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PubMed1985

A comparative study of the effects of adrenoceptor antagonists on platelet aggregation and thromboxane generation.

Platelet aggregation and thromboxane A2 have been implicated in the pathogenesis of several forms of vascular disease. The aim of this study was to determine the effect of a wide range of adrenoceptor antagonists on platelet aggregation, and thromboxane A2 production, from normal human platelet rich plasma in vitro. Labetalol, pindolol and propranolol inhibited platelet aggregation to collagen in a dose dependent manner. Increasing the concentration of collagen "shifted" the dose response curve to the right. These 3 drugs also significantly inhibited thromboxane A2 generation in response to collagen but not to arachidonic acid. This effect was independent of any inhibitory effect of these drugs on platelet aggregation, and occurred at a drug concentration close to that obtained in vivo. Atenolol, metoprolol, prazosin and timolol were similarly assessed but had no effect on either platelet aggregation or thromboxane A2 generation. This ability of labetalol, pindolol, and propranolol to inhibit platelet aggregation and thromboxane generation, may be of clinical benefit in view of the increasing evidence implicating thromboxane A2 in the pathogenesis of vascular disease.

Adrenergic beta-Antagonists↗
PubMed1989

Trifenagrel: a chemically novel platelet aggregation inhibitor.

Trifenagrel.HCl (trifenagrel) (2-[2-(2-dimethylaminoethoxy) phenyl]-4,5-diphenylimidazole monohydrochloride) is a chemically novel, potent inhibitor (IC50 = 0.3-3.0 microM) of arachidonate (AA)- and collagen-induced aggregation of platelets from several animal species and humans. When trifenagrel was administered p.o. to guinea pigs, there was a sustained (greater than 3 hr) inhibition of AA- and collagen-induced platelet aggregation ex vivo (1 hr ED50 = 1.4 and 9.4 mg/kg, respectively). In humans, trifenagrel inhibited the second phase of ADP-induced aggregation ex vivo up to 6 hr after a single dose of 100 to 300 mg p.o. The mechanism of action of trifenagrel appears to be a reversible inhibition of platelet AA cyclooxygenase. Doses of trifenagrel up to 100 mg/kg p.o. in rats and guinea pigs inhibited gastric mucosal AA cyclooxygenase but did not produce the gastric damage associated with the administration of other cyclooxygenase inhibitors such as aspirin and indomethacin. To our knowledge this is the first report of a compound which inhibits gastric mucosal prostaglandin levels but causes little or no gastrointestinal (g.i.) irritation in rodents. Although trifenagrel caused g.i. irritation in dogs and humans, the nature of the damage suggests that the compound may have acted as a local irritant in these species. Furthermore, compared to aspirin trifenagrel produced significantly less gastric irritation and fecal blood loss in humans. The physiochemical properties of trifenagrel may be important for the lack of g.i. irritation in rodents and for the diminished damage relative to aspirin in humans.

Animals↗
PubMed2000

Increased rate of formation of small-sized platelet aggregates in patients with acute coronary syndromes.

Coronary thrombosis has been implicated in the pathogenesis of acute coronary syndromes, and platelet activation plays a pivotal role in the pathogenesis of coronary thrombus. A new platelet aggregometer using a laserlight scattering beam was trialled for assessment of platelet aggregation. Platelet aggregability, especially small-sized platelet aggregates, was investigated on admission using the laser-light scattering method and again after treatment in 23 patients with acute coronary syndromes. The platelet aggregability in 14 patients with stable exertional angina and in 14 control subjects was also examined. On admission, the number of small- and medium-sized platelet aggregates in the acute coronary syndromes group was significantly greater than in the stable exertional angina group or control group. However, the number of large-sized platelet aggregates on admission was not increased in the acute coronary syndromes group. Furthermore, the number of small- and medium-sized platelet aggregates decreased significantly after treatment in the acute coronary syndromes group. The increased number of small-sized platelet aggregates may sensitively reflect attacks of thrombosis in patients suffering acute coronary syndromes.

Acute Disease↗
PubMed1990

Intralipid infusion in patients with familial hypercholesterolemia. Effect of serum and plasma lipoproteins on platelet aggregation and on macrophage cholesterol metabolism.

