggregation and the fall of systemic blood pressure (to 71% +/- 12% in controls, n = 6) during 2 hours of continuous pumping. CONCLUSION: We conclude that pump-induced platelet aggregation is not caused by factors released from the tube or its coating but is initiated by short bouts of high shear stress, and its continuation is critically dependent on adenosine diphosphate. The latter might have clinical relevance for patients connected to extracorporeal systems.

Adenosine Diphosphate↗
PubMed1998

The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel.

Recently we showed that the P2Y1 receptor coupled to calcium mobilization is necessary to initiate ADP-induced human platelet aggregation. Since the thienopyridine compound clopidogrel specifically inhibits ADP-induced platelet aggregation, it was of interest to determine whether the P2Y1 receptor was the target of this drug. Therefore we studied the effects of clopidogrel and of the two specific P2Y1 antagonists A2P5P and A3P5P on ADP-induced platelet events in rats. Although clopidogrel treatment (50 mg/kg) greatly reduced platelet aggregation in response to ADP as compared to untreated platelets, some residual aggregation was still detectable. In contrast, A2P5P and A3P5P totally abolished ADP-induced shape change and aggregation in platelets from both control and clopidogrel-treated rats. A2P5P and A3P5P (100 microM) totally inhibited the [Ca2+]i rise induced by ADP (0.1 microM) in control and clopidogrel-treated platelets, whereas clopidogrel treatment had no effect. Conversely, the inhibition of adenylyl cyclase induced by ADP (5 microM) was completely blocked by clopidogrel but not modified by A2P5P or A3P5P (100 microM). A3P5P (1 mM) reduced the number of [33P]2MeSADP binding sites on control rat platelets from 907 +/- 50 to 611 +/- 25 per platelet. After clopidogrel treatment, binding of [33P]2MeSADP decreased to 505 +/- 68 sites per platelet and further decreased to 55 +/- 12 sites in the presence of A3P5P (1 mM). In summary, these results demonstrate that the platelet P2Y1 receptor responsible for the initiation of aggregation in response to ADP is not the target of clopidogrel. Platelets may express another, as yet unidentified, P2Y receptor, specifically coupled to the inhibition of adenylyl cyclase and necessary to induce full platelet aggregation, which could be the target of this drug.

Adenosine Diphosphate↗
PubMed1988

Platelet aggregation and thromboxane A2 release in primary biliary cirrhosis and effect of D-penicillamine treatment.

Platelet function was assessed in 28 patients with primary biliary cirrhosis (PBC), of whom 10 were receiving D-penicillamine. Patients not on D-penicillamine treatment had platelet aggregation similar to that in the healthy control group; the group treated with D-penicillamine showed significantly enhanced platelet aggregation in response to threshold doses of adrenaline and collagen but not ADP. Median thromboxane B2 production was also higher in D-penicillamine treated patients than in controls or untreated patients; this difference did not reach statistical significance. The addition of D-penicillamine in vitro to platelet rich plasma from normal subjects was shown to enhance adrenaline- and collagen-induced platelet aggregation. Abnormalities of platelet function in PBC patients did not correlate with serum cholesterol concentration or with liver function tests but were related to the stage of disease. The present study emphasises the need to consider the aetiology, disease stage and type of treatment when assessing platelet function and prostanoid release in liver disease.

Aged↗
PubMed2006

Effect of combined administration of clopidogrel and lysine acetylsalicylate versus clopidogrel and aspirin on platelet aggregation and activated GPIIb/IIIa expression in healthy volunteers.

Platelet activation contributes to thrombotic events in cardiovascular disease. Acetylsalicylic acid (ASA) is used in combination with clopidogrel to reduce cardiovascular events. Lysine acetylsalicylate (L-ASA), also inhibits platelet activation with fewer gastrointestinal side effects than ASA. Dual therapy with L-ASA and clopidogrel may result in an antiplatelet effect with fewer side effects. We compared the antiplatelet effect of combined ASA/clopidogrel versus L-ASA/clopidogrel in healthy subjects. Fourteen volunteers (seven men and seven women, aged 25-45 years) received antiplatelet therapy during 14-day periods in the following sequence: 75 mg ASA; 160 mg L-ASA; 75 mg clopidogrel; 160 mg L-ASA plus 75 mg clopidogrel, and 75 mg ASA plus 75 mg clopidogrel. We evaluated platelet aggregation and glycoprotein IIb/IIIa activation. Our results show that administration of L-ASA/clopidogrel is as effective as ASA/clopidogrel combination.

