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PubMed2004

Role of the Pyk2-MAP kinase-cPLA2 signaling pathway in shear-dependent platelet aggregation.

Mechanisms of shear-induced platelet aggregation are not established. Data that ristocetin-induced von Willebrand factor (VWF) binding to glycoprotein (Gp) Ibalpha activates proline-rich tyrosine kinase 2 (Pyk2) and extracellular-regulated kinase (ERK) has led to speculation that these events are coupled and that a MAP kinase may activate cytosolic phospholipase A2 (cPLA2)-mediated arachidonic acid (AA) release. To test this hypothesis and clarify the role of AA metabolism in shear-induced VWF-dependent platelet aggregation, we examined Pyk2, ERK1/2, and p38 phosphorylation, and arachidonic acid release and metabolism in platelets subjected to pathological shear stress in vitro. We observe tyrosine phosphorylation of Pyk2, p38, and ERK1/2 but no measurable increase in free AA, 12-hydroxyeicosatetraenoic acid, or thromboxane A2. Inhibitors of ERK, p38, or cyclooxygenase activation fail to affect shear-induced platelet aggregation. When washed platelets are aspirin-pretreated, arachidonic acid release becomes measurable and aggregation at 60 and 120 s is attenuated. These data indicate that shear-induced VWF binding to platelet GpIb-IX-V activates Pyk2, ERK1/2, p38, and cPLA2, but that the magnitude of these responses is below the threshold needed to enhance shear-induced VWF-dependent platelet aggregation in the presence of plasma. These results provide a mechanistic basis for the long-standing observation that shear-dependent platelet aggregation is unaffected by the antiplatelet drug aspirin.

Acetyltransferases↗
PubMed1986

Prolonged bleeding time, reduced platelet aggregation, altered PAF-acether sensitivity and increased platelet mass are a trait of asthma and hay fever.

In a case control study 31 asymptomatic patients with asthma and/or hay fever and 31 normal controls had their bleeding time measured using the Simplate II device and venostasis. Mean bleeding time in the atopic group (527 s) was significantly prolonged compared to the controls (393 s) (p less than 0.0005). Platelet aggregation to collagen and ADP (but not to PAF-acether) was significantly depressed in the atopics. Mean circulating platelet mass was significantly greater in atopics than in the controls (p = 0.006). Stepwise multiple regression analysis showed that within the control group bleeding time was best predicted by platelet mass (p = 0.007). No such relationship was found in the atopics. However stepwise multiple regression analysis showed that bleeding time in the atopics (but not in the controls) was best predicted by PAF-acether induced platelet aggregability (p less than 0.05). In neither group was bleeding time related to collagen induced platelet thromboxane B2 production. It is hypothesised that in respiratory atopy the depressed aggregatory function of platelets is not compensated for sufficiently by an increase in platelet mass, leading to prolongation of the bleeding time. This haemostatic imbalance, whose cause remains to be established, appears to constitute a trait of atopy.

Adenosine Diphosphate↗
PubMed1999

Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content.

Shear forces induce platelet aggregation and stimulate the endothelial production of anti-aggregatory factors. Among them, endothelin-3 (ET-3) has been reported to reduce aggregation and to increase platelet cyclic GMP (cGMP) content. Since hypercholesterolemia modifies both platelet aggregability and endothelial function, we compared in 14 hypercholesterolemic and 15 normocholesterolemic subjects the influences of shear forces (240 and 650 s(-1)) on platelet aggregation and cGMP content, and their modulation by ET-3. Spontaneous maximal aggregation occurred earlier and at a greater extent in hypercholesterolemic than in normocholesterolemic subjects (63+/-2 vs 46+/-6% P < 0.01). Pre-treatment with ET-3 abolished the shear-induced facilitation of maximal aggregation in platelets of normocholesterolemic (from 70+/-2 to 52+2% at 240 s(-1) and from 73+/-1 to 59+/-2S at 650s(-1); P < 0.05) and hypercholesterolemic (from 78+/-3 to 64+/-2 at 240 s(-1) and from 78+/-2 to 66+/-3 at 650 s(-1); P < 0.05) subjects. cGMP content did not significantly differ between normocholesterolemic and hypercholesterolemic subjects (6.1+/-0.5 vs 6.9+/-0.7 pmol/10(9) platelets). It was reduced in platelets submitted to shear forces (P < 0.05). This shear-dependent reduction was suppressed by ET-3 pre-treatment. These results demonstrate that shear forces enhance platelet aggregation and diminish their cGMP content. ET-3 reduces the pro-aggregating effects of shear, suggesting a rise in cGMP content as a dynamic associated mechanism.

Blood Platelets↗
PubMed1989

Platelet aggregation in whole blood--studies with a platelet counting technique--methodological aspects and some applications.

We describe a method for measuring platelet aggregation in whole blood by single platelet counting. The importance of a low stirring speed (100 rpm) to obtain agonist-specific aggregation is stressed. Despite this low stirring speed, the sensitivity to agonists equals that of the turbidometric technique in platelet-rich plasma. The optimal concentration of formaldehyde for fixing the aggregates, the effects of storage times and anticoagulant are studied. Applicability to the study of platelet function inhibitors or of inherited platelet function disorders is illustrated. It is concluded that this technique, used under the appropriate conditions, combines the advantage of measuring platelet aggregation in a more physiologic environment with the advantages of the turbidometric technique such as high sensitivity.

