High concentrations of arachidonic acid induce platelet aggregation and serotonin release independent of prostagladin endoperoxides and thromboxane A2

1985 ◽  
Vol 841 (3) ◽  
pp. 283-291 ◽  
Author(s):  
Yoshiaki Hashimoto ◽  
Chikayuki Naito ◽  
Shoji Kume ◽  
Hirokazu Kato ◽  
Tsuyoshi Watanabe ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Thromboxane A2 ◽  
Serotonin Release ◽  
Induce Platelet Aggregation ◽  
High Concentrations

scholarly journals Hydrogen Peroxide Is Involved in Collagen-Induced Platelet Activation

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 484-490 ◽  
Author(s):  
Pasquale Pignatelli ◽  
Fabio M. Pulcinelli ◽  
Luisa Lenti ◽  
Pier Paolo Gazzaniga ◽  
Francesco Violi
Keyword(s):  
Hydrogen Peroxide ◽  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Phospholipase C ◽  
Platelet Activation ◽  
Acid Metabolism ◽  
Thromboxane A2 ◽  
Arachidonic Acid Metabolism ◽  
H2o2 Production ◽  
High Concentrations

Abstract In this study, we investigated whether (1) collagen-induced platelet aggregation is associated with a burst of H2O2, (2) this oxidant species is involved in the activation of platelets, and (3) the pathways of platelet activation are stimulated by H2O2. Collagen-induced platelet aggregation was associated with production of H2O2, which was abolished by catalase, an enzyme that destroys H2O2. H2O2 production was not observed when ADP or thrombin were used as agonists. Catalase inhibited dose-dependently thromboxane A2 production, release of arachidonic acid from platelet membrane, and Inositol 1,4,5P3 (IP3) formation. In aspirin-treated platelets stimulated with high concentrations of collagen, catalase inhibited platelet aggregation, calcium mobilization, and IP3 production. This study suggests that collagen-induced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway.

scholarly journals Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 399-406 ◽  
Author(s):  
JA Jakubowski ◽  
JM Maraganore
Keyword(s):  
Platelet Aggregation ◽  
Antithrombin Iii ◽  
Thromboxane A2 ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Thrombin Time ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Apparent Lack

A synthetic, tyrosine-sulfated, dodecapeptide (BG8865) modeled on residues 53–64 of hirudin was found to elevate the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human plasma in a dose-dependent manner. The most sensitive assay was the TT, which was prolonged 2 and 3 times control values at 2.2 and 4.1 micrograms/mL hirudin peptide, respectively. The sulfated dodecapeptide exhibited no dependency on antithrombin III as monitored by the APTT in the presence of sheep anti-human antithrombin III antibodies, and its activity was not neutralized by platelet releasates or platelet factor 4. In studies of thrombin-induced platelet activation, the hirudin peptide was found to block aggregation, serotonin release and thromboxane A2 generation. At thrombin concentrations of 0.25 U/mL, the IC50 (concentration resulting in 50% inhibition) for inhibition of platelet aggregation was 0.72 micrograms/mL peptide. Inhibition of TXA2 generation and serotonin release correlated closely with inhibition of aggregation. Using platelets from patients with clinically documented heparin-induced thrombocytopenia anticoagulant doses of heparin were found to induce platelet aggregation and thromboxane A2 generation. In sharp contrast, anticoagulant-equivalent doses of hirudin peptide had no effect on patient platelets, as evidenced by a lack of platelet aggregation and thromboxane A2 generation. These data provide compelling in vitro evidence that the hirudin peptide has several potential advantages over heparin, namely effective inhibition of thrombin-induced platelet activities, co-factor independence, insensitivity to endogenous heparin- neutralizing factors, and an apparent lack of direct or immune-mediated platelet stimulating properties.

scholarly journals Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 399-406
Author(s):  
JA Jakubowski ◽  
JM Maraganore
Keyword(s):  
Platelet Aggregation ◽  
Antithrombin Iii ◽  
Thromboxane A2 ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Thrombin Time ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Apparent Lack