Intralipid infusion into normal volunteers was recently shown to possess anti-atherogenic properties. We studied the effect of intralipid infusion in patients with severe Familial Hypercholesterolemia (FH) refractory to conventional therapy. FH patients and normal subjects, who served as controls, were given an intravenous infusion of intralipid for 6 h. Serum samples taken from both groups before, during and after intralipid infusion were studied for their ability to inhibit cellular cholesterol accumulation by macrophages. A significantly lower rate of cellular cholesterol esterification (of 46%, P less than 0.005 and 44%, P less than 0.005 in patients and normals, respectively) was demonstrated in macrophages incubated with serum obtained during intralipid infusion compared to those incubated with preinfusion serum. The maximal effect was demonstrated with serum samples taken at the end of the infusion, but the inhibitory effect persisted even at 24 h post-infusion. It was found that chylomicron like particles could induce the above-mentioned effects on macrophage cholesterol esterification. A significant decrement of 50% (P less than 0.005) in aggregation of platelets isolated from plasma samples taken during and after intralipid infusion from both groups was demonstrated, when compared to platelets isolated in the preinfusion state. This effect persisted 18 h subsequent to infusion. We conclude that intralipid infusion abolishes serum ability to stimulate cholesterol esterification in cultured macrophages, and exhibits inhibitory effects upon platelet aggregation. If similar events occur in the arterial wall, intralipid might inhibit foam cell formation.

Adolescent↗
PubMed1994

Chylomicron-induced prothrombin activation and platelet aggregation.

The effects on platelet aggregation of native rat chyle chylomicrons, chylomicron remnants, and chylomicrons that had been preincubated with rat or human EDTA-plasma, serum, whole blood, or pure human prothrombin were examined. The native chyle chylomicrons did not induce platelet aggregation but decreased ADP- and thrombin-induced platelet aggregation and [14C]serotonin release. Chylomicron remnants also failed to induce platelet aggregation, but they potentiated the aggregation and the [14C]serotonin release induced by ADP and thrombin. Aggregation, after a lag phase of 15 to 20 minutes, was seen when platelets were incubated with chylomicrons that had been preincubated with plasma and then isolated as the top layer after a single centrifugation at d = 1.006. This aggregation was inhibited in a dose-dependent manner by an antiserum against prothrombin that also inhibited thrombin-induced platelet aggregation. After washing by centrifugation the plasma-preincubated chylomicrons did not induce platelet aggregation, but this effect could be restored by adding a small amount of prothrombin, which did not cause aggregation when added alone or together with native chyle chylomicrons. Addition of 2% (vol/vol) plasma, however, induced aggregation when added together with either native chyle chylomicrons or washed preincubated chylomicrons, but not when added alone. Binding of 125I-labeled prothrombin to native chyle chylomicrons was demonstrated by gradient ultracentrifugation. During incubation of washed plasma-preincubated chylomicrons with 125I-prothrombin and platelets, a significant conversion of 125I-prothrombin to 125I-prethrombin and 125I-thrombin occurred, as demonstrated by autoradiography after separation on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The interaction between chylomicrons and prothrombin, and possibly other coagulation proteins, thus enhances prothrombin activation in the presence of platelets.

Animals↗
PubMed2002

Morphine-potentiated agonist-induced platelet aggregation through alpha2-adrenoceptors in human platelets.

Morphine dose-dependently (0.6, 1, and 5 microM) potentiated platelet aggregation and ATP release stimulated by agonists (i.e., collagen and U46619) in washed human platelets. Furthermore, morphine (1 and 5 microM) markedly potentiated collagen (1 microg/ml) evoked an increase of intracellular Ca2+ mobilization in fura 2-AM loading human platelets. Morphine (1 and 5 microM) did not influence the binding of fluorescein isothiocyanate-triflavin to platelet glycoprotein IIb/IIIa complex. Yohimbine (0.1 microM), a specific alpha2-adrenoceptor antagonist, markedly abolished the potentiation of morphine in platelet aggregation stimulated by collagen. Moreover, morphine (0.6-5 microM) markedly inhibited prostaglandin E1 (10 microM)-induced cAMP formation in human platelets, and yohimbine (0.1 microM) significantly reversed the inhibition of cAMP by morphine (0.6 and 1 microM) in this study. Morphine (1 and 5 microM) significantly potentiated thromboxane B2 formation stimulated by collagen in human platelets, and yohimbine also reversed this effect of morphine in this study. In addition, morphine (1 and 5 microM) did not significantly affect nitrate production in human platelets. Morphine may exert its potentiation in platelet aggregation by binding to alpha2-adrenoceptors in human platelets, which leads to reduced cAMP formation and subsequently to increased intracellular Ca2+ mobilization; this, in turn, is followed by increased thromboxane A formation and finally potentiates platelet aggregation and ATP release.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1976

