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PubMed1982

Effect of membrane cholesterol on phospholipid metabolism in thrombin-stimulated platelets. Enhanced activation of platelet phospholipase(s) for liberation of arachidonic acid.

The cholesterol to phospholipid mole ratio (C/PL) of human platelets was increased 1.3-fold or maintained at a normal value by incubating platelets with sonicated dispersions of cholesterol and phosphatidylcholine (PC) (C/PL = 3 or 1, respectively). Thrombin-induced mobilization of [3H]arachidonic acid from prelabeled phospholipids and subsequent formation of labeled cyclo-oxygenase and lipoxygenase products were increased in cholesterol-enriched platelets as a function of thrombin concentration. Elevated platelet cholesterol content affected thrombin-induced changes in platelet phospholipids: (a) hydrolysis of PC was more sensitive to thrombin and was markedly enhanced over a wide range of thrombin concentrations (0.1-2 units/ml); (b) hydrolysis of phosphatidylinositol (PI) was increased at thrombin concentrations greater than or equal to 0.2 unit/ml. Increased metabolism of [3H]arachidonic acid in stimulated cholesterol-enriched platelets was due to loss of [3H]arachidonate from PC at 0.1 unit/ml of thrombin. At higher thrombin concentrations (0.2-2 units/ml) it reflected enhanced hydrolysis of predominantly PC, but also PI. We conclude that cholesterol, possibly through its effect on platelet lipid organization, influences arachidonic acid metabolism in stimulated plates by promoting enhanced activity of platelet phospholipase(s) for liberation of arachidonic acid.

Arachidonic Acids↗
PubMed1982

Protein synthesis in human platelets correlation with platelet size.

Protein synthesis was investigated in human platelets by measuring incorporation of radio actively labelled amino acids into trichloroacetic acid (TCA) precipitable material. Platelet polysomes were characterized by their sedimentation rate in a sucrose gradient. It was confirmed that platelets synthesize proteins in their cytoplasm and that a part of their polysomes are bound to the skeletal framework. A higher level of protein synthesis was found in a population of small platelets separated on Ficoll (2%-4%) density gradient. Moreover, small platelets contained more polysomes than larger platelets. These results show that small platelets are more active in protein turnover or de novo synthesis. These findings can be related to peripheral maturation of platelets.

Blood Platelets↗
PubMed1980

Influence of the amount of platelet-bound IgG on platelet survival and site of sequestration in autoimmune thrombocytopenia.

Seventeen patients with idiopathic autoimmune thrombocytopenic purpura were studied in order to establish whether the amount of platelet-bound antibody influenced the rate and site at which these platelets were destroyed. Platelet-bound antibody was measured by a quantitative antiglobulin consumption technique, and platelet survival and sites of sequestration were determined by the use of 51Cr-labeled platelets and surface radioactivity measurements. A correlation significant at the 5% level was observed between the amount of platelet-bound antibody and the rate of platelet destruction. A highly significant correlation (p less than 0.001) existed between antiplatelet antibody and spleen: liver surface radioactivity ratios, demonstrating that greater amounts of antibody bound to platelets result increasingly in their destruction within the liver.

Adult↗
PubMed1993

Regulation of fibrinolysis by platelet-released plasminogen activator inhibitor 1: light scattering and ultrastructural examination of lysis of a model platelet-fibrin thrombus.

We have investigated the role of plasminogen activator inhibitor 1 (PAI-1) in the regulation of fibrinolysis using a model thrombus composed of thrombin-stimulated platelets, fibrin(ogen), plasminogen, and recombinant tissue-type plasminogen activator. Laser light scattering kinetic measurements showed that clot lysis was significantly delayed both by thrombin-stimulated platelets and their cell-free releasate. This delay in lysis was almost fully reversed by the addition of a PAI-1-specific monoclonal antibody that blocks the ability of PAI-1 to inhibit plasminogen activators. Lysis half-times exhibited a linear dependence on the concentration of PAI-1 antigen present, as determined by enzyme-linked immunosorbent assay (ELISA). Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting confirmed the presence of PAI-1 antigen in the platelet releasates. Scanning electron micrographs of the model thrombus components sampled late in lysis showed considerable unproteolyzed fibrin still attached to platelets. Immunogold cytochemistry detected large amounts of PAI-1 antigen in the partially lysed platelet-fibrin thrombi. This PAI-1 appeared to be bound to the fibrin network rather than to the platelet surface itself. We conclude that the residual clots observed late in lysis represent platelet-associated fibrin to which platelet-released PAI-1 has bound, rendering it less susceptible to degradation.

