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PubMedDate not supplied

Abnormalities of platelet aggregation in chronic myeloproliferative disorders.

A large variety of platelet dysfunctions has been described in chronic myeloproliferative disorders. These abnormalities may be due to deficiency of platelet granules, arachidonic acid metabolism defects or platelet membrane glycoproteins abnormalities. In this study we intend to detect the incidence of platelet function defects in 76 patients with various types of chronic myeloproliferative disorders. The platelet activity was studied in vitro by measuring platelet aggregation in response to ADP, epinephrine, collagen, arachidonic acid and ristocetin. These results were subsequently correlated with bleeding time and clinical aspects (bleeding or thrombosis). We found complex changes in platelet response with all agonists, in varied proportions. These abnormalities include absent, decreased or abnormal platelet aggregation response. In a few cases we found a markedly decreased, almost absent platelet response to all agonists while in some patients a normal platelet aggregation was noted. The correlation between these results and template bleeding time, thrombotic or hemorrhagic events and the type of diseases was difficult to establish and sometimes conflictual. Despite this fact, we consider that investigating platelet aggregation may be useful not only for the assessment of the hemostatic balance in chronic myeloproliferative disorders but also for a better insight into cell abnormalities occurring in these pathologic conditions.

Adenosine Diphosphate↗
PubMed1989

The mechanism of heparin-induced platelet aggregation.

When heparin was added to platelet-rich plasma, mild but irreversible platelet aggregation was demonstrated. This platelet response was not accompanied by release of alpha-granules and dense body constituents, nor by prostaglandin biosynthesis. It did, however, require metabolic energy and divalent cations as metabolic inhibitors (anti-mycin A and 6-deoxyglucose) and EDTA blocked the reaction. Bernard-Soulier syndrome platelets, which lack glycoprotein (GP) Ib, but not Glanzmann's Thrombasthenia platelets, which lack GP IIb/IIIa, were aggregated by heparin. Monoclonal antibody (mAb) against GP IIb/IIIa, but not mAb against GP Ib, strongly inhibited the reaction. These combined results suggest the participation of GP IIb/IIIa but not GP Ib in heparin-induced platelet aggregation. Fibrinogen was a cofactor in the reaction as gel-filtered platelets were unreactive to heparin but addition of fibrinogen restored their reactivity. Antithrombin III and fibronectin inhibited platelet response to heparin, suggesting that these proteins may protect platelets from aggregation by heparin.

Antibodies, Monoclonal↗
PubMed1996

Internalization of bound fibrinogen modulates platelet aggregation.

In agonist-stimulated platelets, the integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) is converted from an inactive to an active fibrinogen receptor, thereby mediating platelet aggregation. With time after agonist addition, at least two events occur: fibrinogen becomes irreversibly bound to the platelet and, when stirring is delayed, platelets lose the ability to aggregate despite the presence of maximally bound fibrinogen. Because we previously identified an actively internalized pool of alpha IIb, beta 3 in platelets, we explored the possibility that both of these events might result from the internalization of fibrinogen bound to active alpha IIb beta 3. Under conditions of irreversible fibrinogen binding, fluorescence microscopy showed that biotinylated fibrinogen is rapidly internalized by activated platelets to a surface-inaccessible, intracellular pool. Flow cytometric analysis showed that the observed loss in accessibility to extracellular probes immediately precedes a loss in ability to the platelets to aggregate. Moreover, prevention of irreversible fibrinogen binding results in a prevention of internalization and a retention of aggregation capacity. Thus, the internalization of fibrinogen from the activated platelet surface appears to contribute not only to the irreversible phase of fibrinogen binding, but also to the downregulation of platelet adhesiveness. Fibrinogen internalization is therefore likely to represent a fundamental regulatory mechanism that modulates platelet function.

Adenosine Diphosphate↗
PubMed2004

Contribution of PAR-1, PAR-4 and GPIbalpha in intracellular signaling leading to the cleavage of the beta3 cytoplasmic domain during thrombin-induced platelet aggregation.