Adenosine Diphosphate↗
PubMed1982

Inhibition of platelet aggregation by primary amines. Evidence for a possible role of membrane-associated calcium.

The aggregation of human blood platelets by thrombin, adenosine diphosphate, wheat germ agglutinin or ristocetin was inhibited by primary amines. In general, thrombin-induced platelet aggregation was strongly affected by the amines while the effect was weak on cell aggregation by ristocetin. Usually, the diamines were stronger inhibitors of aggregation than the monoamines with cadaverine as the strongest and ethylamine as the weakest inhibitor. At concentration where platelet aggregation was inhibited, the amines neither displaced serotonin from serotonin-loaded platelets nor caused lysis of human red cells. The lectin activity of wheat germ agglutinin on human red cells was not affected by the amines indicating that the amines probably acted on platelets and not on the agglutinin. The clotting activity of thrombin on fibrinogen was partially inhibited by the amines while its esterolytic activity remained unaltered. The inhibitory action of the amines on platelet aggregation could be overcome with small amounts of calcium while other divalent cations tested had little effect. It is suggested that the amines affect platelet aggregation by interfering with the actions of membrane-associated calcium.

Adenosine Diphosphate↗
PubMed1991

Effect of diabetes on photochemically induced thrombosis in femoral artery and platelet aggregation in rats.

Effect of diabetes on thrombogenesis was examined by using a thrombus model with photochemical reaction in the rat femoral artery. In streptozotocin-induced diabetic rats for 8 weeks, the formation of thrombus following endothelial injury was significantly slower than that in non-diabetic rats. Insulin treatment normalized the abnormality of thrombogenesis. Aggregation in washed platelets from rats with diabetes was enhanced. However, platelet aggregation in whole blood was reduced in diabetic rats, and plasma from diabetic rats attenuated platelet aggregation. These results suggest that plasma factor(s) and/or other blood cells modify the hyperaggregability of platelets per se in vivo in diabetic rats. Treatment with insulin improved the aggregation in whole blood and washed platelets. In conclusion, diabetes induces the prolongation of thrombogenesis in the rat femoral artery. Hypoaggregability of whole blood is likely to be partly involved in the abnormal thrombogenesis.

Animals↗
PubMed1985

Human platelet aggregation and release reaction induced by platelet activating factor (PAF-acether)--effects of acetylsalicylic acid and external ionized calcium.

The effects of the cyclo-oxygenase inhibition on PAF-acether-induced human platelet aggregation and secretion are controversial. We studied the above parameters on citrated platelet-rich plasma of 12 normal subjects before and after the in vivo administration of acetylsalicylic acid (ASA). Individual sensitivities to PAF-acether were highly variable. ASA completely inhibited the platelet secretion induced by low concentrations of PAF-acether, but caused only partial inhibition when platelets were exposed to high concentrations of PAF-acether. The concentration of PAF-acether which overcame the cyclo-oxygenase inhibition varied substantially, depending on the individual sensitivity of the platelets to it. The addition of CaCl2 2 mM to the samples did not affect the extent of the platelet secretion, but increased irreversible aggregation in samples taken both before and after the ASA administration. These data suggest that low concentrations of PAF-acether stimulate the human platelet secretion by activating the cyclo-oxygenase pathway, whereas higher concentrations also trigger other mechanism(s) that suffice to induce human platelet secretion and full aggregation.

Aspirin↗
PubMed1991

Platelet aggregation induced by uncommon serotypes of Streptococcus sanguis isolated from patients with Behçet's disease.

Uncommon serotypes were tested for their ability to induce aggregation in platelet-rich plasma. Both uncommon and common serotypes induced platelet aggregation in rabbit platelet-rich plasma, but serotonin release was higher with the uncommon serotypes. Aggregation at ATP release varied between uncommon and common serotypes. With human platelet-rich plasma, only uncommon serotypes showed aggregation. Differences in serotype selectivity and the rate of aggregation were noted among platelet donors. About half of the patients with Behçet's disease and 30% of health controls showed platelet aggregation. Plasma from non-responder patients with Behçet's disease inhibited aggregation of healthy responder platelets within 20 min. Thus selective binding of uncommon serotypes of Strep. sanguis to platelets might cause the vasculitis in Behçet's disease.

Adenosine Triphosphate↗
PubMed1979

Properdin factor D: effects on thrombin-induced platelet aggregation.

Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less than that of thrombin. These phenomena occur at physiologic concentrations of factor D. Therefore, factor D may function in vivo as an inhibitor of platelet aggregation.

Binding, Competitive↗
PubMed1975

Electronic particle size measurements of platelet aggregates formed in vitro.

