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At least 19 recordsLinked to original sources
PubMed1976

Activation of platelets by platelet activating factor (PAF) derived from IgE-sensitized basophils. IV. PAF does not activate platelet factor 3 (PF3).

Platelet activating factor (PAF) derived from antigen-stimulated, IgE-sensitized rabbit basophils acts on platelets to induce aggregation and secretion of their content of granule-bound vasoactive amines. Despite this, PAF did not activate platelet factor 3. In contrast, collagen induced aggregation, secretion and PF3 activation in the washed platelets. Other stimuli (ADP, C3b, thrombin) also initiated both secretion and PF3 activation. A wide dose range of PAC, including those giving maximal secretion and aggregation, were ineffictive in making PF3 available and the possibility that PAF inhibited PF3, or its generation, was also excluded. It is concluded that PAF is a unique stimulus for platelets and that secretion and aggregation are not necessarily accompanied by PF3 generation.

Animals↗
PubMed2026

Neutrophil extracellular traps induced by a monoclonal anti-phosphatidylserine/prothrombin antibody activate platelets in vitro.

Antiphospholipid syndrome (APS) is an autoimmune thrombotic disorder characterized by the presence of antiphospholipid antibodies, including anti-phosphatidylserine/prothrombin antibodies (aPS/PT). While neutrophil extracellular traps (NETs) are implicated in the pathogenesis of APS, the role of aPS/PT in NET induction and its contribution to thrombosis remain unclear. This study aimed to clarify the effects of NETs induced by a monoclonal aPS/PT antibody on platelet activation and their potential contribution to thrombo-inflammatory responses. NETs were induced by stimulating peripheral blood neutrophils from healthy donors with aPS/PT. Their morphology and platelet-activating capacity were compared with NETs induced by anti-neutrophil cytoplasmic antibodies (ANCAs). Proteomic analyses were conducted to comprehensively compare protein compositions of these NETs, and candidate proteins associated with platelet activation in aPS/PT-induced NETs were identified. Functional inhibition assays were then conducted to assess whether blocking these candidates would suppress aPS/PT-induced NET-mediated platelet activation. We found that binding of aPS/PT to neutrophils induced NET formation, with a larger and more fibrous morphology compared to ANCA-induced NETs. Platelets trapped in aPS/PT-induced NETs showed significantly higher activation compared to those trapped in ANCA-induced NETs. Proteomic analyses identified histone H3 as a potential mediator of platelet activation in aPS/PT-induced NETs. Correspondingly, plasma concentrations of H3.1 nucleosome were significantly higher in patients with APS than in healthy controls. Blockade of histone H3 using a neutralizing antibody significantly suppressed platelet activation mediated by aPS/PT-induced NETs. These findings suggest that aPS/PT-induced NETs contribute to platelet activation and may promote thrombo-inflammatory responses in APS. Targeting histone H3 within aPS/PT-induced NETs may provide a potential therapeutic strategy for thrombo-inflammatory processes in APS.

Humans↗
PubMed1976

Activation of platelets by platelet-activating factor (PAF) derived from IgE-sensitized basophils. II. The role of serine proteases, cyclic nucleotides, and contractile elements in PAF-induced secretion.

Secretion of serotonin from platelets induced by platelet-activating factor (PAF) derived from antigen-stimulated, IgE-sensitized rabbit basophils was studied to further characterize the biochemical requirements. Inhibition of secretion with diisopropylphosphofluoridate (DFP) was observed if the DFP was present during the reaction, but not if platelets or PAF were pretreated with the inhibitor. This suggested a role for an activatable serine protease in the secretion. Supporting evidence came from the observation that other protease inhibitors and a variety of low molecular weight amino acid esters were also inhibitory. TAMe was most effective, and AGLMe and LeuMe were inactive, indicating a specificity for different esters. Secretion was reduced by agents that increased intracellular cyclic AMP (cAMP), but enhanced by alpha-adrenergic stimulation, which reduced the levels of cAMP. Concurrent with PAF-induced secretion, a reduction in cAMP levels was observed. No effect of cyclic GMP or cholinergic stimulation was found. Secretion was inhibited by colchicine and enhanced by cytochalasin B, suggesting a role for microfilaments and microtubules. The effects of these three systems on PAF-induced secretion indicate the basic uniformity of the secretory process in platelets (and other cells) whatever the stimulus. The uniqueness of the reaction apparently lies in the stimulus-receptor interaction and the nature of the serine protease which is activated.