Adult↗
PubMed1991

Streptokinase-induced platelet aggregation. Prevalence and mechanism.

BACKGROUND: Streptokinase (SK) is a bacteria-derived protein and one of the plasminogen activators that is currently available for therapeutic use. Exposure to SK induces synthesis of specific antibodies that may initiate platelet aggregation and paradoxical clot propagation during treatment. METHODS AND RESULTS: Using platelet-rich plasma (PRP), we found that SK (5,000 units/ml) but not urokinase (2,500 units/ml) or recombinant tissue-type plasminogen activator (2,500 units/ml) caused platelet aggregation in PRP from 14 of 100 normal volunteers. In 13 consecutive patients treated with SK for acute myocardial infarction, SK-mediated platelet aggregation was induced in five patients within 1 week after treatment. SK-mediated platelet aggregation was associated with significantly increased titers of both anti-SK antibodies and SK-neutralizing activity in plasma; it was partially inhibited by aspirin (1 mM) and by aprotinin (500 kallikrein inhibitor units/ml) and completely inhibited by tranexamic acid (1 mM) and by prostaglandin E1 (9 microM). Addition of SK (1,000 or 5,000 units/ml) induce a statistically significant dose-dependent thromboxane B2 release in mixtures of PRP with plasma from subjects with SK-induced aggregation but not in samples of PRP mixed with plasma from nonresponders; addition of recombinant tissue-type plasminogen activator (1 or 50 micrograms/ml) did not induce thromboxane B2 release. Mixing experiments with PRP and immunoglobulin G from reactive and nonreactive donors revealed that SK-induced aggregation requires the presence of anti-SK antibodies. When 125I-SK (50 nM) was used, platelets preincubated with plasminogen (0.5 microM) bound 9,500 +/- 600 (mean +/- SEM, n = 6) molecules SK/platelet, which increased to 25,000 +/- 3,100 molecules/platelet after thrombin stimulation. Tranexamic acid (1 mM) blocked specific binding of SK to resting platelets. CONCLUSIONS: These data demonstrate that SK-induced platelet aggregation is initiated by the binding of anti-SK antibodies to the SK-plasminogen complex located on the platelet surface. SK-induced platelet activation may limit the therapeutic effectiveness of the drug, and in view of the high prevalence of aggregation in a normal population, prospective evaluation of the effects of platelet aggregation during treatment with SK is warranted.

Adult↗
PubMed1986

Effects of iloprost, a stable prostacyclin analog, on exercise capacity and platelet aggregation in stable angina pectoris.

The effects of iloprost, a chemically stable compound with prostacyclin mimetic activity, on exercise capacity and platelet aggregation were assessed in 24 patients with effort angina and proved critical (at least 70% diameter narrowing) coronary artery disease. Upright bicycle ergometer testing (25-W increments every 2 minutes) was performed during drug and placebo infusions using a crossover, randomized, single-blind protocol. Samples for measurements of adenosine diphosphate-induced platelet aggregation in platelet-rich plasma were obtained in all patients before and during the study. Compared with placebo, intravenous iloprost consistently (p less than 0.001) prolonged exercise duration and time to onset of significant (0.1 mV) ST depression. Angina and ST depression occurred at a greater heart rate and rate-pressure product. Benefits were remarkable in some patients (67%) and not in others. Iloprost administration resulted in reduced platelet aggregation at peak exercise in all patients, whether they had consistent or little response to the drug. Thus, iloprost administration may improve exercise capacity in patients with stable exertional angina pectoris. Improvements are independent of changes in the major determinants of myocardial oxygen demand and associated with markedly reduced platelet aggregation, which may account for increased myocardial perfusion in patients with high sensitivity to coronary constriction.

Angina Pectoris↗
PubMed1987

Effects of a small dose of ethanol and calcium carbimide-induced acetaldehyde intoxication on human platelet aggregation, associated thromboxane formation and urinary excretion of 2,3-dinor-6-keto prostaglandin F1 alpha.

We studied ADP-induced platelet aggregation, associated thromboxane B2 (TXB2) formation, urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1 alpha (2,3-dinor-6-keto PGF1 alpha) and formation of malondialdehyde in 10 healthy volunteers after ingestion of a small dose of ethanol (0.25 g per kg of body weight) and calcium carbimide (50 mg). Platelet aggregation in platelet-rich plasma (PRP) was suppressed (p less than 0.05) by ethanol, but no change occurred in platelet TXB2 formation. Ingestion of calcium carbimide caused significant elevations in blood acetaldehyde (p less than 0.001) and ethanol (p less than 0.05) levels, but acetaldehyde did not influence platelet aggregability or the aggregation-associated TXB2 formation. However, calcium carbimide per se significantly (p less than 0.05) elevated TXB2 formation. No effects were found on plasma malondialdehyde levels and urinary excretion of 2,3-dinor-6-keto PGF1 alpha. These observations indicate that a small dose of ethanol attenuates platelet aggregation without any significant effect on aggregation-associated TXB2 formation. By contrast, ingestion of calcium carbimide per se may enhance TXB2 formation.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Effect of dienogest on bleeding time, coagulation, fibrinolysis, and platelet aggregation in female rats.