Integrin alphaIIbbeta3 plays a pivotal role in platelet aggregation by binding to fibrinogen. The beta3 cytoplasmic domain of alphaIIbbeta3 interacts with cytoskeletal and signaling proteins and is cleaved by micro -calpain, a calcium regulated cysteine protease. In the present study, we have investigated in more detail the cleavage of the beta3 cytoplasmic domain during platelet aggregation induced by thrombin, TRAP-1 and TRAP-4. Our data show that beta3 is cleaved in all three cases. The time course of beta3 cleavage and the amount of cleaved beta3 depends on the way platelets are activated and on the complete activation of micro -calpain, with a maximum of 90% of cleaved beta3 obtained when thrombin is used. Furthermore, our results also show that the cleaved alphaIIbbeta3 is mainly distributed in the Triton soluble fraction, indicating its inability to bind to the cytoskeleton. Interestingly, in the absence of GPIbalpha or following inhibition of thrombin binding to GPIbalpha, there is a reduction in the thrombin-induced calcium flux, beta3 cleavage and micro -calpain activation. These results suggest that cleavage of the beta3 cytoplasmic domain by micro -calpain might be an important step regulating the link between the cytoskeleton and alphaIIbbeta3 during platelet aggregation, and that GPIbalpha could function as a cofactor for the complete activation of platelets by thrombin.

Calpain↗
PubMed1992

Papaverine inhibits human platelet aggregation induced by ADP.

1. The in vitro and ex vivo effect of therapeutic levels of papaverine on human platelet aggregation induced by 3-5 microM adenosine-5'-diphosphate (ADP) was evaluated in platelet-rich plasma (PRP) by photometric and impedance aggregometry, and in whole blood by impedance aggregometry. 2. Platelet aggregation induced by 3-5 microM ADP in whole blood was significantly inhibited by 5.32 and 10.64 microM papaverine in vitro. This effect was also observed in PRP enriched with erythrocytes but not in PRP alone or enriched with leukocytes. 3. Papaverine (5.32 microM) significantly enhanced the antiplatelet activity of adenosine (0.75 microM) in human whole blood, an effect that was not observed in PRP. 4. A single oral dose of 100 mg papaverine hydrochloride, given to eight healthy human volunteers 1 h before the platelet aggregation evaluation, significantly inhibited the platelet aggregation induced by 3-5 microM ADP in whole blood. This effect was not observed in PRP. 5. Oral administration of the same dose at 8-h intervals (10 times) to seven additional healthy human volunteers led to a significant negative correlation (r = -0.55, P < 0.01) between the slope of platelet aggregation in whole blood and plasma papaverine levels (0.12-0.75 microM). 6. Papaverine and adenosine, alone or together, had no in vitro effect on whole blood platelet aggregation of male Wistar rats measured by impedance aggregometry. 7. These results suggest that papaverine inhibits human platelet aggregation in whole blood by an interaction with red blood cells.

Adenosine Diphosphate↗
PubMedDate not supplied

The L-arginine-nitric oxide system regulates platelet aggregation in pregnancy.

OBJECTIVE: To investigate the ex vivo platelet aggregation in response to a substrate (L-arginine [L-Arg]) and a donor (sodium nitroprusside [SN]) of nitric oxide (NO) in nonpregnant women and in normotensive pregnancies. METHODS: Platelet aggregation was studied with a dual-channel aggregometer and expressed as a percentage of light transmission. Measurements were done at baseline and after preincubation with scalar doses of L-Arg and SN. The intraplatelet L-citrulline (L-Cit) levels were measured by high-performance liquid chromatography (HPLC). RESULTS: In both groups, the baseline aggregation values were similar for adenosine diphosphate (ADP) and collagen stimuli. Wilcoxon rank-sum testing demonstrated that in both groups the addition of L-Arg had a significant effect on aggregation: Doses of 50 to 5000 mumol decreased ADP-induced aggregation. Conversely, collagen-induced aggregation was affected only by the highest dose of L-Arg. Sodium nitroprusside administered in doses of 2.5 to 250.0 nmol decreased ADP- and collagen-induced platelet aggregation equally. ADP-induced aggregation values obtained after (SN) incubation were positively correlated with gestational age. Intraplatelet L-Cit levels showed a significant rise after the incubation with L-Arg, and this effect was negatively correlated with gestational age. CONCLUSION: The L-Arg-NO system regulates platelet aggregation during pregnancy. Moreover, a physiologic reduction of platelet sensitivity to the antithrombotic effect of NO occurs.

Adenosine Diphosphate↗
PubMed1983

Storage of platelets for tests of platelet function: effects of pH on platelet aggregation and liberation of beta-thromboglobulin.