Adrenergic Agonists↗
PubMed1979

Aggregation of activated platelets with Walker 256 carcinoma cells.

Walker 256 carcinoma cells form irreversible aggregates with rat platelets activated by ADP or serotonin. Since serotonin induces platelet shape change but not platelet aggregation the degree of activation indicated by the disc-sphere transformation is sufficient for platelets to interact with these tumor cells. This is confirmed by experiments with spheroid washed platelets which form irreversible mixed aggregates with Walker 256 carcinoma cells without a stimulus being required. This type of tumor cells could react with platelets in vivo, provided the platelets are activated by disturbed blood flow or contact with subendothelium. Our observations can explain why other authors found no interaction between Walker 256 carcinoma cells and non-activated platelets in vitro even though platelets contributed to the formation of bloodborne metastases of this tumor.

Adenosine Diphosphate↗
PubMed1978

Activation of human platelets by platelet activating factor (PAF) derived from sensitized rabbit basophils.

Rabbit basophil-derived platelet activating factor (PAF), a mediator of anaphylaxis, induces the aggregation and release of serotonin from rabbit platelets. In the present study, we report that PAF obtained by challenge of specifically sensitized rabbit basophils induced the noncytotoxic release of serotonin from human platelets; maximal extent of release ranged between 34-46%. This release was unaltered in the presence of indomethacin, indicating that such secretion was not a consequence of contaminating arachidonic acid; further, as previously demonstrated with platelets of rabbit origin, it was markedly independent of a requirement for an intact prostaglandin biosynthetic pathway. In contrast to its effect upon rabbit platelets, rabbit PAF did not induce aggregation of human platelets, suggesting that the aggregation and secretion reactions induced by this agent are separable and that this cross-species activation may be incomplete. Whether this is a result of the differential ability of rabbit PAF to bind to and activate rabbit as compared to human platelets or to the existence of a family of PAF molecules is not yet known. The capacity of PAF to participate in a secretory event involving human platelets lends support to the belief that PAF may play an important ubiquitous role in the cooperative, leucocyte-dependent, release of vasoactive amines which results in increased vascular permeability.

Animals↗
PubMed1977

Activation of rabbit platelets by platelet-activating factor derived from IgE-sensitized basophils. Characteristics of the aggregation and its dissociation from secretion.

Platelet-activating factor (PAF) is liberated from antigen-stimulated, IgE-sensitized rabbit basophils and induces aggregation of platelets and secretion of their content of vasoactive amines. Experiments were performed to determine the relationship between these two platelet responses to this stimulus.(a) Aggregation was initiated by appreciably lower concentrations of PAF than were required to produce even minimal release of constituents. PAF-induced aggregation was also resistant to agents which destroy ADP, such as creatine phosphate/creatine phosphokinase or apyrase, and occurred with platelets made unresponsive (refractory) to ADP. It was concluded that PAF can induce aggregation by a mechanism which is distinguishable from the release reaction and from the aggregating effect of ADP.(b) Secretion can probably occur independently of aggregation because incubation without agitation resulted in secretion without detectable aggregation.(c) Despite the suggestion that the two platelet responses can be independent, they may be induced by the same stimulus. This was indicated by experiments in which platelets specifically desensitized to PAF-induced secretion were also found to be unresponsive to PAF-stimulated aggregation. Moreover, identical levels of inhibition and identical inhibition profiles were obtained for both responses with serine esterase inhibitor, diisopropylphosphofluoridate, and with amino acid esters. It was concluded that the same stimulus-specific activable protease (esterase) was most likely involved in PAF-induced aggregation and secretion.

Adenosine Diphosphate↗
PubMed1976

Activation and desensitization of platelets by platelet-activating factor (PAF) derived from IgE-sensitized basophils. I. Characteristics of the secretory response.

The secretion of vasoactive amines from rabbit platelets induced by the platelet-activating factor (PAF) derived from IgE-sensitized rabbit basophils, was examined. The secretion required calcium has previously been shown to be noncytotoxic and was optimal in both rate and extent at 37 degrees C and pH 7.2. Different temperature-sensitive steps were rate limiting for secretion above or below 20 degrees C. The rate of secretion was dependent upon the concentration of PAF and also of platelets. Maximal rates were observed with relatively low concentrations of platelets (2.5 X 10(8)/ml), sharply contrasting with other platelet stimuli such as C3 or thrombin. The extent of secretion was dependent upon PAF concentration until a maximum of 50 or 60% of the serotonin was released and then declined with increasing amounts of PAF. This was interpreted to result from the platelets becoming desensitized to the PAF, a process that shuts off the secretion. Such a desensitization was demonstrated and was shown to be stimulus specific, i.e., other stimuli could still induce secretion from PAF-desensitized platelets. PAF extracted with ethanol from the albumin to which it is usually bound during preparation, exhibited similar characteristics, except that secretion of up to 90% of the serotonin was induced. The extracted PAF thus seemed less able to induce the desensitization. Its use did provide important evidence that populations of rabbit platelets are relatively homogenous in their ability to respond to PAF.

