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PubMed2006

Inhibition of rat platelet aggregation by Urtica dioica leaves extracts.

Platelet hyperactivity plays an important role in arterial thrombosis and atherosclerosis. The present study was undertaken to investigate the effects of different extracts of Urtica dioica leaves on platelet aggregation. Rat platelets were prepared and incubated in vitro with different concentrations of the tested extracts and aggregation was induced by different agonists including thrombin (0.5 U/mL), ADP (10 microm), epinephrine (100 microm) and collagen (5 mg/mL). The crude aqueous extract inhibited thrombin-induced platelet aggregation in a dose-dependent manner. At 1 mg/mL, the percent inhibition was 17.1 +/- 4.2%. Soxhlet extraction of the plant leaves with different successive solvents showed that the ethyl acetate extract exhibited the most antiaggregant effect with an inhibition of 76.8 +/- 6.1% at 1 mg/mL. Flavonoids isolated from the plant leaves, produced a strong inhibitory effect on thrombin-induced platelet aggregation with an IC(50) of 0.25 +/- 0.05 and 0.40 +/- 0.04 mg/mL for genins and heterosidic flavonoids, respectively. Flavonoids also markedly inhibited platelet aggregation induced by ADP, collagen and epinephrine. It is concluded that Urtica dioica has an antiplatelet action in which flavonoids are mainly implicated. These results support the traditional use of Urtica dioica in the treatment and/or prevention of cardiovascular disease.

Animals↗
PubMed1987

Room temperature ADP induced first stage hyperaggregation of human blood platelets: a previously undescribed phenomenon and its relationship to spontaneous cold induced platelet aggregation.

ADP induced human platelet aggregation was shown to be accentuated when tested at 20-30 degrees C as increased sensitivity and as a greater change of optical density although second stage aggregation and the release reaction did not occur. This previously undescribed phenomenon is defined as room temperature ADP induced first stage hyperaggregation. Aggregation, which occurs under the above mentioned conditions with a quantity of ADP insufficient to maintain the aggregation (usually less than 1.5 micron), is reversible when the temperature is raised to 37 degrees C. After rewarming to these temperatures, second stage aggregation appeared in the presence of larger quantities of ADP (usually more than 2 microns) and could be blocked by aspirin. The absence of the release reaction was demonstrated with a lumi-aggregometer. Spontaneous cold induced platelet aggregation seen after chilling platelets to 0-4 degrees C is shown to be a distinct phenomenon.

Adenosine Diphosphate↗
PubMed1979

Effects of time, platelet concentration, and sex on the human platelet aggregation response.

The platelet aggregation responses induced by adenosine diphosphate (ADP) and collagen were characterized by parameters defining rate and extent of reaction. Values were compared on the basis of platelet concentration, time elapsed between sample collection and test performance, and sex of donors. Rate and extent of aggregation varied as a function of platelet concentration. Maximal responses were obtained for platelet concentrations greater than 100,000/microliter. Results from samples processed after 90 min of incubation at room temperature were consistently and significantly lower than those obtained from samples processed immediately. ADP-induced aggregation responses elicited by samples from male and female normal donors differed significantly. This indicates that comparisons between normal and patient results should be made with sex-matched individuals to avoid erroneous interpretations.

Adenosine Diphosphate↗
PubMed1994

Comparative effects of the dihydropyridine-type calcium-agonists (-)-S-Bay K 8644, (+/-)-Bay-W 5035 and (+/-)-Bay-T 5006 on human platelet aggregability.

1. Human platelet aggregation induced by collagen is concentration-dependently inhibited by dihydropyridine (DHP)-type calcium(Ca)-agonists. 2. There was no significant difference between the maximal anti-aggregatory effects or the anti-aggregatory potencies of (-)-S-Bay-K 8644 (EC50: 5.3 +/- 1.5 x 10(-5) M), (+/-)-Bay-W 5035 (EC50: 14.9 +/- 8.8 x 10(-5) M) or (+/-)-Bay-T 5006 (EC50: 2.7 +/- 1.9 x 10(-5) M) (P > 0.05). 3. Antiaggregatory effects of DHP-type Ca-agonists seem to be independent of Ca-channel activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Secretory products from human monocyte-derived macrophages enhance platelet aggregation.