We investigated the effect of dienogest on bleeding time, coagulation, fibrinolysis, and platelet aggregation in female rats compared with that of medroxyprogesterone acetate (MPA) and danazol, in order to elucidate the reason for relatively high incidence of bleeding in dienogest-treated patients with endometriosis. Dienogest caused no change in the bleeding time at a single dose of 100 mg/kg or at a repeated dose of 10 mg/kg per day for 2 weeks. The drug increased the fibrinogen level, coagulation factor II and V activities, and antithrombin III activity, but had no effect on fibrinolysis or on platelet aggregation at repeated doses of 1 and 10 mg/kg per day for 4 weeks. MPA significantly shortened the bleeding time at the same doses as dienogest. MPA increased the fibrinogen level and plasminogen activity, potentiated the platelet aggregation, and increased the platelet cholesterol-to-phospholipid ratio at a repeated dose of 10 mg/kg per day for 4 weeks. Danazol significantly shortened the bleeding time like MPA. Danazol increased the fibrinogen level, coagulation factor II, V, VII, VIII, IX, X, XI, and XII activities, and antithrombin III activity, but had no influence on the platelet aggregation at repeated doses of 10 and 100 mg/kg per day for 4 weeks. In comparison with MPA and danazol, dienogest may induce a relatively high incidence of bleeding in patients with endometriosis partially because of its minimal effect on hemostasis.

Animals↗
PubMed2005

Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers.

OBJECTIVES: We investigated whether and how soon smoking cessation ameliorates the smoking-induced intracellular oxidative stress and platelet aggregability in long-term smokers. BACKGROUND: Smoking is a major risk factor of atherothrombosis. Smoking cessation reduces cardiac events. However, the underlying mechanisms of the beneficial effects remain to be elucidated. METHODS: Twenty-seven male long-term smokers were divided into two groups. Group A (n = 14) quit smoking for four weeks whereas group B (n = 13) resumed smoking two weeks after quitting. Smoking status was monitored by measurement of urinary cotinine. Using gel-filtered platelets, agonist (adenosine diphosphate and collagen)-induced platelet aggregation, platelet-derived nitric oxide (PDNO), intraplatelet nitrotyrosine production, intraplatelet levels of the reduced form of glutathione (GSH) and its oxidized form (GSSG), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), as markers of systemic oxidative stress, were measured. The baseline measurements were similar between the two groups. RESULTS: Smoking cessation quickly reduced agonist-induced platelet aggregations, intraplatelet nitrotyrosine level, and urinary productions of 8-OHdG and 8-iso-PGF(2alpha) by two weeks in both groups. In group A, they were maintained at the low levels until four weeks, whereas they were reversed by resmoking in group B; PDNO release and intraplatelet GSH/GSSG ratio were time-dependently increased by smoking cessation but reversed by resmoking. CONCLUSIONS: The present findings are the first demonstration that only two weeks of smoking cessation can ameliorate the enhanced platelet aggregability and intraplatelet redox imbalance in long-term smokers, possibly by decreasing oxidative stress. Our findings may strengthen the motivation for smokers to quit smoking.

Adult↗
PubMed1993

Inhibition of integrin-mediated platelet aggregation, fibrinogen-binding, and interactions with extracellular matrix by nonpeptidic mimetics of Arg-Gly-Asp.