Platelet aggregation responses are influenced by conditions of storage of platelet-rich plasma (PRP). The aim of the present study was to further define the necessity for pH control during storage of PRP for tests of platelet function. Aliquots of citrated PRP were maintained at different pH levels by alteration of the CO2 content of the atmosphere in an incubation chamber. At intervals over 2-2 1/2 hours, plasma beta-thromboglobulin and 14C-serotonin were measured as well as platelet aggregation induced by ADP and collagen. At each time a dose response curve was studied for aliquots stored at each pH level. When two aliquots were maintained at different pH levels in the range 6.85-7.90, there was a significant increase in aggregation at the higher pH, even when the pH difference was as small as 0.2 units. In this range, pH did not influence the rate of deterioration of the aggregation response, but when pH was above 8.0, there was marked deterioration of the response. Increased pH was associated with an increase in plasma levels of beta-thromboglobulin and 14C-serotonin, which was more marked when pH was above 8.0. It appears that increases in pH are harmful to platelets and even small pH changes should be avoided during storage of platelet-rich plasma for tests of platelet function.

Adenosine Diphosphate↗
PubMed1971

Platelet aggregation and strenuous exercise.

1. Platelet aggregation in the Chandler's tube has been found to be increased in a group of normal male and female volunteers who undertook strenuous physical exercise. This coincided with acceleration of the ;intrinsic' blood clotting system and a rise in fibrinogen. The rise in fibrinogen occurred despite increased fibrinolysis.2. The study confirms the sensitivity of the platelet aggregation system to changes in the ;intrinsic' clotting mechanism. Acceleration of this system in this study resulted from a physiological cause and produced accelerated aggregation in the coagulation-affected phase.

Adult↗
PubMedDate not supplied

Increased phosphatidic acid and decreased lysophosphatidic acid in response to thrombin is associated with inhibition of platelet aggregation.

Thromboxane A2, produced from the arachidonic acid released from platelet phospholipids by phospholipase A2, stimulates platelet aggregation. It remains unresolved whether additional products of platelet phospholipase A2 might promote aggregation. To address this question, we have used aspirin-treated platelets to block thromboxane A2 formation and studied the influence of the phospholipase A2 inhibitor U10029A on platelet aggregation and secretion in response to thrombin. U10029A at 100 microM markedly inhibited platelet aggregation, but had no effect on platelet secretion. Since this concentration of U10029A effectively blocked lysophosphatidic acid (LPA) formation, LPA was added and found to substantially reverse the inhibitory effect of U10029A in these platelets. Furthermore, the action of U10029A was not due to inhibition of phosphatidate phosphohydrolase because U10029A, unlike propranolol, did not inhibit this enzyme. Although it is not possible to conclusively rule out an effect of U10029A in addition to its inhibition of phospholipase A2, our results reveal that a product of phospholipase A2 other than thromboxane A2 is important for platelet aggregation, but not for secretion in response to thrombin. Our data suggest that this product is LPA. Since the amount of phosphatidic acid (PA) increased dramatically concurrent with inhibition of platelet aggregation, it is safe to conclude that PA has no direct role to promote platelet aggregation in response to thrombin.

Arachidonic Acid↗
PubMed1992

Molecular determinants of the platelet aggregation inhibitory activity of carbamoylpiperidines.

A series of alpha,alpha'-bis[3-(N,N-dialkylcarbamoyl)piperidino]-p- xylenes were synthesized and tested for their inhibitory activity on ADP-induced aggregation of human platelets. A parabolic curve was obtained when log 1/C (activity) was plotted against log P (octanol/water partition coefficient). Using this as a model, a new analogue, alpha,alpha'-bis-[3-(N-methyl-N-butylcarbamoyl)piperidino]-p-xylen e (3g), was synthesized with a predicted IC50 of 25 microM. When this compound was subsequently evaluated, the IC50 was 22.1 +/- 5.5 microM, demonstrating the applicability of this model. The amide oxygen of the carbamoyl substituent appeared necessary for activity. Thus, for example, when the amide carbonyl group of 3a (IC50 = 44.5 microM) was reduced to CH2, the resulting compound 4 had a dramatically reduced activity, IC50 = 1565 microM. Compound 3a was resolved into (+) and (-) enantiomers and a meso (0) diastereomer using fractional crystallization, diastereomeric tartrate formation, and chiral HPLC. Compared to (-)-3a, the (+) isomer was 15 times more potent when ADP was the agonist and 19 times more active when collagen was used as the agonist. Molecular modeling of R,R- and S,S-3a using the SYBYL program was used to examine their interactions with phosphatidylinositol (PI). There was a better fit between PI and the R,R-3a with the energy of interaction being 17.6 kcal/mol less than that of the S,S-3a/PI complex. Although the absolute stereochemistry of individual enantiomers is not known, this study shows that R,R-3a interacts more favorably with PI than does S,S-3a and that (+)-3a is a more potent inhibitor of human platelet aggregation than (-)-3a. It is postulated that because of their lipophilicity, these compounds penetrate the platelet membrane and are then protonated at the pH of the cytosol. The protonated N then neutralizes the anionic charge on the membrane phosphoinositides, thereby rendering them less susceptible to hydrolysis by phospholipase C. Thus, the determinant parameters for optimum antiplatelet activity in 3-carbamoylpiperidines are (1) the amide carbonyl, (2) appropriate stereochemistry of the 3-substituent and (3) a log P value of about 4.5.