Antagonism of 5-hydroxykynurenamine against serotonin action on platelet aggregation.

Serotonin induced an aggregation of human platelets, whereas 5-hydroxykynurenamine, produced from serotonin by the action of indoleamine 2,3-dioxygenase, did not cause any significant degree of platelet aggregation. 5-Hydroxykynurenamine specifically inhibited both a serotonin-induced aggregation of platelets and the potentiation of the ADP-induced platelet aggregation by serotonin. It did not, however, alter the profiles of the platelet aggregation induced by ADP, collagen, or adrenaline. The degree of inhibition was proportional to the time of preincubation of platelets with 5-hydroxykynurenamine, and to the concentration of 5-hydroxykynurenamine used. Available evidence indicated that 5-hydroxykynurenamine completed with serotonin for the same receptor sites. Studies with analogues of 5-hydroxykynurenamine indicated that the substitutions of 0-amino-benzyl moiety with hydroxy or methoxy groups were somewhat tolerated, whereas the masking of alkylamine moiety with N-acetylation completely lost the inhibitory activity.

Adenosine Diphosphate↗
PubMed2003

Differential effect of the GPIIb/IIIa antagonist orbofiban on human platelet aggregate formation in vitro.

Platelet microaggregates have been demonstrated in the systemic circulation of patients with atherosclerotic cardiovascular diseases. Glycoprotein IIb/IIIa antagonists have been reported to play roles in platelet activation, which may be associated with pro-thrombotic events. We report the effect of the orally active GPIIb/IIIa antagonist, orbofiban, on human platelet microaggregate formation in vitro. Laser light scatter (LSS) technology was used to monitor small, medium and large platelet aggregates formed in platelet-rich plasma in response to ADP or thrombin receptor activating peptide (TRAP)-6. ADP at 0.5 microM induced only small platelet aggregates that were prevented by orbofiban in a concentration-dependent manner. Likewise, orbofiban dissolved small aggregates after their formation. In marked contrast, in the presence of strong agonist stimulation (20 microM ADP or 3 microM TRAP-6) which generated primarily large platelet aggregates, orbofiban blocked the large aggregates while significantly augmenting small aggregates by three- to sixfold. The data suggest that GPIIb/IIIa antagonists do not induce platelet microaggregation directly but may augment small platelet microaggregate formation indirectly at conditions of strong stimuli. The percentage of the microaggregate population expressing P-selectin remained the same in the presence of orbofiban, indicating that these small microaggregates remain activated, although the mean intensity of expression was diminished, possibly reflecting the reduced size of the particles or density of P-selectin molecules. In summary, an increase in small platelet microaggregates might have contributed to pro-thrombotic events in orbofiban-treated patients.

Adenosine Diphosphate↗
PubMed1997

Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets.