Both macrophages and platelets play an important role in atherogenesis. We studied the effect of conditioned medium obtained from human monocyte-derived macrophages on in vitro platelet aggregation. Incubation of macrophage-conditioned medium (MCM) with platelets resulted in enhanced platelet aggregation (up to 35% difference between basal and MCM-stimulated activity), which was time dependent. This MCM effect on platelet function was increased both with time of mononuclear cell culturing (up to 10 days) and with the time of macrophage incubation in serum-free medium (up to 24 hours) prior to MCM collection. MCM from either cholesterol-loaded macrophages or from macrophages obtained from patients with familial hypercholesterolemia demonstrated a 37% and 20% increased effect, respectively, in comparison to MCM derived from normal subjects. Macrophage activation with lipopolysaccharide resulted in the harvesting of a MCM that enhanced platelet activity 60% more than MCM obtained from nonactivated cells. The active component of MCM was inhibited fivefold following heating at 100 degrees C for 10 minutes or after treatment with trypsin or protease, but was not affected by antioxidants. MCM activation of blood platelets may be of importance in atherogenesis. Understanding the mechanisms involved may contribute to an improved appreciation of the role of both platelets and macrophages in atherosclerosis.

Animals↗
PubMed1992

[Platelet aggregations and glycoproteins].

Platelet membrane glycoproteins play important roles in platelet functions. In this symposium, we reported three types of deficiency of platelet membrane glycoproteins; Glanzmann's thrombasthenia, Bernard-Soulier syndrome, GPIV-deficiency and discussed the roles of GPIIb/IIIa, GPIb and GPIV, respectively, in the aggregation of these abnormal platelets. In a patient with Bernard-Soulier syndrome, the abnormality in the patient's GPIb was caused by the double heterozygote from her parents who were unrelated. Roles of GPIV were negligible in platelet aggregation since the GPIV-deficient platelets (Naka-) found in healthy donors showed normal platelet aggregations. We developed two monoclonal antibodies, TM83 and TM60 against GPIIIa and GPIb, respectively, and showed that these antibodies inhibited the function of GPIb and GPIIb/IIIa complex, respectively. We demonstrated that TM83 inhibited an epitope of GPIIIa and/or GPIIb/IIIa complex which changes its conformation due to Ca2+ deprivation and is essential for exposure of the fibrinogen-binding site.

Adult↗
PubMed1992

Effect of anethole dithiolthione on human platelet aggregation.

Anethole dithiolthione (ADT) (10 mumol/l) inhibited platelet aggregation and the formation of thromboxane (Tx)B2 in plasma in response to adenosine diphosphate (ADP), epinephrine and arachidonic acid (AA). ADT partially inhibited platelet aggregation and TxB2 formation in plasma induced by thrombin, phorbol myristate acetate and calcium ionophore A23187 and increased the lag time of collagen-induced aggregation at concentrations in the range 10-40 mumol/l. ADT (100 mumol/l) completely inhibited the aggregation of washed platelets challenged with thrombin. ADT had no additive effect on the inhibition of thrombin-induced platelet aggregation by acetylsalicylic acid. ADT was a more effective inhibitor of AA-induced platelet aggregation than butylated hydroxytoluene. ADT inhibited the release of 3H-AA from platelet phospholipids in response to ADP and collagen. It is suggested that ADT inhibits platelet aggregation by inhibiting thromboxane synthesis and preventing AA release.

Adenosine Diphosphate↗
PubMed1995

Staphylococcus aureus induces platelet aggregation via a fibrinogen-dependent mechanism which is independent of principal platelet glycoprotein IIb/IIIa fibrinogen-binding domains.