Animals↗
PubMed1978

[Macrophage origin of platelet activating factor].

Platelet-activating factor (P.A.F.) is a mediator of anaphylaxis released from human and Rabbit basophils which causes aggregation of platelets and release of their vasoactive amines. We have induced the release of P.A.F. from Rat peritoneal cells (P.C.) with ionophore A 23187. After fractionation of P.C. on 5-15% Ficoll gradients, P.A.F. was obtained from macrophage-rich but not from mastocyte-rich fractions and from adherent cells but not from non adherent cells. These data suggest an important new function for the macrophage: aggregation of platelets and release of their vasoactive amines and others mediators of inflammation.

Animals↗
PubMedDate not supplied

[Isolation and partial characterization of (PAF) platelet-activating-factor].

Platelet-activating-factor is a new mediator of anaphylaxis released in numerous mammalian species from basophils and mastocytes by antigens, anti-IgE antiserum, ionophore A 23187, C3a, C5a and neutrophil cationic protein. It is probably a lyso-1-phosphatidylcholine, as evidenced by structural studies isomg phospholipases. It may explain the involvement of platelets in immunopathology.

Animals↗
PubMed1977

Platelet activation in acute cerebral ischaemia. Serial measurements of platelet function in cerebrovascular disease.

Circulating platelet aggregates formed in vivo were serially measured, and platelet-aggregation thresholds were determined in vitro in 82 patients with acute cerebral ischaemia. The percentage of aggregated platelets was increased in 53 patients with completed stroke (30.9% +/- 2.0) and in 29 patients with transient ischaemic attacks (34.1% +/- 2.3), all studied within 10 days of the acute event. These values were higher (P less than 0.001) than levels of aggregated platelets in 30 patients with non-vascular neurological disease (16.8% +/- 2.3). The percentage of aggregated platelets returned to normal 10 days to 6 wk after acute cerebral ischaemia. Aspirin and dipyridamole did not affect either the increase in or subsequent normalisation of circulating-platelet-aggregate levels in these patients. Platelet-aggregation sensitivity to adenosine diphosphate and adrenaline was also increased in patients with acute cerebral ischaemia, but this abnormally resolved during convalescence. Platelet activation is abnormal in acute cerebral ischaemia but usually returns to normal with or without anti-platelet therapy. This activation of platelets may contribute to the clinical manifestations of occlusive vascular disease.

Acute Disease↗
PubMed2026

Systemic Platelet Activation and Respiratory Exacerbations, Pulmonary Symptoms, and Mortality among Current and Former Smokers in SPIROMICS.

RATIONALE: Platelet activation is elevated in chronic obstructive pulmonary disease (COPD) and associated with self-reported respiratory symptoms. Observational studies link the antiplatelet drug aspirin to lower exacerbation rates and fewer symptoms. However, it is unknown if platelet activation predicts incident respiratory exacerbations or mortality. OBJECTIVE: Is systemic platelet activation prospectively associated with respiratory exacerbations and mortality among ever-smokers with or at risk for COPD? METHODS: We measured two systemic platelet activation biomarkers, urinary 11-dehydro-thromboxane B2 (11dTxB2) and plasma soluble CD40 ligand (sCD40L), at baseline in self-reported aspirin non-users in the longitudinal SPIROMICS cohort. Adjusted generalized negative binomial and linear mixed-effects models assessed associations between these biomarkers and prospective rates of total and severe exacerbations, plus cross-sectional and longitudinal respiratory health (St. George's Respiratory Questionnaire, COPD Assessment Test, modified Medical Research Council questionnaire, and six minute walk distance). Cox proportional hazard and competing risk models evaluated associations between platelet activation biomarkers and all-cause and cause-specific mortality. RESULTS: Among 2,711 participants, 1,572 (58.0%) reported aspirin non-use; of these, 1,433 and 1,437 had 11dTxB2 and sCD40L measured, respectively. Over a median 6.6 years, a two-fold higher baseline 11dTxB2 was associated with increased rates of total (8.8%; 95%CI: 0.4-17.8%) and severe (18.1%; 95%CI: 5.1-32.6%) exacerbations. Although there were no significant interactions, there was a trend toward higher severe exacerbation rates among current cigarettes smokers and those with COPD. There were no significant results for sCD40L. Among aspirin non-users, higher 11dTxB2, but not sCD40L, was associated with worse cross-sectional respiratory health and modestly increased all-cause mortality over a median 8.2 years (adjusted hazard ratio 1.11; 95%CI: 1.00-1.24). After covariate adjustment, there were no associations with longitudinal respiratory health or cause-specific mortality. CONCLUSIONS: Systemic platelet activation, measured by urinary 11dTxB2, is a statistically significant but modest predictor of respiratory exacerbations and all-cause mortality in individuals with or at risk for COPD, suggesting its potential utility as a prognostic and predictive biomarker for antiplatelet therapy trials. CLINICAL TRIAL REGISTRATION: NCT01969344.