AIMS: High plasma cholesterol concentration and increased platelet activity are two major risk factors for atherosclerosis. Lovastatin, the lipophilic drug was shown to inhibit platelet aggregation whereas pravastatin, the hydrophilic drug had no such effect. Analysis of the effect of fluvastatin which is both a lipophilic and hydrophilic drug, on platelet aggregation was the goal of the present study. METHODS: Fluvastatin 40 mg daily was administered to 25 patients with hypercholesterolaemia for up to 24 weeks. Normal subjects acted as controls. The influence of fluvastatin on plasma lipids and on platelet aggregation and fluidity was studied. The direct effect of fluvastatin on platelets was compared with that of other statins. RESULTS: Fluvastatin therapy (40 mg day (-1) for a period of 4 weeks) in hypercholesterolaemic patients resulted in a 23% and 29% reduction in plasma levels of total cholesterol and LDL-cholesterol respectively. Platelet cholesterol/phospholipids molar ratio was reduced by 26% and platelet aggregation was significantly (P<0.02) reduced by 10% after 4 weeks of fluvastatin treatment. On continuing fluvastatin therapy for additional 20 weeks, no further decrement in plasma LDL cholesterol levels or in platelet cholesterol/phospholipid ratio were noted. However, platelet aggregation was further significantly (P<0.01) reduced by up to 15%. Incubation of platelets with increasing concentrations of fluvastatin or lovastatin, demonstrated a dose-dependent reduction in platelet aggregation, whereas pravastatin showed no effect. This inhibitory effect of fluvastatin or lovastatin on platelet aggregation (up to 34% or 22% respectively at a concentration of 1 microg statin ml (-1) was found both in platelet rich plasma and in washed platelet suspensions. Fluvastatin and lovastatin (but not pravastatin), seem to share similar platelet binding sites, as non labelled fluvastatin or lovastatin were able to displace [3H]-labeled-fluvastatin from its binding sites on platelets. CONCLUSIONS: Fluvastatin therapy reduces platelet aggregation via a dual effect which involves its in vivo hypocholesterolaemic action on platelet cholesterol content, and also a direct effect of the drug binding to the platelets. The antiatherogenicity of fluvastatin may be related, in addition to its plasma cholesterol lowering ability, to its inhibitory effect on platelet activation.

Adult↗
PubMed1987

The ultrasonic detection of platelet aggregates.

The echogenicity of platelet aggregates in platelet-rich plasma and whole blood was evaluated in stirring and flowing in vitro models. Real-time two dimensional ultrasonic images were obtained with transducers operating at 3.0, 5.0, 10 and 12 mHz. Platelet-rich plasma was not echogenic. The addition of adenosine diphosphate (ADP) resulted in the formation of multiple, discrete echoes that increased in size and intensity. This echogenicity was time and dose-dependent and could be quantitated by videodensitometry. Whole blood was echogenic, but the addition of ADP resulted in a time and dose-dependent increase in the size and echogenicity of the reflections. The overall echogenicity of whole blood declined with the development of platelet aggregates. There is inter- and intra-aggregate variability in the echogenicity of aggregates. Aggregates were best seen with transducers operating at the higher frequencies. These results imply that the detection of in vivo platelet aggregates may be feasible with ultrasonic imaging.

Adenosine Diphosphate↗
PubMed1981

Platelet aggregation induced by arachidonic acid and thromboxane generation in patients with hypertension or cerebrovascular disease.

The aggregability of platelets to arachidonic acid (AA) was investigated in 26 control subjects, 40 patients with essential hypertension, 20 patients with ischemic cerebrovascular diseases (CVD) not taking aspirin and 11 patients with CVD taking aspirin. The aggregability of platelets was evaluated on the basis of threshold concentrations of AA to induce irreversible platelet aggregation. The enhanced sensitivity of platelets to AA was observed more frequently in hypertensives and/or CVD patients not taking aspirin than in the controls. The relationship between platelet aggregation induced by AA and thromboxane B2 (TXB2) formation from AA or prostaglandin H2 (PGH2) in platelets was also studied in the subjects taking or not taking aspirin. It was proposed that the assessment of platelet aggregability with AA could provide a tool for identifying a subgroup of patients who might substantially benefit from the secondary preventive treatment with aspirin or other anti-platelet drugs. The clinical usefulness of this aggregation test for the management of the patients taking aspirin was also discussed.

Adolescent↗
PubMed1978

Purification and properties of porcine platelet aggregating factor.