Adult↗
PubMed1993

Platelet interactions with fibronectin: divalent cation-independent platelet adhesion to the gelatin-binding domain of fibronectin.

Divalent cation-dependent platelet adhesion to fibronectin (FN) is mediated by the integrin receptors alpha 5 beta 1 (GP Ic-IIa) and alpha IIb beta 3 (GP IIb-IIIa), which recognize the RGD (Arg-Gly-Asp) sequence in the cell-binding domain. However, FN can also support divalent cation-independent platelet adhesion. To determine which domain of FN mediates divalent cation-independent adhesion, proteolysis with thermolysin and affinity chromatography were used to isolate the cell-binding, gelatin-binding, and heparin-binding domains of FN. Unactivated and thrombin-activated platelets adhered to intact FN and the 45-Kd gelatin-binding domain in the presence of either Ca2+ or EDTA. Platelet spreading was mediated only by the 105-Kd cell-binding domain and required divalent cations. The heparin-binding domains did not support platelet adhesion. Reduction of intrachain disulfide bonds or removal of carbohydrate side chains on the gelatin-binding domain did not alter the ability to support platelet adhesion. Divalent cation-independent adhesion to the 45-Kd gelatin-binding domain was not inhibited by RGDS (Arg-Gly-Asp-Ser) synthetic peptides or monoclonal antibodies (MoAbs) directed against known platelet receptors. We conclude that platelets can adhere but not spread on the gelatin-binding domain of FN by a novel divalent cation-independent mechanism.

Amino Acid Sequence↗
PubMed1993

Dysfunctional platelet glycoprotein IIb/IIIa associated with a platelet release defect: a family study.

We are reporting on a 36-year-old white female with a bleeding history attributed to dysfunctional platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and a coexisting platelet release defect. Platelet aggregation studies (PAS) revealed markedly diminished to absent responses to ADP, epinephrine, collagen and arachidonic acid; the ristocetin response was normal. ATP content was normal with poor release to the agonists as measured by luminescent technique. DDAVP infusion shortened bleeding time from 13.5 min to 8.0 and 12 min (at 1 and 2 hours). Flow cytometry and immunoblotting revealed normal amounts of GPIIb and diminished GPIIIa (50% of control). Using a previously reported ELISA which measures the binding of GPIIb/IIIa to immobilized fibrinogen, the patient's platelet extract showed no binding to fibrinogen. Both the father and mother were found to have decreased PAS responses and normal amounts of GPIIb/IIIa determined by both Western blot and flow cytometry. However, the ELISA showed decreased binding of their GPIIb/IIIa to fibrinogen (71% and 62% as compared to controls, respectively). The patient's dysfunctional fibrinogen receptor was clearly demonstrated by the ELISA. The parents had moderately reduced GPIIb/IIIa function in this assay, but they did not demonstrate a reduced GPIIIa as was noted in the patient. The parents' PAS indicated a platelet release defect. These findings suggest an inherited platelet release defect and a dysfunctional GPIIIa. The partial response to DDAVP would be compatible with the presence of a platelet release defect.

Adult↗
PubMed2003

Platelet activity measured by plasma levels of beta-thromboglobulin and platelet factor 4 in seasonal allergic rhinitis during natural pollen exposure.

BACKGROUND: Upon activation, platelets release mediators with potent inflammatory properties in IgE-mediated immune responses. Moreover, the atopic state leads towards functional abnormalities of these cells. OBJECTIVE: The aim of our study was to examine the degree of activation of circulating platelets in patients with seasonal allergic rhinitis (SAR) during the symptomatic period, to improve the understanding of platelet function in atopy. SUBJECTS AND METHOD: Plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) - specific markers of platelet activation were measured by enzyme-linked immunoassay in 20 patients suffering from SAR and in 15 healthy, nonatopic subjects. RESULTS: There were no significant differences in peripheral blood platelet numbers and plasma levels of beta-TG and PF4 in SAR patients when compared with control subjects. CONCLUSION: It seems that increased in vivo platelet activity, assessed by measuring plasma beta-TG and PF4, may not occur during allergic inflammation that is associated with SAR.

Adolescent↗
PubMed1989

The fibrinogen-derived peptide (RGDS) prevents proteolytic degradation of protein kinase C in platelets by inhibiting platelet aggregation.