Platelet aggregation by bacteria is felt to play an important role in the pathogenesis of infective endocarditis. However, the mechanisms involved in bacterium-induced platelet aggregation are not well-defined. In the present study, we examined the mechanisms by which Staphylococcus aureus causes rabbit platelet aggregation in vitro. In normal plasma, the kinetics of S. aureus-induced platelet aggregation were rapid and biphasic. The onset and magnitude of aggregation phase 1 varied with the bacterium-platelet ratio, with maximal aggregation observed at a ratio of 5:1. The onset of aggregation phase 2 was delayed in the presence of apyrase (an ADP hydrolase), suggesting that this later aggregation phase may be triggered by secreted ADP. The onset of aggregation phase 2 was delayed in the presence of prostaglandin I2-treated platelets, and this phase was absent when paraformaldehyde-fixed platelets were used, implicating platelet activation in this process. Platelet aggregation phase 2 was dependent on S. aureus viability and an intact bacterial cell wall, and it was mitigated by antibody directed against staphylococcal clumping factor (a fibrinogen-binding protein) and by the cyclooxygenase inhibitor indomethacin. Similarly, aggregation phase 2 was either delayed or absent in three distinct transposon-induced S. aureus mutants with reduced capacities to bind fibrinogen in vitro. In addition, a synthetic pentadecapeptide, corresponding to the staphylococcal binding domain in the C terminus of the fibrinogen delta-chain, blocked aggregation phase 2. However, phase 2 of aggregation was not inhibited by two synthetic peptides (alone or in combination) analogous to the two principal fibrinogen-binding domains on the platelet glycoprotein (GP) IIb/IIIa integrin receptor: (i) a recognition site on the IIIa molecule for the Arg-Gly-Asp (RGD) sequence of the fibrinogen alpha-chain and (ii) a recognition site on the IIb molecule for a dodecapeptide sequence of the fibrinogen delta-chain. This differs from ADP-induced platelet aggregation, which relies on an intact platelet GP IIb/IIIa receptor with an accessible RGD sequence and dodecapeptide recognition site for fibrinogen. Furthermore, a monoclonal antibody directed against the RGD recognition site on rabbit platelet GP IIb/IIIa receptors failed to inhibit rabbit platelet aggregation by S. aureus. Collectively, these data suggest that S. aureus-induced platelet aggregation requires bacterial binding to fibrinogen but is not principally dependent upon the two major fibrinogen-binding domains on the platelet GP IIb/IIIa integrin receptor, the RGD and dodecapeptide recognition sites.

Adenosine Triphosphate↗
PubMed1992

Effect of treatment at night with S-1452, a thromboxane A2 receptor antagonist, on the morning rise in platelet aggregation.

It is well known that platelet aggregation shows a morning rise, which may contribute to the increase in the onset of ischaemic heart diseases during the morning period. The present study was undertaken to determine whether nocturnal dosage with S-1452, a thromboxane A2 receptor antagonist, would blunt the morning rise in platelet aggregability. S-1452 50 mg or placebo were given orally to 8 healthy subjects at 10.00 h (day trial) or 22.00 h (night trial) according to a cross-over design. Plasma concentrations of S-1452 and its metabolites, bisnor-(+)-S-145 and tetranor-(+)-S-145, and platelet aggregation were determined during the 12-hour period following the dose. Mean plasma concentrations of S-1452, bisnor-(+)-S-145 and tetranor-(+)-S-145 during the absorption phase were lower after the nocturnal dose than after the morning dose. The maximum plasma concentration and area under the plasma concentration-time curve of the compounds were also lower and the time to the maximum concentration were delayed after the treatment at night. A morning rise in platelet aggregation was observed following placebo treatment. The inhibitory effect of S-1452 on platelet aggregation was observed at 3 hours and persisted for up to 9 h in both trials. The results suggest that S-1452 is absorbed more slowly after the nocturnal dose than after the morning dose. However nocturnal treatment with 50 mg S-1452 may blunt the morning rise in platelet aggregability.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Phenotypic properties of cultured tumor cells: integrin alpha IIb beta 3 expression, tumor-cell-induced platelet aggregation, and tumor-cell adhesion to endothelium as important parameters of experimental metastasis.

