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At least 199 records · Page 11Linked to original sources
PubMed1992

Okadaic acid and vanadate inhibit collagen-induced platelet aggregation; the functional relation of phosphatases on platelet aggregation.

The different specific inhibitors for phosphoserine/threonine and phosphotyrosine protein phosphatases were used to study the role of these protein phosphatases in collagen-platelet interaction. The collagen-induced platelet aggregation and the release reaction as measured ATP release were inhibited in a dose-dependent fashion by the addition of okadaic acid, a specific inhibitor of phosphoserine/threonine protein phosphatase 1 and 2A. The inhibition was also observed by the addition of a phosphotyrosine protein phosphatase inhibitor, vanadate. Suboptimal concentrations of both inhibitors together also inhibited collagen-induced platelet aggregation and release reaction in a concentration-dependent fashion. These results suggest that collagen-platelet interaction is modulated by both protein phosphatases.

Adenosine Triphosphate↗
PubMed1988

Platelet-activating factor binding and metabolism during human platelet aggregation.

Platelet-activating factor (PAF) binding and metabolism were quantified during human platelet aggregation induced by [3H]PAF. Platelet aggregation was maximal within 45 to 75 sec. PAF binding was maximal within 15 to 60 sec and then remained stable for at least 20 min. Total binding during aggregation elicited by 1.2 pmol [3H]PAF was 13.4% +/- 1.0% (0.16 +/- 0.01 pmol/8 x 10(7) platelets) (mean +/- SEM) and specific, receptor binding was 4.3% +/- 0.3% (0.05 +/- 0.003 pmol/8 x 10(7) platelets). Specific binding was fully reversible at the time of maximal aggregation. Scatchard analysis of PAF binding at the time of maximal platelet aggregation revealed 124 +/- 56 receptors per platelet with a dissociation constant of 0.56 +/- 0.04 nM. Binding of 52 +/- 23 PAF molecules per platelet elicited maximal platelet aggregation (mean +/- SD). Less than 2% of the bound PAF was metabolized at the time of maximal aggregation and the principal metabolite was the inactive product lysoPAF. Increased metabolism to alkyl-acyl-glycero-3-phosphocholine was observed at later times. These studies indicate that PAF receptor internalization and PAF metabolism are not essential to human platelet activation by PAF.

Binding, Competitive↗
PubMed1998

Platelet aggregation in acute coronary syndromes: use of a new aggregometer with laser light scattering to assess platelet aggregability.

OBJECTIVE: Platelet aggregation has been implicated in the pathogenesis of acute coronary syndromes. Small aggregates consisting of < or = 100 platelets cannot be quantified with a conventional aggregometer employing optical density. Using a recently developed aggregometer based on laser light scattering, we studied platelet aggregability in patients with acute coronary syndromes. METHODS: Peripheral blood samples were obtained from 39 patients with acute myocardial infarction or unstable angina who had received no prior antiplatelet or anticoagulant therapy, to be assayed immediately using a PA-100 platelet aggregometer. Blood samples from 14 healthy volunteers were used as controls. RESULTS: Spontaneous formation of platelet aggregates was observed only in patients with acute coronary syndromes. The size of these aggregates was small, consisting of < or = 100 platelets (primary aggregation). Agonist-induced aggregation consisted of two phases. In the first few minutes, the number of small aggregates increased markedly (primary aggregation), followed by an increase in larger aggregates (secondary aggregation). The EC50 of epinephrine for primary aggregation was nearly 50 times lower in acute coronary patients than in controls (P < 0.001), while the EC50 for secondary aggregation was only 2 times lower (P < 0.001). CONCLUSIONS: Aggregometry using light scattering suggests that platelet hyperaggregability and hypersensitivity in acute coronary syndromes may occur in primary but not secondary aggregation.

Acute Disease↗
PubMed1981

[Exercise-induced platelet aggregation: in vitro and ex-vivo aggregation of human platelets after administration of crystalline adrenaline and after ergometric exercise (author's transl)].