The effects of the fibrinogen-derived tetrapeptide, Arg-Gly-Asp-Ser (RGDS), on platelet activation processes was studied. At concentrations of 100-300 microM, RGDS completely prevented platelet aggregation induced by all the common platelet agonists, 'weak' and 'strong'. In agreement with earlier views on the aggregation-dependency of weak agonist-induced thromboxane synthesis and 5-hydroxytryptamine (5HT) secretion, RGDS (100-300 microM) inhibited these events induced by ADP, adrenaline and low concentrations of thrombin and collagen but not that induced by high concentrations of thrombin and collagen. 5HT secretion induced by the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), was also not affected by RGDS, but proteolytic degradation of the translocated membrane-bound enzyme in PMA-treated platelets, due to the actions of the Ca2+-dependent protease (Ca-DP), was completely prevented such that in the presence of RGDS, sustained increases in membrane-bound PKC activity were observed. PMA alone caused only transient increases in membrane-bound PKC. This effect of RGDS was similar to the effect of E64-d, a recently described inhibitor of Ca-DP in platelets, or the effects seen with PMA in unstirred non-aggregating platelets. It is concluded that RGDS inhibits the actions of Ca-DP in platelets via inhibition of aggregation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

Inhibition by sulphinpyrazone of the platelet-dependent bronchoconstriction due to platelet-activating factor (PAF-acether) in the guinea pig.

Platelet-activating factor (PAF-acether) injected into guinea-pigs induced platelet-dependent bronchoconstriction and thrombocytopenia. Treatment of the animals with sulphinpyrazone suppressed bronchoconstriction without affecting thrombocytopenia. When tested ex vivo and in vitro, sulphinpyrazone suppressed the PAF-acether-induced platelet release reaction, as measured by the release of ATP, more efficiently than platelet aggregation. In contrast, bronchoconstriction and thrombocytopenia in vivo, as well as platelet aggregation and the release reaction ex vivo and in vitro, induced by arachidonic acid (AA), were suppressed by sulphinpyrazone. This effect is accounted for by the known anti-arachidonate cyclooxygenase activity of sulphinpyrazone. Finally, aggregation by ADP was only marginally inhibited by sulphinpyrazone, and the inhibition was easily surmounted when the amounts of ADP added were increased. Sulphinpyrazone exerts a specific and cyclooxygenase-independent protective effect towards platelet activation by PAF-acether, which results in inhibition of platelet-dependent bronchoconstriction even though aggregation, and consequently in vivo thrombocytopenia, may persist.

Adenosine Diphosphate↗
PubMed1986

Anesthetics and anticoagulants used in the preparation of rat platelet-rich-plasma alter rat platelet aggregation.

Aggregation of platelets in heparin- and citrate-anticoagulated platelet-rich-plasma (PRP) from rats anesthetized with methoxyflurane (M), diethyl ether (E), acepromazine/ketamine (A/K), or sodium pentobarbital (P) is described, as are platelet counts. Platelet counts were highest in heparin- or citrate-PRP from E and A/K anesthetized rats. Collagen and arachidonic acid (AA) induced aggregation in heparin-PRP only, and ADP induced greater aggregation in heparin-PRP than in citrate-PRP. Differences between citrate-PRP and heparin-PRP are probably due to citrate inhibition of platelet aggregation, since addition of citrate to heparin-PRP decreased aggregation, while addition of heparin to citrate-PRP did not alter aggregation. Aggregation of hirudin-PRP was slightly less than heparin-PRP. Anesthetics affected rat platelet aggregation: the rank order of the maximal extent of ADP-induced aggregation in citrate-PRP was M greater than E = A/K greater than P, and that for AA and collagen in heparin-PRP was E = A/K greater than M = P. The correlation between the effect of the anesthetics and activation of the sympathoadrenal system is discussed. It appeared that of the commonly used anticoagulants and anesthetics, heparin and methoxyflurane had the least influence on rat platelet aggregation.

Anesthetics↗
PubMed1993

Interaction of annexin V and platelets: effects on platelet function and protein S binding.

Intact annexin V but not its fragments bound specifically to platelets in the presence of calcium. Maximal binding observed was 0.87 pmole annexin V per 10(8) platelets with an apparent dissociation constant of 2.13 x 10(-11) M. This represents approximately 5000 binding sites per platelet. Platelet stimulation by thrombin increased the binding of annexin V by 40-fold. Addition of phospholipid vesicles or treatment with phospholipase C inhibited annexin V binding to platelets, suggesting that phospholipid is the binding site for annexin V and that phosphatidylcholine forms at least part of this site. Binding of annexin V did not cause platelet aggregation and did not affect thrombin or collagen induced aggregation. However annexin V significantly inhibited the binding of protein S to the platelet surface.

Annexin A5↗
PubMed1994

Calpain-induced down-regulation of protein kinase C inhibits dense-granule secretion in human platelets. Inhibition of platelet aggregation or calpain activity preserves protein kinase C and restores full secretion.