The interaction of the activated platelet integrin, glycoprotein IIb-IIIa (GPIIb-IIIa) with fibrinogen and von-Willebrand factor (vWF) is essential for platelet aggregation. The minimal structure required for this integrin's binding to fibrinogen is the Arg-Gly-Asp (RGD) sequence. Inasmuch as normal level of GPIIb-IIIa-RGD interactions are required for maintaining hemostasis, elevated platelet aggregation can cause adverse pathological effects. We have previously reported that nonpeptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear 11-atom spacer, acquired a significant affinity for the GPIIb-IIIa integrin and inhibited platelet aggregation. The structural requirements for the interactions of the RGD sequence with GPIIb-IIIa and the inhibitory potential of a newly designed series of mimetics on platelet aggregation and interactions with extracellular matrix (ECM) were assayed herein. Adenosine-diphosphate (ADP)-induced platelet aggregation was inhibited in a dose-dependent manner by various RGD mimetics, with a maximal inhibition of 80-100% with an IC50 of 3 microM for the most potent inhibitor, NS-11, in which a six-membered ring was introduced into the spacer chain, which exceeded the IC50 attained with the original RGDS peptide. The inhibitory effect of the RGD mimetics was attributed to their specific interaction with the GPIIb-IIIa integrin, since these mimetics inhibited the binding of the PAC-1 mAb to GPIIb-IIIA. Furthermore, the binding of 125I-labeled fibrinogen to platelets was inhibited by the RGD surrogates in a dose-dependent and saturable manner. The RGD-mimetics also inhibited up to 70% the adhesion, aggregation, and deposition of platelets onto ECM.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

Heterogeneity of endothelium-dependent and endothelium-independent responses to aggregating platelets in porcine pulmonary arteries.

Experiments were designed to determine the endothelium-dependent and endothelium-independent responses to aggregating platelets in porcine pulmonary arteries. Isolated rings with and without endothelium from large (5-7-mm-diameter) and small (2-3-mm-diameter) pulmonary arteries were suspended in modified Krebs-Ringer bicarbonate solution bubbled with 95% O2-5% CO2 in the presence of indomethacin. Aggregating platelets caused relaxations in rings with endothelium but contractions in rings without endothelium, both of which were significantly larger in small versus large pulmonary artery rings. Serotonin and ADP caused concentration-dependent endothelium-augmented relaxations that were unaffected by ketanserin. Methiothepin, but not apyrase, significantly decreased the platelet-induced endothelium-dependent relaxations; the residual relaxation was abolished when rings were incubated with methiothepin, apyrase, and theophylline but was unaffected if apyrase was absent, indicating that ADP is responsible for the residual relaxation caused by aggregating platelets. Quiescent rings, with and without endothelium, contracted in a dose-dependent manner to norepinephrine and histamine but not to serotonin or vasopressin. The contraction to aggregating platelets was blocked by methiothepin, pyrilamine, and diphenhydramine but was unaffected by phentolamine, ketanserin, or incubation of the platelets with dazoxiben. These data indicate that, in large and small porcine pulmonary arteries, serotonin and ADP are the major contributors to the endothelium-dependent relaxation caused by aggregating platelets, while histamine appears to be responsible for the contraction that platelets cause in rings without endothelium.

Adenosine Diphosphate↗
PubMed1994

Whole-blood platelet aggregation, buccal mucosa bleeding time, and serum cephalothin concentration in dogs receiving a presurgical antibiotic protocol.

Whole-blood platelet aggregation (using the impedance method) and adenosine triphosphate (ATP) release, buccal mucosal bleeding time (BT), and serum cephalothin concentration were measured in 21 adult female Beagles before (PRE) and 1 hour (1 HR) after IV administration of cephalothin (22 mg/kg). A second injection of cephalothin (22 mg/kg) was given 3 hours after the first, and blood samples were obtained 1 hour (4 HR, 4 hours after the first injection) and 3 hours (6 HR, 6 hours after the first injection) after the second injection. Samples of jugular blood were obtained from each dog, using citrate as an anticoagulant. A platelet count was obtained for each sample. Platelet aggregation and ATP released from the aggregating platelets were measured within 1 hour of sample collection, using a whole-blood aggregometer. Adenosine diphosphate (ADP) and collagen were used as aggregating agents. Aggregation was measured over 6 minutes for each aggregating agent; ATP release in response to collagen, but not to ADP, was measured over the same period. For 1 HR samples, there was a significant (P < 0.01) reduction from PRE values in the ability of platelets to aggregate in response to ADP. Bleeding time was determined, using a published procedure, with each dog as its own control. Bleeding time during the same period was found to be significantly increased over PRE values for 1 HR (P < 0.01) and 6 HR (P < 0.02) samples. There was no significant difference between BT for 1 HR and 4 HR samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1997

Anti-platelet aggregation activity of some pyrazines.

This report describes the anti-platelet aggregation activity of 48 pyrazines. Among alkyl- and arylpyrazines tested, 2,3-diphenylpyrazines showed the strongest anti-platelet aggregation activity. Then, various substituents were introduced into the phenyl groups, and the 2,3-bis(p-methoxyphenyl)pyrazine derivatives were consequently found to possess considerably strong inhibitory activity.

Animals↗