Even at an adrenaline concentration of 10(-9) mol/l, using strictly defined in-vitro flow conditions at 37 degrees C and physiological pH levels, there is a significant rise in platelet aggregation above control values (nine subjects, P lesser than 0.025). According to published reports, this concentration range is reached during physical exercise. Accordingly, there was also a rise in platelet number and spontaneous aggregation (P lesser than 0.01) in eleven healthy male subjects (average age 25, range 22-33, years) during ergometric exercise. These results and published reports indicate the potential danger of untrained elderly persons with vascular disease developing an increase in platelet aggregation during exercise.

Adult↗
PubMed1982

Study of platelet aggregation in vivo. IX. Effect of nafazatrom on in vivo platelet aggregation and spontaneous tumor metastasis.

Nafazatrom (Bay g 6575) was explored for its ability to inhibit platelet aggregation. In vitro, it had no effect on ADP, serotonin, epinephrine, or collagen induced platelet aggregation in platelet rich plasma of monkeys. On the other hand, in vivo it was a powerful inhibitor of ADP induced platelet aggregation as measured by the in vivo platelet aggregation recording instrument described previously (Ambrus et al., 1976). This effect was potentiated by dipyridamole. On the other hand, following parenteral administration of Bay g 6575, no ex vivo inhibition was noticed of ADP, serotonin, epinephrine, and collagen induced platelet aggregation. The hypothesis was presented that Bay g 6575 acts by increasing prostacyclin synthesis and/or release or interferes with its decomposition. This may explain in vivo activity; rapid decomposition may explain inability to demonstrate ex vivo activity. This also explains potentiation by the phosphodiesterase inhibitor dipyridamole. Bay g 6575 also was highly effective as a platelet aggregation inhibitor in monkeys after oral administration. In mice, Bay g 6575 increased circulation time of intravenously injected polyploid Ehrlich ascites tumor cells. In Furth-Wistar rats implanted with Furth-Columbia Wilms' tumor, in A/J mice implanted with C1300 neuroblastoma and in Wistar rats implanted with SMT-2A (Kim) breast cancer, Bay g 6575 significantly reduced spontaneous pulmonary metastasis. On the other hand, no effect was seen in the metastatic rate of NIH renal adenocarcinoma in BALB/cCr mice.

Adenocarcinoma↗
PubMed1990

Measuring platelet aggregation with microplate reader. A new technical approach to platelet aggregation studies.

Platelet aggregation measurements were done with the use of a commercially available microtiter plate reader with specific modification of the mode of agitation of the samples. Satisfactory aggregation curves were obtained with use of an external horizontal agitator, with an amplitude of 1.3 mm and minimum frequency of 1,360 cycles/minute. With the use of the 96 available wells in the microtiter plates, all test and control platelet samples, with replicates, were observed simultaneously and the output data obtained within 10-15 minutes. The technique was validated by demonstrating the similarity of dose-response curves, obtained with a standard aggregometer and with the microtiter technique, of platelets stimulated by adenosine diphosphate, thrombin, and arachidonic acid.

Humans↗
PubMed2004

Effect of orthovanadate on platelet aggregation induced by platelet-activating factor.

Orthovanadate (vanadate) inhibited the platelet aggregation induced by platelet-activating factor (PAF) in a dose-dependent manner. Propranolol, a nonspecific beta-adrenergic receptor antagonist, and H-8, a selective inhibitor of cAMP-dependent protein kinase (PKA), suppressed the inhibition of the PAF-induced platelet aggregation by vanadate. Vanadate increased the cAMP content in platelets accompanied by the activation of PKA. The beta-adrenergic receptors of platelets have been reported to be abundant in the beta(2) isoform, coupled to adenylyl cyclases (R. Kerry and M. C. Scrutton, Br. J. Pharmacol., 79, 681-691 (1983)). When the washed platelets were preincubated with vanadate, salbutamol, a selective beta(2)-adrenergic receptor agonist, or 8-Br-cAMP, the latter two mimicked the vanadate-induced anti-platelet aggregation and prolongation of clotting time of plasma, suggesting involvement of the increased intracellular cAMP content in both actions of vanadate. Butoxamine, a selective beta(2)-adrenergic receptor antagonist, suppressed both actions of vanadate. The vanadate-induced increase in cAMP content was inhibited in part by butoxamine or genistein. These results suggest that vanadate inhibits the PAF-induced platelet aggregation by the stimulation of a cAMP/PKA-dependent process via the beta(2)-adrenergic receptor and receptor tyrosine kinases, and that the anti-platelet aggregation is involved in part in mechanisms of the anticoagulant action of vanadate.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

beta-Amyloid protein induces platelet aggregation and supports platelet adhesion.