The present study was undertaken to investigate the factors involved in determining the metastatic potential of cultured cells derived from solid tumors. We first investigated the effects of cell source and culture conditions on lung colony formation by i.v. injected B16a (B16 amelanotic melanoma) cells and inhibition of tumor colony formation by the thromboxane A2 synthase inhibitor, CGS14854. Prolonged culture resulted in a 10-fold decrease in the incidence of B16a lung colonies, whereas passage in vivo for 150 days did not affect lung colony formation by tumor cells isolated from enzymatic dispersates by centrifugal elutriation. Cultured B16a cells maintained at low density (LD) and harvested at low passage (LP) formed significantly more lung colonies than B16a cells harvested at high densities (HD) or high passage (HP). Over-confluent tumor cells produced even lower number of lung colonies. Lung colony formation by elutriated B16a cells (i.e., cells freshly isolated from tumor tissue) was consistently inhibited by CGS14854, whereas inhibition of lung colony formation by cultured B16a cells was dependent upon culture conditions. CGS14854 was ineffective or less effective against HD/HP B16a cells. The differences in lung colony formation between LD, HD and elutriated B16a cells were not due to differential cell-cycle distribution. Mechanistic studies indicated that LD/LP tumor cells induced aggregation of homologous platelets, whereas HD/HP B16a cells failed to induce significant platelet aggregation. Aggregation of homologous platelets correlated positively with lung-colonizing ability. Additionally, LD/LP cells demonstrated higher adhesion to endothelium than HD/HP B16a cells. Finally, LD/LP B16a cells expressed higher levels of alpha IIb beta 3 integrins than HD/HP tumor cells, as determined by flow cytometry and immunofluorescence.

Animals↗
PubMed1991

Inhibition of platelet aggregation by some flavonoids.

The inhibitory effects of five flavonoids on the aggregation and secretion of platelets were studied. These flavonoids inhibited markedly platelet aggregation and ATP release of rabbit platelets induced by arachidonic acid or collagen, and slightly those by platelet-activating factor. ADP-induced platelet aggregation was also suppressed by myricetin, fisetin and quercetin. The IC50 on arachidonic acid-induced platelet aggregation was: fisetin, 22 microM; kaempferol, 20 microM; quercetin, 13 microM; morin, 150 microM less than IC50 less than 300 microM. The thromboxane B2 formations were also inhibited by flavonoids in platelets challenged with arachidonic acid. Fisetin, kaempferol, morin and quercetin antagonized the aggregation of washed platelets induced by U46619, a thromboxane A2/prostaglandin endoperoxides mimetic receptor agonist. In human platelet-rich plasma, quercetin prevented the secondary aggregation and blocked ATP release from platelets induced by epinephrine or ADP. These results demonstrate that the major antiplatelet effect of flavonoids tested may be due to both the inhibition of thromboxane formation and thromboxane receptor antagonism.

Adenosine Triphosphate↗
PubMedDate not supplied

Effects of ethanol and hemolysis on in vivo and in vitro platelet aggregation.

In vivo and in vitro platelet function were measured in male rats after intravenous injection of ethanol or water. There was a dose-related ethanol suppression of platelet aggregation induced by extravasation. Increased volumes of preformed microaggregates were seen in samples taken directly from the vena cava after injection of ethanol in doses that caused hemolysis. Lower doses of ethanol produced no demonstrable microaggregates or hemolysis: however, extravasation-induced aggregation was inhibited. Hemolysis was noted after intravenous injection of water, which also reduced the total volume and mean aggregate size of platelet aggregates induced by extravasation. Blood drawn from the inferior vena cava after induction of hemolysis had an increased volume of microaggregates, regardless of the agent producing hemolysis. In vitro studies revealed changes in spontaneous and ADP-induced aggregation only at very high concentrations of ethanol (greater than 3,000 mg/dl) and no effects at ethanol levels that altered in vivo aggregation. Ethanol, in doses that do not hemolyze erythrocytes, decreases platelet aggregation.