Adenosine Diphosphate↗
PubMed1989

Effect of metronidazole on platelet aggregation.

The effects of metronidazole on platelet aggregation induced by several agonists were studied on guinea pig and human platelet-rich plasma. Metronidazole (0.25-2.5 mg/ml) showed a dose-dependent inhibitory effect on in vitro aggregation of platelets from either source induced by adenosine-5-diphosphate (ADP), platelet aggregating factor (PAF), epinephrine, collagen or convulxin (extracted from Crotalus durissus terrificus venom). Total or partial inhibition was also detected in metronidazole pre-treated guinea pig platelet-rich plasma when challenged with PAF or ADP 45 and 135 min after oral treatment, respectively. This inhibition was both dose and time dependent.

Adenosine Diphosphate↗
PubMed1985

Platelet aggregation occurs in congenital afibrinogenaemia despite the absence of fibrinogen or its fragments in plasma and platelets, as demonstrated by immunoenzymology.

Platelet aggregation of an afibrinogenaemic patient's platelet rich plasma (PRP) was greatly decreased when ADP was used for stimulation. In the presence of collagen or arachidonic acid the changes in light transmission recorded during platelet aggregation of patient's PRP were similar to those observed with normal PRP but the size of aggregates appeared to be smaller in comparison with those observed with normal platelets. In addition, thrombin-induced aggregation of washed platelets was similar to normal platelets. The interpretation was made possible because the fibrinogen level in plasma and in platelets was found to be almost nil as demonstrated by both an Elisa procedure described here and the determination of fibrinopeptide A (fpA). Furthermore, fibrinogen fragments, which could result from abnormal synthesis and therefore replace fibrinogen in platelet aggregation, were undetectable by immunological analysis using specific antibodies against A alpha, B beta and gamma chains and 10 different monoclonal antibodies against fibrin degradation products.

Adenosine Diphosphate↗
PubMed1998

Effect of Gosha-jinki-gan, a Kampo medicine, on enhanced platelet aggregation in streptozotocin-induced diabetic rats.

We evaluated the effects of Gosha-jinki-gan on platelet aggregation in streptozotocin-induced diabetic rats. Enhanced ADP (2 microM)-induced aggregation of platelets obtained from diabetic rats was inhibited by a single treatment with Gosha-jinki-gan (0.3, 1.5 g/kg, p.o.). The anti-platelet aggregatory effect of Gosha-jinki-gan (1.5 g/kg, p.o.) was attenuated by simultaneous administration of atropine (1 mg/kg, i.p.) and was abolished by combination of atropine with Hoe 140 (250 microg/kg x 2, i.p.), a bradykinin B2 receptor antagonist or L-NAME (10 mg/kg, i.p.), an inhibitor of nitric oxide-synthase. These results suggested that Gosha-jinki-gan could improve platelet aggregation in diabetes through increased production of nitric oxide via bradykinin B2-receptors and muscarinic acetylcholine receptors.

Adenosine Diphosphate↗
PubMed1988

Sex- and age-dependence of platelet aggregation in diabetes mellitus.

Platelet aggregate ratios (PAR) were determined, and threshold concentrations (ED50) of epinephrine, adenosine diphosphate (ADP), and collagen were estimated by platelet aggregometry in 88 IDDM and 52 NIDDM patients without hyperlipidaemia or azotaemia, and in 106 healthy volunteers to revise the question of hyperaggregability in diabetes. ED50-s showed a tendency for negative correlation with age, significant in female but not in male controls. Similar trends were obtained in IDDM and NIDDM females, but were not in IDDM and NIDDM males. The ED50-s of different aggregating agents positively correlated with each other. ED50-s were higher in men than in women in both controls and IDDM patients. Similar but minor differences were observed between women and men in NIDDM. IDDM patients had significantly lower PAR and collagen ED50, and a tendency for epinephrine and ADP to be lower as compared to the sex- and age-matched controls. The differences of PAR were the same, while those of ED50-s were diminished in older NIDDM patients compared to the matched controls. It is concluded, that the previously observed general hyperaggregability in diabetic patients may have partly resulted from sex- and age differences. Threshold concentrations should be compared to sex- and age-matched controls.