The amyloid precursor protein (APP) is found in many cells including neurons, endothelial cells and blood platelets. Beta-amyloid protein (beta AP) is derived from APP and is deposited in brain and in cerebral microvasculature of individuals with Alzheimer's disease. In this study we demonstrate that beta AP interacts with human blood platelets. We found that human beta AP peptide (1-40) fibrils aggregate platelets and support their adhesion, and these interactions are mediated through platelet membrane integrin receptors.

Alzheimer Disease↗
PubMed1996

Fluorescent indicators give biased estimates of intracellular free calcium change in aggregating platelets: implication for studies with human von Willebrand factor.

The ratiometric fluorescent indicators Fura-2 and Indo-1 are considered optimal probes for monitoring intracellular free calcium concentration ([Ca2+]i). Unique problems arise, however, in studying [Ca2+]i changes induced in platelets by von Willebrand factor (vWF). Binding of native multimeric vWF causes extensive platelet aggregation, and is reported to evoke a gradual [Ca2+]i increase. the present investigation examined the reliability of platelet [Ca2+]i measurements in these circumstances. Ristocetin-mediated binding of vWF to human platelets promoted a slow rise in Fura-2 fluorescence ratio. Fura-2 extrusion contributed substantially to this rise, unless blocked by probenecid. Despite this precaution, the platelets were invariably contaminated slightly with extracellular indicator. As aggregation progressively reduced the number of platelets in the spectrofluorometer beam, through settling of the larger aggregates, such extracellular Fura-2 contributed proportionately more to the observed fluorescence. This extraneous signal accounted completely for the fluorescence ratio increase, and apparent [Ca2+]i rise, in response to native multimeric vWF. The same problem arose with Indo-1, whereas the single wavelength indicator Fluo-3 showed the opposite pattern of apparent [Ca2+]i changes. Thus, none of these indicators provides reliable data on [Ca2+]i signals in aggregating platelets. Use of a dimeric form of vWF eliminated the problem of platelet aggregates settling out of suspension, but also virtually abolished the [Ca2+]i increase. These observations may explain some of the inconsistencies among previous investigations of vWF-induced calcium signaling. Moreover, similar problems may arise in studies with other adhesive proteins.

Alkylation↗
PubMed1999

Role of intracellular signaling events in ADP-induced platelet aggregation.

Human platelets express two distinct G protein-coupled ADP receptors, one coupled to phospholipase C through Gq, P2Y1, and the other to inhibition of adenylyl cyclase through Gi, P2TAC. We have recently shown that concomitant intracellular signaling from both the P2TAC and P2Y1 receptors is essential for ADP-induced platelet aggregation. Previous studies have tested whether ADP causes a decrease in the basal cAMP level and this reduction promotes platelet aggregation, but did not study the effect of decreased cAMP levels when the Gq pathway is selectively activated. Since we are now aware that platelet aggregation requires activation of two receptors, we investigated whether the function of P2TAC receptor activation, leading to inhibition of platelet adenylyl cyclase, could be replaced by direct inhibition of adenylyl cyclase, when Gq pathway is also activated, a possibility that has not been addressed to date. In the present study, we supplemented the P2Y1 mediated Gq signaling pathway with inhibition of the platelet adenylyl cyclase by using SQ22536 or dideoxyadenosine, or by selective activation of the alpha2A adrenoceptors with epinephrine. Although SQ22536, dideoxyadenosine, and epinephrine reduced the cAMP levels, only epinephrine could mimic the P2TAC receptor mediated signaling events, suggesting that reduction in basal cAMP levels does not directly contribute to ADP-induced platelet activation. Adenosine-5'-phosphate-3'-phosphosulfate, a P2Y1 receptor antagonist, completely blocked ADP-induced inositol 1,4,5-trisphosphate and inositol 1,3.4-trisphosphate formation suggesting that P2TAC-mediated activation of Gi (or other G proteins) does not activate phospholipase C. These results suggest that a signaling event downstream from Gi, independent of the inhibition of platelet adenylyl cyclase, contributes to alphaIIb beta3 activation.