Abstract A synthetic, tyrosine-sulfated, dodecapeptide (BG8865) modeled on residues 53–64 of hirudin was found to elevate the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human plasma in a dose-dependent manner. The most sensitive assay was the TT, which was prolonged 2 and 3 times control values at 2.2 and 4.1 micrograms/mL hirudin peptide, respectively. The sulfated dodecapeptide exhibited no dependency on antithrombin III as monitored by the APTT in the presence of sheep anti-human antithrombin III antibodies, and its activity was not neutralized by platelet releasates or platelet factor 4. In studies of thrombin-induced platelet activation, the hirudin peptide was found to block aggregation, serotonin release and thromboxane A2 generation. At thrombin concentrations of 0.25 U/mL, the IC50 (concentration resulting in 50% inhibition) for inhibition of platelet aggregation was 0.72 micrograms/mL peptide. Inhibition of TXA2 generation and serotonin release correlated closely with inhibition of aggregation. Using platelets from patients with clinically documented heparin-induced thrombocytopenia anticoagulant doses of heparin were found to induce platelet aggregation and thromboxane A2 generation. In sharp contrast, anticoagulant-equivalent doses of hirudin peptide had no effect on patient platelets, as evidenced by a lack of platelet aggregation and thromboxane A2 generation. These data provide compelling in vitro evidence that the hirudin peptide has several potential advantages over heparin, namely effective inhibition of thrombin-induced platelet activities, co-factor independence, insensitivity to endogenous heparin- neutralizing factors, and an apparent lack of direct or immune-mediated platelet stimulating properties.

scholarly journals Hydrogen Peroxide Is Involved in Collagen-Induced Platelet Activation

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 484-490 ◽  
Author(s):  
Pasquale Pignatelli ◽  
Fabio M. Pulcinelli ◽  
Luisa Lenti ◽  
Pier Paolo Gazzaniga ◽  
Francesco Violi
Keyword(s):  
Hydrogen Peroxide ◽  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Phospholipase C ◽  
Platelet Activation ◽  
Acid Metabolism ◽  
Thromboxane A2 ◽  
Arachidonic Acid Metabolism ◽  
H2o2 Production ◽  
High Concentrations

In this study, we investigated whether (1) collagen-induced platelet aggregation is associated with a burst of H2O2, (2) this oxidant species is involved in the activation of platelets, and (3) the pathways of platelet activation are stimulated by H2O2. Collagen-induced platelet aggregation was associated with production of H2O2, which was abolished by catalase, an enzyme that destroys H2O2. H2O2 production was not observed when ADP or thrombin were used as agonists. Catalase inhibited dose-dependently thromboxane A2 production, release of arachidonic acid from platelet membrane, and Inositol 1,4,5P3 (IP3) formation. In aspirin-treated platelets stimulated with high concentrations of collagen, catalase inhibited platelet aggregation, calcium mobilization, and IP3 production. This study suggests that collagen-induced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway.

In Vitro Incorporation and Metabolism of Icosapentaenoic and Docosahexaenoic Acids in Human Platelets - Effect on Aggregation

1986 ◽  
Vol 56 (01) ◽  
pp. 057-062 ◽  
Author(s):  
Martine Croset ◽  
M Lagarde
Keyword(s):  
Arachidonic Acid ◽  
Fatty Acid ◽  
Platelet Aggregation ◽  
Fatty Acid Distribution ◽  
Thromboxane A2 ◽  
Human Platelets ◽  
Aggregation Response ◽  
Docosahexaenoic Acids ◽  
Membrane Level

SummaryWashed human platelets were pre-loaded with icosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or EPA + DHA and tested for their aggregation response in comparison with control platelets. In fatty acid-rich platelets, an inhibition of the aggregation could be observed when induced by thrombin, collagen or U-46619. The strongest inhibition was observed with DHA-rich platelets and it was reduced when DHA was incorporated in the presence of EPA.Study of fatty acid distribution in cell lipids after loading showed that around 90% of EPA or DHA taken up was acylated into phospholipids and a very small amount (less than 2%) remained in their free and hydroxylated forms. DHA was more efficiently acylated into phosphatidylethanolamine (PE) than into phosphatidylinositol (PI) in contrast to what observed with EPA, and both acids were preferentially incorporated into phosphatidylcholine (PC). EPA inhibited total incorporation of DHA and increased its relative acylation into PE at the expense of PC. In contrast, DHA did not affect the acylation of EPA. Upon stimulation with, thrombin, EPA was liberated from phospholipids and oxygenated (as judged by the formation of its monohydroxy derivative) whereas DHA was much less metabolized, although consistently transferred into PE.It is concluded that EPA and DHA might affect platelet aggregation via different mechanisms when pre-loaded in phospholipids. Whereas EPA is known to alter thromboxane A2 metabolism from endogenous arachidonic acid, by competing with it, DHA might act directly at the membrane level for inhibiting aggregation.