Animals↗
PubMed1986

The importance of aspartate aminotransferase for platelet aggregation.

In bovine platelets aspartate aminotransferase has a high activity. The enzyme in vitro is inhibited in a dose dependent manner by aminooxyacetate (IC50 = 10(-4) M), hydroxylamine (IC50 = 10(-4) M), and cycloserine (IC50 = 5 X 10(-3). The inhibitory effect of all the three compounds is strongest at low substrate (aspartate) concentration. Blocking of aspartate aminotransferase activity by these compounds in intact platelets is accompanied by the inhibition of ADP and collagen-induced aggregation. Among the three compounds the strongest inhibitor of platelet aggregation was hydroxylamine, which was also the most effective inhibitor of aspartate aminotransferase. Other metabolic blockers, i.e. dinitrophenol (DNP), rotenone and antimycin also inhibited the aggregation of platelets, and a synergism has been demonstrated between DNP, rotenone and antimycin A action on platelet aggregation and blockade of aspartate aminotransferase activity. The results are interpreted to mean that transamination is of importance in the energy production in the activated platelet, probably through its participation in reducing equivalents transport from the cytosol to the mitosol via the malate: oxaloacetate: aspartate shuttle.

Adenosine Diphosphate↗
PubMed1984

Action mechanism of the potent platelet aggregation inhibitor from Trimeresurus gramineus snake venom.

The platelet aggregation inhibitor (PAI) purified from T. gramineus snake venom inhibited platelet aggregation even when it was added after platelet shape change had occurred. It inhibited the initial platelet aggregation phase in rabbit platelet-rich plasma (PRP), but not the second lytic phase induced by thimerosal (0.5 mM), a -SH reagent. In human platelet-rich plasma, the venom inhibitor also inhibited the platelet aggregation induced by ADP, collagen, epinephrine or ristocetin. The epinephrine-induced platelet aggregation was more susceptible to the venom inhibitor. The venom inhibitor (10 micrograms/ml) as well as N-ethylmaleimide (1.2 mM), a -SH reagent, completely inhibited the thrombin-induced clot retraction of PRP. It is concluded that PAI acts on a common step of platelet aggregation. It acts on membrane -SH containing macromolecule which directly mediates the platelet aggregation subsequent to platelet shape change.

Animals↗
PubMed1996

Effects of insulin on calcium metabolism and platelet aggregation.

The influence of insulin on platelets in vitro has not been exhaustively investigated. To clarify whether insulin affects Ca2+ metabolism in platelets directly or through alteration of other systems regulating intracellular Ca2+ homeostasis, we examined the effect of insulin both alone and in combination with prostaglandin E1 on platelet aggregation and Ca2+ metabolism. Incubation of rat platelets with insulin reduced thrombin-induced Ca2+ influx but did not change thrombin-evoked release of Ca2+ from internal stores or the size of internal Ca2+ stores. The interactive effects of insulin with prostaglandin E1 were only additive, and insulin did not augment the effects of prostaglandin E1 on platelet Ca2+ metabolism. In contrast, insulin did not inhibit thrombin-induced platelet aggregation but did augment inhibition of platelet aggregation by prostaglandin E1. Our results suggest that insulin inhibits platelet function by both prostaglandin E1-dependent and -independent mechanisms.

Animals↗
PubMed1981

Prostaglandins and platelet aggregation.