Adenine↗
PubMed1986

Evidence that the rat is not an appropriate model to study the role of prostaglandins in normal or abnormal platelet aggregation.

Abnormal platelet aggregation seen in experimentally induced diabetic, hypercholesterolemic and spontaneously hypertensive rats (SHR) has been linked with increased prostaglandin synthesis. The present study was conducted to examine the role of prostaglandins in rat platelet activation using normal Wistar Kyoto (WKY) and SHR rats. Up to 30 microM ADP did not induce secondary phase of platelet aggregation in rat PRP and up to 30 microM epinephrine did not produce any response in rat PRP. In other experiments ADP (1.0 microM) and epinephrine (2.0 microM) induced typical biphasic aggregation responses in human PRP. Up to 20 microM U46619, a stable analog of prostaglandin H2, did not induce platelet aggregation in rat PRP or washed rat platelets. In contrast 2.0 microM U46619 caused maximal aggregation in human PRP and washed human platelets. Arachidonic acid (1.5-2.0 mM) induced aggregation in washed rat platelets. However, this was associated with excessive (67% and 94%) loss of cytoplasmic LDH. The low concentrations of thrombin (0.04 and 0.05 U/ml), induced two to three-fold increase in aggregation response in SHR platelets as compared to WKY platelets. Higher concentrations of thrombin (0.1 and 0.3 U/ml) induced similar aggregation responses in SHR and WKY platelets. Thrombin (0.04-0.3 U/ml) induced serotonin secretion in a concentration dependent manner. The extent of secretion was the same in SHR and WKY platelets at all concentrations. Thrombin-induced synthesis of thromboxane A2 (TXA2) in WKY and SHR platelets was quantified using a radioimmunoassay for TXB2. Thrombin (0.04-0.3 U/ml) produced TXB2 in WKY and SHR platelets in a concentration dependent manner. The SHR platelets produced significantly larger amounts of TXB2 as compared to WKY platelets. In other experiments aspirin (500 microM) inhibited thrombin (0.05 U/ml) induced TXB2 synthesis by 75% in both WKY and SHR platelets but failed to inhibit aggregation or secretion in either WKY or SHR platelets. Based on these data it is suggested that: (a) rat platelets inspite of their ability to synthesize TXA2 do not require TXA2 for aggregation; and (b) the rat may not be an appropriate model to study the role of prostaglandins in normal or abnormal platelet aggregation.

Adenosine Diphosphate↗
PubMed1976

Vagal reflexes in the bronchoconstriction occurring after induced intravascular platelet aggregation.

Intravascular platelet aggregation induced in cats by i.v. infusions of collagen caused a transient increase in pulmonary vascular resistance (PVR) and in non-elastic pulmonary resistance (RL), and a transient decrease in dynamic lung compliance (dyn CL). PVR,dyn CL and platelet aggregation after collagen infusions were unaffected by bilateral cervical vagotomy and atropinization, wheras these procedures reduced the post-infusion rise in RL by about 50 per cent. The administration of indomethacin inhibited platelet aggregation as well as bronchoconstriction after collagen infusion. The present investigation indicates that intravascular platelet aggregation will cause reflex bronchoconstriction mediated by vagal efferent fibres.

Animals↗
PubMed1998

Hemoglobin A0 and alpha-crosslinked hemoglobin (alpha-DBBF) potentiate agonist-induced platelet aggregation through the platelet thromboxane receptor.

Chemically modified hemoglobins are potential oxygen-carrying blood substitutes, but their in vivo administration has been associated with a variety of unexpected side events, including increased platelet reactivity. We studied the effects of hemoglobin A0 (HbA0) and alpha-crosslinked hemoglobin (alpha-DBBF) on platelets in vitro. Neither hemoglobin A0 nor alpha-DBBF activated platelets when added alone, but both proteins potentiated submaximal agonist-induced platelet aggregation without increasing other markers of platelet activation such as serotonin secretion. Only agonists that are known to cause release of platelet arachidonic acid (AA) were potentiated while aggregation induced by ADP, which does not release AA, was not potentiated. Blockade of the thromboxane receptor with SQ-29,548 prevented the HbA0-induced and the alpha-DBBF-induced potentiation suggesting that the AA/thromboxane signaling pathway mediates the interaction of platelets with hemoglobin.