scholarly journals Lipid peroxidation, prostacyclin and thromboxane A2 in pigs depleted of vitamin E and selenium and supplemented with linseed oil

1995 ◽  
Vol 74 (3) ◽  
pp. 369-380 ◽  
Author(s):  
Maeve R. Nolan ◽  
Seamus Kennedy ◽  
W. John Blanchflower ◽  
D. Glenn Kennedy
Keyword(s):  
Lipid Peroxidation ◽  
Arachidonic Acid ◽  
Vitamin E ◽  
Platelet Aggregation ◽  
Plasma Concentration ◽  
Linseed Oil ◽  
Thromboxane A2 ◽  
Dietary Factors ◽  
Biochemical Effects ◽  
Skeletal Myopathy

In a 2×2 balanced factorial experiment the biochemical effects on pigs of two dietary factors were investigated. The first factor was α-tocopherol and Se supplementation and the second factor was supplementation with α-tocopherol-stripped linseed oil. In pigs fed on diets depleted of α-tocopherol and Se, increases in concentrations of markers of lipid peroxidation (4-hydroxynonenal and hexanal) were observed. However, skeletal myopathy was only observed in those pigs fed on diets depleted of α-tocopherol and Se and supplemented with oil. In those pigs, increased lipid peroxidation was observed in heart and supraspinatus muscle. The plasma concentration of thromboxane B2 was increased in pigs fed on diets depleted of α-tocopherol and Se, suggesting an increased tendency towards platelet aggregation. However, this change was reversed in pigs depleted of α-tocopherol and Se, but supplemented with oil. This may have been a consequence of loss of arachidonic acid, the substrate for thromboxane formation, as a result of lipid peroxidation.

scholarly journals Activation of human platelets by immune complexes prepared with cationized human IgG

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3045-3051
Author(s):  
M Schattner ◽  
M Lazzari ◽  
AS Trevani ◽  
E Malchiodi ◽  
AC Kempfer ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Immune Complexes ◽  
Platelet Rich Plasma ◽  
Human Platelets ◽  
Human Igg ◽  
Experimental Conditions ◽  
Induce Platelet Aggregation ◽  
Soluble Immune Complexes ◽  
High Concentrations

The present study shows that the ability of soluble immune complexes (IC), prepared with human IgG and rabbit IgG antibodies against human IgG, to trigger platelet activation was markedly higher for IC prepared with cationized human IgG (catIC) compared with those prepared with untreated human IgG (cIC). CatIC induced platelet aggregation and adenosine triphosphate release in washed platelets (WP), gel-filtered platelets (GFP), or platelet-rich plasma (PRP) at physiologic concentrations of platelets (3 x 10(8)/mL) and at low concentrations of catIC (1 to 30 micrograms/mL). On the contrary, under similar experimental conditions, cIC did not induce aggregation in PRP, WP, or GFP. Low aggregation responses were only observed using high concentrations of both WP (9 x 10(8)/mL) and cIC (500 micrograms/mL). Interestingly, catIC were also able to induce platelet activation under nonaggregating conditions, as evidenced by P-selectin expression. Cationized human IgG alone did not induce platelet aggregation in PRP but triggered either WP or GFP aggregation. However, the concentration needed to induce these responses, was about eightfold higher than those required for catIC. The responses induced either by catIC or cationized human IgG were completely inhibited by treatment with heparin, dextran sulphate, EDTA, prostaglandin E1, or IV3, a monoclonal antibody against the receptor II for the Fc portion of IgG (Fc gamma RII). The data presented in this study suggest that IgG charge constitutes a critical property that conditions the ability of IC to trigger platelet activation.