The relationship between platelet aggregation, calpain activation, PKC activities and the secretory response have been examined in PMA-and ionomycin-stimulated platelets. Co-addition of PMA and ionomycin resulted in a maximal synergistic secretion of [14C]5-hydroxytryptamine ([14C]5-HT) from platelet dense granules. However, prior addition of PMA for 5 or 10 min resulted in a reduction of this secretory response. Inclusion of either RGDS (to inhibit platelet aggregation) or E64-d (to inhibit calpain activity) resulted in full restoration of the secretory response. In experiments to determine the activity status of PKC, PMA was found to induce a loss in cytosolic and total PKC activity without an increase in membrane-associated activities during this time period. Inhibition of either platelet aggregation or calpain activity resulted in preservation of total and cytosolic activities with a measurable increase in membrane translocated activity. PMA-induced phosphorylation of a number of PKC substrates was measured in 32P-labelled platelets. PMA induced potent phosphorylation of the 45 and 20 kDa species and also proteins of the molecular masses 66, 80, 97 and 119 kDa. Phosphorylation was maximal at either 1 or 2 min after which dephosphorylation occurred. Inclusion of either RGDS or E64-d resulted in a reduction of the dephosphorylation rates, and sustained phosphorylation of the 66, 80, 97 and 119 kDa proteins. These studies suggest that the activity status of PKC is an important factor in the level of secretion obtained and that platelet aggregation is involved in calpain-initiated down-regulation of PKC.

Blood Platelets↗
PubMed2003

Effects of lipid-esterified conjugated linoleic acid isomers on platelet function: evidence for stimulation of platelet phospholipase activity.

The effects of four conjugated linoleic acid (CLA) isomers on in vitro collagen-induced human platelet aggregation and thromboxane (TXB(2), the inactive metabolite of the proaggregatory TXA(2)) production were examined. As the free fatty acid (FFA), 9t, 11t-CLA was the most effective inhibitor of these two processes (I(50)s of 2.2 and 4 microM, respectively) and the 9c, 11c-CLA was the least effective (I(50)s of 8.3 and 37 microM) of the isomers tested. When platelets were preesterified with either 25 microM 9t, 11t-CLA or 9c, 11c-CLA, CLA incorporation in total platelet lipids increased from 0.24% to 0.31% and 0.38%, and most of this increase was found to be in the phosphatidyl choline and phosphatidyl ethanolamine subclasses. The decrease in arachidonic acid (AA) content in total fatty acids or phospholipids was an order of magnitude greater. Furthermore, no significant differences between platelets prelabeled with either 9t, 11t- or 9c, 11c-CLA in the inhibition of collagen-induced aggregation and TXB(2) formation were observed. However, platelets prelabeled with 9c, 11c-CLA stimulated basal TXB(2) production (4-fold) which was not observed with platelets pretreated with either 9t, 11t-CLA, linoleic acid or stearic acid. This enhancement was associated with a 2.4-5-fold increase in the release of endogenous AA. Our results suggest that the presence of a conjugated cis, cis double bond appears to change the lipid environment sufficiently to stimulate the basal platelet phospholipase activity, which in turn increases the formation of TXB(2).

Arachidonic Acid↗
PubMed2005

Inhibitory effect of the Korean herbal medicine, Dae-Jo-Whan, on platelet-activating factor-induced platelet aggregation.

The anti-thrombic properties of the Korean herbal medicine, Dae-Jo-Hwan (DJW) were investigated. Water extracts, a 70% methanol (MeOH) extract and an ethyl acetate (EtOAc) soluble fraction (III) from DJW inhibited platelet-activating factor (PAF)-induced platelet aggregation in vitro and in vivo assays. The extracts of DJW and eleven herbs from which it is derived, except for Panax ginseng Meyer, Angelica sinensis (OLIV.) DIELS and Schisandra chinensis Baill., inhibited AA-induced blood platelet aggregation to various extents. The effects observed with total DJW was synergistic over-additive rather that additive since the sum of single contributions was lower than the effect of the total extract. Fraction III was specially protected against the lethality of PAF, while verapamil did not afford any protection. Exogenously applied arachidonic acid (AA) (100 microM) led to a 89% platelet aggregation, the release of 14 pmol of ATP, and the formation of either 225 pg of thromboxane A2 (TXA2) or 45 pg of prostaglandin E2 (PGE2), each parameter being related to 10(6) platelets. An application of DJW 5 min before AA, dose-dependently diminished aggregation, ATP-re lease, and the synthesis of TXA2 and PGE2, with IC(50) values of 70, 87, 65 and 72 microg/ml, respectively. The similarity of the IC(50) values suggests the inhibition of cyclooxygenase (COX) by DJW as the primary target, thus suppressing the generation of TXA2, which induces platelet aggregation and the exocytosis of ATP by its binding on TXA2-receptors. These results indicate that DJW shows anti-thrombotic action on human platelets and inhibits the action of PAF in vivo by an antagonistic effect on PAF. Therefore, it may be useful in treating disorders caused by PAF.