The aggregation of human platelets induced by adenosine diphosphate (ADP) was used to evaluate electronic particle size analyzer measurements of platelet aggregates in plasma. As platelets began to clump in plasma, the total volume and the diameter of individual aggregates increased; after a time dependent on experimental conditions, the diameter increased but the total volume remained unchanged. Similar but opposite changes in size distribution occurred during platelet deaggregation. The total volume of aggregates formed in plasma varied (linear correlation coefficient = 0.99) with the total volume of platelets which were available to clump and with simultaneous changes in optical density. The diameter of the aggregates varied with the concentration of, and time of exposure to, ADP and with the total volume of platelets and aggregates in plasma was not different from that of control platelets in untreated plasma, the individual platelets aggregated without an accompanying increase in size. This study demonstrates that platelet aggregation can be characterized by electronic measurements of the size distribution of platelet aggregates.

Adenosine Diphosphate↗
PubMed1982

Impairment of platelet aggregation in hemolytic uremic syndrome: evidence for platelet "exhaustion".

Thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure are the hallmarks of hemolytic-uremic syndrome (HUS). This report presents the results on platelet studies from 10 consecutive HUS patients in childhood. During their acute illness, they all displayed a characteristic pattern of impaired platelet function: no aggregating responses to epinephrine, some to ADP, and moderate to collagen. In addition, platelet contents of beta-thromboglobulin (beta TG) were markedly reduced. As these patients improved clinically, their platelet-aggregating responses also normalized despite their uremic state. Incubation of platelets with uremic plasma or guanidino-succinic acid, a uremic toxin, had minor effects on platelet-aggregating activity. Since low levels of platelet beta TG suggest that these platelets were in an exhausted state, in vitro experiments were performed to exhaust normal platelets by incubation at 37 degrees C. A proportional impairment of platelet-aggregating responses and decreasing levels of platelet beta TG were noted. Furthermore, the pattern of impairment was similar to that found in the platelet-aggregating activities of HUS patients. Thus, "exhaustion," in addition to azotemia and thrombocytopenia, are factors that contribute to the functional impairment of platelets in these patients. Further studies to reveal mechanisms that lead to platelet exhaustion in HUS are of fundamental importance in the understanding of this illness.

Blood Platelets↗
PubMed1998

The light-scattering whole blood aggregometer: a novel device for assessment of platelet aggregation in undiluted blood.

OBJECTIVE: A novel whole blood platelet aggregometer has been developed. Based on differential light-scattering principles, the device detects platelet aggregates in undiluted blood. The primary objectives of this report are to introduce the design of this novel device and to evaluate its ability to assess platelet aggregation. DESIGN: In the light-scattering whole blood aggregometer, anticoagulated blood is dispensed into a self-contained sample loop and circulated with the help of a peristaltic pump. Laser light is directed into the circulating blood, and the scattered light signals are converted to electrical signals and analyzed. When platelet aggregates pass through the illuminated region, they produce peak signals, which are detected and quantified; the platelet aggregation profile is the time-dependent development of the total aggregate volume. ASSESSMENT: After the calibration of the light-scattering signals using polystyrene microspheres, platelet aggregation was measured by the light-scattering aggregometer, and the results were compared with those obtained with the conventional turbidometric (based on light transmission) and electrical impedance aggregometers. Scanning electron microscopy was used to confirm the presence of platelet aggregates in the whole blood samples taken from the light-scattering aggregometer. RESULTS: Scanning electron micrographs and light-scattering observations confirmed that the peak signals detected after the addition of platelet aggregating reagents to blood were caused by platelet aggregates. Results of platelet aggregation and its inhibition in blood were similar to those obtained with the impedance whole blood aggregometer. CONCLUSION: The novel light-scattering whole blood aggregometer has been shown to be a valid device to measure platelet aggregation and may be well suited for the assessment of platelet function in research and clinical blood samples.

Electric Impedance↗
PubMedDate not supplied

Dipyridamole and aspirin in relation to platelet aggregation and vessel wall prostaglandin generation.

Modification of platelet function and vessel wall prostaglandin synthesis by pharmacologic intervention has attracted considerable attention. We report our observations on the effects of aspirin and dipyridamole alone and their combination on platelet aggregation and vessel wall prostacyclin (PGI2) generation. Although dipyridamole alone had no effects on platelet aggregation, it potentiated the platelet aggregation inhibitory effects of aspirin in vitro in a dose-related fashion. Dipyridamole also enhanced the platelet aggregation inhibitory effect of synthetic PGI2 in vitro. Potentiation of aspirin- and PGI2-induced platelet aggregation inhibition was observed in therapeutic range (5-10 micrograms/ml). In an isolated umbilical vein model dipyridamole stimulated release of PGI2 at much higher concentration (50-100 microgram/ml). Treatment of umbilical vein with aspirin (180 micrograms/ml) for 10 min blocked the spontaneous release of PGI2. In aspirin-treated umbilical vein segments dipyridamole treatment did not cause PGI2 release as in the untreated segments. These experiments suggest that although dipyridamole enhances both aspirin- and PGI2-induced platelet aggregation inhibition in clinically achieved concentrations, much higher levels are necessary for PGI2 release from intact human vessels. Furthermore, aspirin treatment of human vessels may prevent release of PGI2 in response to dipyridamole by blocking cyclooxygenase enzyme.

6-Ketoprostaglandin F1 alpha↗