aspirin↗
PubMed1979

Role of platelets in lysis of dilute plasma clots: requirement for metabolically active platelets.

The role of platelets in clot lysis has been investigated functionally with the use of dPRP clots formed at 4 degrees and shifted to 37 degrees. Clots handled in this manner lysed in 6 hr (+/- 1 hr), whereas clots formed at 4 degrees or at 37 degrees and held at those temperatures, or clots formed from dPPP did not lyse in less than 20 hr. dPRP clots having the shorter (6 hr) lysis time released 14C-5-HT at the time of the temperature shift. Preincubation of dPRP with antimycin A and 2-deoxy-D-glucose before addition of thrombin prolonged the clot lysis to 26 hr and inhibited release of 14C-5-HT at the time of the temperature shift. These studies demonstrate that metabolically active platelets are required to mediate the optimal clot lysis seen in the 4 degrees to 37 degrees system and that they continue to function (i.e., take up and release 5-hydroxytryptamine) after they have been incorporated into a clot. Thus the dPRP clot lysis system provides a model by which the timing and sequence of the interaction of metabolically active platelets with the fibrin framework of the formed clot can be studied.

Blood Coagulation↗
PubMed2018

Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model.

Platelet hyperaggregation and hypercoagulation are associated with increase of thrombogenic risk, especially in patients with type 2 diabetes (T2D). High activity of P2Y12 receptor is found in T2D patients, exposing such patients to a prothrombotic condition. P2Y12 is a promising target for antiplatelet, but due to P2Y12 receptor constitutive activation, the clinical practical phenomena such as "clopidogrel resistance" are commonly occurring. In this study, we investigate the role of lncRNA on platelet activation. By lncRNA array, we screened thousands of differentially expressed lncRNA in megakaryocytes from T2D patients and confirmed that lncRNA metallothionein 1 pseudogene 3 (MT1P3) was significantly upregulated in megakaryocytes from T2D patients than in healthy controls. And we further investigate the biofunction of MT1P3 on platelet activation and the regulatory mechanism on p2y12. MT1P3 was positively correlated with p2y12 mRNA levels and promoted p2y12 expression by sponging miR-126. Knockdown of MT1P3 by siRNA reduced p2y12 expression, inhibiting platelet activation and aggregation in diabetes animal model. In conclusion, our findings identify MT1P3 as a key regulator in platelet activation by increasing p2y12 expression through sponging miR-126 under T2D condition. These findings may provide a new insight for managing platelet hyperactivity-related diseases.

Animals↗
PubMed1975

Passage of immune complexes through vascular walls. Evidence for the role of an immediate hypersensitivity mechanism and its mediator: platelet-activating factor.

An anaphylactic mechanism involving IgE-sensitized basophils is necessary for immune complex deposition in rabbits. Basophils under stimulation by the IgE-bound antigen actively release a platelet-activating factor. Increased vascular permeability results from action of vasoactive amines from basophils and from aggregated platelets and possibly direct action of PAF on vascular walls. This allows trapping of circulating complexes along vascular membranes. Once deposited complexes produce tissue injury by neutrophil-complement-dependent mechanisms. However, complex deposition seems pathogenic in itself for the glomerular basement membrane. PAF is a 1,100-dalton MW lipid, with hydrophobic properties and positive charge; it exists in human basophils. Patients suffering from SLE or undergoing anaphylactic shocks exhibit marked reduction of basophil counts and PAF level. We propose that anaphylactic increase of vasopermeability may be a common feature at early stages of many immune diseases associated with severe structural injury.

Animals↗