Adolescent↗
PubMedDate not supplied

Inhibition of human blood platelet aggregation and the stimulation of nitric oxide synthesis by aspirin.

Incubation of platelet-rich plasma with 80 microM aspirin that resulted in the inhibition of both the secondary phase of ADP induced platelet aggregation and prostaglandin synthesis simultaneously stimulated the production of NO in platelets. Furthermore it was found that the treatment of platelet-rich plasma either with 80 microM ibuprofen or salicylic acid, like aspirin, which inhibited the secondary phase of platelet aggregation by ADP and prostaglandin synthesis, also stimulated the production of NO in the absence of added ADP. However the inhibition of prostaglandin synthesis by ibuprofen or salicylic acid, unlike aspirin, was transient in nature. Incubation of washed platelets with any of these three compounds also stimulated NO synthesis indicating that the effect of these compounds was not mediated through plasma proteins. The in vitro effect of aspirin on the increase of NO in platelets could also be demonstrated by in vivo exposure of platelets to the compound. It was concluded that either a temporary or a lasting inhibition of prostaglandin synthesis by these inhibitors resulted in the synthesis of NO in resting platelets. Since NO is a potent inhibitor of platelet aggregation the inhibition of platelet aggregation, by these compounds may not be the consequence of the inhibition of prostaglandin synthesis alone, but could also be related, at least partly, to the stimulated synthesis of NO by these inhibitors.

Adenosine Diphosphate↗
PubMed2005

Effects of magnesium sulphate on leptin-dependent platelet aggregation: an ex vivo study.

Magnesium sulphate has well known antiplatelet properties. Its effect on leptin-dependent platelet aggregation has not been studied previously. Thus, we performed this ex vivo study to investigate whether magnesium sulphate is able to inhibit leptin-dependent aggregation of human platelets. We obtained platelet rich plasma (PRP) from venous blood samples of 16 healthy male volunteers, and we measured ADP-induced platelet aggregation in the presence of leptin alone (5-500 ng/mL) or leptin and magnesium sulphate (0.25-8 mM). Platelet pre-incubation with leptin led to a significant and dose-dependent increase in ADP-induced platelet aggregation. Magnesium sulphate was able to inhibit the pro-aggregating effect of leptin in a dose-dependent manner. The inhibitory effect was apparent at 1 mM of magnesium sulphate concentration (% maximal aggregation=38.1 +/- 12.2) and reached its maximum at 8 mM (% maximal aggregation=20.0 +/- 7.8). Our results demonstrate that leptin-dependent platelet aggregation is inhibited by magnesium sulphate in a dose-dependent manner. It seems conceivable that the blocking of hydrolysis of phosphoinositide and of intracellular calcium mobilization by magnesium sulphate may be involved in these findings.

Adenosine Diphosphate↗
PubMed1980

Effect of synthetic estrogen on platelet aggregation and vascular release of PGI2-like material in the rabbit.

Treatment of adult female New Zealand white rabbits with ethinyl estradiol, the synthetic estrogen used in many oral contraceptives, results in a significant increase in in vivo aggregation. This alteration in platelet behavior is accompanied by diminished vascular release of antiaggregatory PGI2 (prostacyclin)-like material. Addition of a progestin prevents the change in platelet aggregation seen with the estrogen alone. Diminished vascular PGI2 release may be an important factor in the pathogenesis of thrombotic occurrences experienced by some oral contraceptive users. In vivo platelet aggregation may be of value in identifying individuals at risk of developing thrombotic disturbances while taking oral contraceptives.

Adenosine Diphosphate↗
PubMed2003

Adenine, an inhibitor of platelet aggregation, from the leaves of Cassia alata.

Adenine was isolated as a platelet aggregating inhibitor from the leaves of Cassia alata by HPLC using a triacontylsilyl silica (C(30)) column. The inhibitory effects of adenine and adenosine (positive control) on the platelet aggregation induced by collagen or adenosine 5'-diphosphate (ADP) as an aggregating agent was evaluated with a platelet aggregometer using a laser-scattering method. As a result, the inhibitory effect of adenine was observed in the platelet aggregation induced by collagen (1.0 microg/ml as the final concentration), but little inhibitory effect was noted in the aggregation induced by ADP (5.0 microM as the final concentration), whereas adenosine exhibited potent inhibitory effects on platelet aggregation induced both by collagen and ADP under the same experimental conditions.

Adenine↗