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

Effects of low-dose EPA-E on glycemic control, lipid profile, lipoprotein(a), platelet aggregation, viscosity, and platelet and vessel wall interaction in NIDDM.

OBJECTIVE: To assess the effects of low-dose eicosapentaenoic acid-ethyl-ester on diabetes regulation, lipid metabolism, blood rheology, and platelet reactivity. RESEARCH DESIGN AND METHODS: In a double-blind, randomized, placebo-controlled study, 24 NIDDM subjects received 1800 mg of EPA-E, 900 mg of EPA-E, or a placebo (1656 mg olive oil) daily for 8 wk. RESULTS: The EPA:arachidonic acid plasma ratio increased over an 8-wk period, then declined after a 4-wk wash-out period in the fish-oil groups in a dose-dependent way. Platelet-activating factor-induced platelet aggregation decreased from 75 +/- 7% at wk 0 to 35 +/- 21% at wk 8 in the 900-mg group (P = 0.016) and from 72 +/- 11 to 40 +/- 30% in the 1800-mg group (P = 0.039), but did not change in the placebo group. No effects on ADP- or collagen-induced aggregation could be attributed to EPA-E. In the 1800-mg group low-density-lipoprotein cholesterol increased significantly, without concomitant rise in apolipoprotein B. Triglycerides, glycemic control, lipoprotein (a), blood and plasma viscosity, erythrocyte deformability, and platelet adhesion to and aggregate formation on extracellular endothelial cell matrix were not significantly influenced. CONCLUSIONS: Purified EPA-E in doses of 900 and 1800 mg reduces Platelet-activating factor-induced platelet aggregation without negatively affecting glycemic control. Low-density-lipoprotein cholesterol was elevated in the 1800-mg group.

Adenosine Diphosphate↗
PubMed1991

Effects of antiplatelet agents on platelet aggregation induced by platelet--activating factor (PAF) in human whole blood.

Impedance aggregometry was used to evaluate the potency of anti-platelet agents on Platelet Activating Factor (PAF)--induced platelet aggregation in citrated human whole blood. Drugs were tested for ability to inhibit maximum aggregation to PAF. Dose response curves were obtained and the concentration of drug producing 50% inhibition of maximum aggregation (ED50) determined. ED50's (microM) for specific PAF antagonists WEB 2086, Ro 19-3704, FR-900452, BN 52021, L-652,731, CV 3988, WEB 2118 and 48740 RP are: 0.39, 2.4, 4.7, 19.5, 21.0, 5.32, 161.0, 924.0, respectively. ED50's for non-specific PAF antagonists, diltiazem, propranolol, ketotifen, procaine HCL, and lidocaine HCL are: 38.0, 56.0, 250.0, 513.0 and 768.0, respectively. Ibuprofen was inactive at 2300 microM. Results are consistent with concept that there are specific receptors on platelets mediating PAF-induced aggregation in whole blood. Aggregation is inhibited potently by specific and competitive PAF receptor antagonists. Whole blood aggregometry may be a valid method for predicting in vivo activity of PAF antagonists.

Adolescent↗
PubMed1976

Factor VIII and human platelet aggregation. III. Further studies on aggregation of humna platelets by neuraminidase-treated human factor VIII.

When highly purified human factor VIII is submitted to agarose gel chromatography in the presence of 0.5 M CaCl2, the procoagulant activity (low molecular weight factor VIII, LMW-F VIII) is separated from the void volume protein (Vo-VIII). Upon incubation of human factor VIII with purfied neuraminidase, a very stable platelet aggregating activity develops in the "Vo-VIII' fraction, not in the "LMS-FVIII' part. Evidence is provided that the generated aggregating activity is a property of the 'carrier protein' for LMW-F VIII. Desialylated factor VIII retains its antigenic reactivity, its procoagulant or ristocetin cofactor properties and the capacity of its subunits to dissociate and recombine. Neuraminidase-treated human factor VIII, in contrast to intact bovine factor VIII or intact human factor VIII in the presence of restocetin, does not induce aggregation of EDTA-platelet rich plasma, of congenitally afibrinogenaemic platelet rich plasma, nor of washed platelets.

Chromatography, Agarose↗