Prostaglandins may induce or inhibit platelet aggregation and constrict ro dilate blood vessels. Recent interest has focused on prostaglandins which are derivatives of arachidonic acid including prostaglandin, endoperoxides, thromboxane A2, prostaglandin E2, prostaglandin D2 and prostacyclin. Prostacyclin (PGI2) is a potent vasodilator and inhibitor of platelet aggregation whose enhanced production by vessel walls should be beneficial. It now appears that the circulating levels of PGI2 in man are extremely low and little is known about the manner in which to increase them. Furthermore, aspirin, in doses of as little as 4 mg/kg inhibits prostacyclin as well as thromboxane formation. Thromboxane A2 may be involved in coronary ischemia because it is a potent vasoconstrictor that is biosynthesized during platelet aggregation. Although thromboxane A2 is very unstable indirect evidence obtained by using thromboxane A generating systems or a stable analogue called carbocyclic thromboxane A2 (CTA2) suggests that it exacerbates ischaemic damage because of a selective increase in vascular resistance due to coronary vasospasm and platelet aggregation which acts to decrease myocardial blood flow. The stable prostaglandins PGD2 and PGE2 are also of interest as both are formed during platelet aggregation. Like PGI2, PGD2 inhibits platelet aggregation.

Alprostadil↗
PubMed1982

Platelet aggregation and thromboxane A2 production after adrenergic stimulation in young healthy humans.

The effects of adrenergic stimulation on platelet aggregation (platelet aggregation ratio; PAR), beta-thromboglobulin (beta-TG) release and plasma thromboxane B2 (TxB2) levels were investigated in 25 healthy young volunteers. Adrenergic stimulation induced by cold application was checked by evaluating the changes in the calculated vascular resistance in the forearm. A prompt increase in platelet aggregates and plasma beta-TG and TxB2 concentrations was observed after adrenergic stimulation. PAR changed from resting values of 0.97 +/- 0.05 to 0.75 +/- 0.08 (p less than 0.001) at the end of cold application. At the same time, beta-TG plasma concentration increased from 32.09 +/- 19.64 to 135.48 +/- 37.97 ng/ml (p less than 0.001) and TxB2 plasma levels changed from 0.49 +/- 0.24 to 0.99 +/- 0.39 pmol/ml (p less than 0.001). TxB2 levels, but not PAR and beta-TG concentration came back to the resting values at the end of the observation period (10 min). Aspirin, as the lysine acetylsalicylate equivalent to 5 mg/kg i.v. of acetylsalicylic acid, although able to completely inhibit platelet cyclooxygenase failed to inhibit the plasma TxB2 increase induced by adrenergic stimulation. This strongly suggests that the increase in plasma TxB2 following adrenergic stimulation is of extraplatelet origin. Also beta-TG and PAR changes were not affected by aspirin administration.

Adolescent↗
PubMedDate not supplied

Conjugation and evaluation of 7E3 x P4B6, a chemically cross-linked bispecific F(ab')2 antibody which inhibits platelet aggregation and localizes tissue plasminogen activator to the platelet surface.

A bispecific F(ab')2 monoclonal antibody which recognizes both the platelet GPIIb/IIIa receptor and human tissue plasminogen activator was produced to target tPA to platelets for enhancement of thrombolysis. A stable, thioether-cross-linked bispecific F(ab')2 (7E3 X P4B6) combining the GPIIb/IIIa-specific monoclonal antibody 7E3, which inhibits platelet aggregation, and a nonneutralizing anti-tPA monoclonal antibody (P4B6) was produced. This was performed by coupling each of the parental Fab' moieties with the homobifunctional cross-linker bis(maleimido methyl) ether (BMME). 7E3 X P4B6 was sequentially purified using gel-filtration chromatography and hydrophobic interaction (HIC) HPLC. HIC was shown to completely resolve each of the parental F(ab')2 species from the bispecific one. 7E3 X P4B6 was shown to retain completely each of the parental immunoreactivities in GPIIb/IIIa and tPA binding EIA's. The bispecific antibody inhibited platelet aggregation in vitro at levels comparable to those for 7E3 Fab. Recruitment of tPA activity to washed human platelets was demonstrated using the S-2251 chromogenic substrate assay. 7E3 X P4B6 recruited 12-fold more tPA to the washed platelets than a mixture of the parental F(ab')2 molecules used as controls.

Antibodies, Monoclonal↗