Porcine platelet aggregating factor was purified from porcine plasma by a rapid batch procedure which included polyethylene glycol precipitation and adsorption on calcium citrate. The aggregating factor was separated from antihemophilic factor by gel chromatography in the presence of 1 M MgCl2. It appeared homogenous when examined by immuno- or SDS-gel electrophoresis. The molecular weight was estimated to be 10 million by exclusion chromatography. After reduction, subunit molecular weight, by sodium dodecyl sulfate (SDS)-gel electrophoresis, was 225 000. Amino acid and carbohydrate composition were similar to those reported for the bovine material. The porcine platelet aggregating factor was found to have no free sulfhydryl groups or exposed disulfide bonds. Binding of formalin-fixed washed human platelets to the aggregating factor linked to Sepharose was inhibited in 0.5 M NaCl or 2.7 M urea and reversed by the presence of free aggregating factor in a concentration-dependent manner. Ristocetin had little or no discernible effect on binding.

Amino Acids↗
PubMed1984

Selective PF4 release in vitro induced by heparin and related glycosaminoglycans (GAGs)--correlation with beta-TG release and platelet aggregation.

We studied human platelet aggregation and beta-TG/PF4 release induced by heparin and related GAGs in vitro both in normal PRP and in PRP after aspirin. In our experimental conditions, heparin and related GAGs always caused PF4 release in vitro from normal platelets, whether or not there was measurable platelet aggregation in the aggregometer. Significant beta-TG release was induced only by the mucosal heparin preparation (which also induced platelet aggregation in some citrated PRP). Therefore, while beta-TG release in vitro seems to correlate with platelet aggregating activity of heparin, the selective PF4 release, caused by heparin and related GAGs also in conditions in which neither platelet aggregation nor beta-TG are measurable, is probably associated with the high affinity of PF4 for heparin. The degree of affinity of GAGs for PF4 (heparin greater than DeS greater than HS) seems to correlate with PF4 release. Moreover, the significant reduction in PF4 release in vitro after aspirin suggests that GAGs-induced PF4 release is related to a cyclooxygenase-dependent activation process.

Adenosine Diphosphate↗
PubMed1993

Inhibitory effect of staphylokinase on platelet aggregation.

We investigated the effect of staphylokinase (SAK), which has specific thrombolytic properties, on human platelet aggregation. Platelet aggregation induced with collagen was observed following preincubation of platelets in platelet-rich plasma (PRP) or washed platelet suspension (WP) with SAK at 37 degrees C for 30 min. SAK inhibited platelet aggregation in PRP only at the highest examined concentration (1 x 10(-4) g/ml). Although SAK did not inhibit platelet aggregation in WP which contained fibrinogen, it did when the platelets had been preincubated with SAK and plasminogen. The most effective concentration in WP was 1 x 10(-6) g/ml. The effect could be inhibited by adding aprotinin or alpha 2-antiplasmin. The highest generation of plasmin in the same preincubation fluid was detected at 1 x 10(-6) g/ml SAK. We concluded that SAK can inhibit platelet aggregation in WP by generating plasmin and/or fibrinogen degradation products, but is only partially effective in PRP because of the existence of alpha 2-antiplasmin.

Amino Acid Sequence↗
PubMed2004

Methanol extract of the oyster mushroom, Pleurotus florida, inhibits inflammation and platelet aggregation.

The antiinflammatory and platelet aggregation inhibiting activities of the methanol extract of Pleurotus florida Eger, an edible and commercially grown mushroom, were investigated. The extract showed significant activity in ameliorating acute inflammation induced by carrageenan and chronic inflammation by formalin at 500 and 1000 mg/kg body weight. The effect was comparable to the standard reference drug, diclofenac. The extract also showed significant platelet aggregation inhibiting activity of washed human platelets. Adenosine 5'-diphosphate (ADP) induced platelet aggregation was inhibited by 88% to 95% at a concentration of 500 microg/mL of the extract after a preincubation time of 5, 10 and 20 min. The marked antiinflammatory and platelet aggregation inhibiting properties of this mushroom suggest its potential therapeutic use against vascular disorders.

Adenosine Diphosphate↗
PubMed1983

Effects of garlic extract and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, release reaction and platelet ultrastructure.