Animals↗
PubMed1987

Glycation of platelet protein in diabetes mellitus: lack of correlation with platelet function.

The relationship of nonenzymatic glycation of platelet proteins to altered platelet function was studied in 33 diabetic patients. Platelets isolated from diabetic patients were glycated to a greater extent than those isolated from nondiabetic controls. No relationship was found between the level of glycation of platelets in diabetics to parameters commonly used to monitor glycemic control (glycated hemoglobin, glycated albumin, fasting blood glucose). Platelets isolated from diabetics did not show an increased level of aggregation and Thromboxane B2 production as compared to nondiabetic controls. No significant relationship was found between the level of glycation and percent aggregation of platelets. The lack of a relationship between glycation and aggregation suggests that the former may not be responsible for the functional changes in platelets seen in diabetics.

Blood Glucose↗
PubMed1998

A new system to detect native microaggregates of platelets in vivo, with a novel platelet aggregometer employing laser light scattering.

Circulating platelets are susceptible to various stimuli in vessels, and a certain portion of platelets may thereby form native microaggregates (NMAs), which can be visualized by a bother scanning electron microscopy (SEM). We developed an easy method to evaluate the existence and extent of NMAs and the subsequent spontaneous platelet aggregation (SPA) induced by not any agonist but stirring force with a novel platelet aggregometer (PA-200; Kowa, Tsukuba, Japan) employing a particle-counting method based on laser light scattering. In this system, platelet-rich plasma obtained by a delicate centrifugation was infused in a cuvette to replace the content and to avoid stirring shear. An insertion attachment was designed in a coaxial shape to maintain a constant sample volume. Our data indicated that NMAs, tentatively defined as a "small" division by their light scattering (25-400 of the intensity threshold), could be detected by not only a complicated SEM but also by our simple system with the PA-200 in a few minutes. No correlation was found in the comparison of the existence of NMAs and the SPA generation, in aliquot platelets, respectively. These results suggested that NMAs and SPA might be mutually different cluster and have meanings as representations of platelet status.

Blood Platelets↗
PubMed2001

Platelet interactions with titanium: modulation of platelet activity by surface topography.

Endosseous implants initially come into contact with blood. Thus, the nature of the interactions between blood and implanted endosseous implants may influence subsequent bone healing events in the peri-implant healing compartment. We conducted studies to address the following question: Does implant surface microtexture modulate platelet activity? We used commercially pure Ti (cpTi) disks with four different surface finishes: dual acid-etched (DAE), 320 grit (320G) abraded, machined, and p1200 polished cpTi. Surfaces were characterized by scanning electron microscopy (SEM) and optical profilometry. The DAE and 320G surfaces presented more complex microtextures than the machined or polished surfaces. Platelet activities were measured by quantifying platelet adherence, platelet-derived microparticle (MP) formation, and P-selectin expression as function of surface type. Platelet adhesion, measured using a lactate dehydrogenase (LDH) assay. was increased on DAE and 320G surfaces compared to machined and polished surfaces (p < 0.05). M P formation and P-selectin expression, assayed by flow cytometry, also showed increased activation of platelets on DAE and 320G surfaces. Because increased activation of platelets may lead to up-regulation of osteogenic responses during bone healing, these results may explain the enhanced osteoconductivity known to occur with DAE cpTi surfaces in comparison with machined cpTi surfaces.

Blood Platelets↗
PubMed2000

Human platelet thrombin receptors. Roles in platelet activation.

Platelets are essential participants in hemostasis and thrombosis. Platelets normally circulate in blood as discoid resting cells that become critical constituents of hemostatic plugs or arterial thrombi only after specific receptors on platelet membranes interact with their ligands (agonists) to initiate the reactions that lead to platelet activation. The well-characterized events associated with platelet activation include activation of membrane receptors, shape change, granular secretion, cytoskeletal reassembly, platelet cohesion, and aggregation. The plasma protease alpha-thrombin is the most potent physiologic platelet agonist; this enzyme has other key roles in hemostasis, in the genesis of arterial thrombi, and in embryonic development, inflammation, wound healing, and cell proliferation.

Blood Platelets↗