We studied the effect of the methanol extract of garlic bulbs (EOG) and of three pure components isolated from it (F1, F2, F3), on human platelet aggregation induced by ADP, epinephrine, collagen, thrombin, arachidonate, PAF, and the ionophore A-23187. Incubation of PRP with EOG, either in methanol or in homologous PPP, inhibits platelet aggregation induced by all of the above mentioned agonists. F1, F2, and F3 also inhibit platelet aggregation, however, F3 was about four times more potent. Addition of EOG or F3 to platelets that have already been irreversibly aggregated by 10 microM ADP, induces rapid deaggregation. Inhibition of aggregation was still present after three hours. The inhibitory effect persisted even after the treated platelets were Gel-Filtered (GFP) or separated from plasma through a metrizamide gradient and resuspended in new homologous PPP. Thrombin-induced release of ATP from GFP was inhibited by 75-80% after EOG or F3 treatment. Incorporation of [3-H]-arachidonate by intact platelets was decreased by 50-60% in treated platelets. However, platelets incubated with the inhibitors after incorporation of radiolabeled arachidonate, although did not aggregate, produced, after thrombin activation similar amounts of radiolabeled TXB2 and lipoxygenase products as the controls. Electron microscopy of inhibited platelets, in the presence of thrombin, showed no degranulation but an increase of spherical forms. Our results suggest that the effects described might be mediate by a perturbation of the physicochemical properties of the plasma membrane rather than by affecting arachidonate or calcium metabolism in the cells. Chemical structures of F1, F2 and F3 have been provisionally assigned: F1 is diallytrisulfide, F2 is 2-vinyl-1,3-dithiene, and F3 is most probably allyl 1,5-hexadienyltrisulfide.

Adenosine Diphosphate↗
PubMed1992

Human platelet aggregation by Yersinia pseudotuberculosis is mediated by invasin.

Plasmid-free strains of Yersinia pseudotuberculosis induce aggregation of human platelets in vitro. It appears that this phenomenon is mediated by invasin (Inv), a 103-kDa outer membrane protein that permits bacteria to penetrate mammalian cells, since (i) an isogenic inv-deficient mutant failed to aggregate platelets compared with the parental strain; (ii) a monoclonal antibody directed against invasin inhibited platelet aggregation; (iii) Inv+ Escherichia coli HB101 promoted platelet aggregation. Platelet receptors for invasin were identified by using a panel of anti-platelet glycoprotein monoclonal antibodies in a bacterial adhesion assay. We found that bacteria bind to platelet membrane glycoproteins Ic and IIa. Electron microscopic study of bacterium-platelet interactions also revealed that bacteria expressing invasin attach to and are phagocytized by thrombocytes, in contrast to inv-deficient bacteria, indicating that these anucleated cells are able to internalize bacteria in vitro after specific interaction with invasin.

Adhesins, Bacterial↗
PubMed1996

Thrombin-induced platelet aggregation is inhibited by the heptapeptide Leu271-Ala277 of domain 3 in the heavy chain of high molecular weight kininogen.

The ability of kininogens to modulate thrombin-induced aggregation of human platelets has been assigned to domain 3 (D3) in the common heavy chain coded for by exons 7, 8, and 9 of kininogen gene. We expressed each of the exons 7, 8, and 9, and various combinations as glutathione S-transferase fusion proteins in Escherichia coli. Each of the exon products 7 (Lys236-Gln292), 9 (Val293-Gly328), and 8 (Gln329-Met357), and their combinations were evaluated for the ability to inhibit thrombin induced platelet aggregation. Only products containing exon 7 inhibited platelet aggregation induced by thrombin with an IC50 of > 20 microM. A deletion mutant of exon 7 product, polypeptide 7A product (Lys236-Lys270) did not block thrombin-induced platelet aggregation, while 7B product (Thr255-Gln292) and 7C product (Leu271-Gln292) inhibited aggregation. These findings indicated that the inhibitory activity is localized to residues Leu271-Gln292. Peptides Phe279-Ile283 and Phe281-Gln292 did not block thrombin, and Asn275-Phe279 had only minimal inhibitory activity. A heptapeptide Leu271-Ala277 inhibited thrombin-induced aggregation of platelets with an IC50 of 65 microM. The effect is specific for the activation of platelets by thrombin but not ADP or collagen. No evidence for a thrombin-kininogen complex was found, and neither HK nor its derivatives directly inhibited thrombin activity. Knowledge of the critical sequence of kininogen should allow design of compounds that can modulate thrombin activation of platelets.

Adenosine Diphosphate↗