Diabetic Retinopathy And Thromboxane Like Substance

1981 ◽  
Author(s):  
M A Lazzari ◽  
M Gimeno ◽  
N M Sutton ◽  
J R Lopez
Keyword(s):  
Diabetes Mellitus ◽  
Arachidonic Acid ◽  
Diabetic Retinopathy ◽  
Risk Factor ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Thromboxane A2 ◽  
Initial Step ◽  
Platelet Activity

Diabetes Mellitus (DM) is a risk factor in the development of vasculopathies and its complications. It produces also its own microangiopathy. Evidence was reported of increased platelet activity in DM in different assays. Platelets aggregation and the arachidonic cycle could play a key role in the increased tendency to thrombosis. A disorder of ratio TXA2/PGI2, two opposing prostaglandin derivatives, could be the initial step. We intended to evaluate a thromboxane like substance (TLS) produced from platelet rich plasma (PRP) and to compare between normals and diabetic retinopathy (DR) patients. TLS was measured in 16 controls and 16 patients. Assay was done with the aggregating activity developed in PRP (considered TLS) after addition of arachidonic acid (f.c. 2 mM). The supernatant of the PRP (100 μl) was taken 40 sec. after the aggregation started and were added to a normal PRP treated with aspirin (f.c. 40 μl/ml) adjusted to 250.000 - 300.000 pl/μl and the degree of platelet aggregation measured in a Chrono Log Aggregometer. TLS was inactivated after its incubation during 2 min. at 37°C. This finding suggests this activity is due to TXA2.The results obtained (expressed in % of platelet aggregation) were: controls x 16.37% ± 6.28 and DR x 36.00% ± 9.72.The increase detected in the DR group supports previous experimental reports suggesting the role of the thromboxane A2 in vaso occlusive complication of diabetes mellitus.

Lack Of Inhibition Of Thromboxane Production Despite Inhibition Of Platelet Function By 1,3-Bis(2 Chloroethyl)-1-Nitrosourea (BCNU)

1981 ◽  
Author(s):  
R McKenna ◽  
T Ahmad ◽  
A Prancan ◽  
D Simon ◽  
H Frischer
Keyword(s):  
Arachidonic Acid ◽  
Oxygen Consumption ◽  
Platelet Aggregation ◽  
Acetylsalicylic Acid ◽  
Platelet Function ◽  
Human Platelet ◽  
Thromboxane A2 ◽  
Rabbit Aorta ◽  
Thromboxane Production ◽  
Platelet Thromboxane

We have previously shown that BCNU inhibits human platelet glutathione reductase (GSSG-R) prior to inhibiting platelet function; since thromboxane production is important in platelet function, we evaluated the effect of BCNU induced inhibition of GSSG-R on platelet thromboxane production.Control platelet GSSG-R activity was 0.091 ]jmoles NAD(P)H oxidized min-1lmg-1 protein at 37°C (±0.015 S.D.; n=9); inhibition was detectable at 10-7M% BCNU (70% of control) with a >90% inhibition at and above 10-5M BCNU. Platelet aggregation in response to 1.5×10-3M Arachidonic acid (AA), 10 μM epinephrine, 6 μg/ml equine collagen and 3 μM ADP were inhibited at 10-5M BCNU and abolished at 10-4 BCNU.BCNU (10-3M) did not affect the increase in oxygen consumption induced by AA. Using the rabbit aorta superfusion bioassay for thromboxane A2 (TXA2), threshold concentrations of AA in 10-5 and 10-4 BCNU platelets resulted in an increased measure of aortic tension 13.5 ± 9.4 mm S.D. (n=6) and 23.2 ± 9.5 mm respectively, compared with control values of 4.5 ± 2.4. Acetylsalicylic acid (5 × l0-4M) inhibited the contraction: 1.7 ± 1.1 (n=5). The conversion of 14C AA to thromboxane B2 (TXB2) and PGE2, as measured by radio TLC, was not decreased in BCNU treated platelets. There is a significant increase in TXB2 (p<0.05;n=4) and in the ratio of TXB2:PGE2 in platelets treated with 10-4M BCNU and 10-3M imidazole when compared to platelets treated with imidazole alone.In conclusion BCNU induced inhibition of platelet GSSG-R and platelet function occurs despite preservation of thromboxane production

Phospholipase A2-Induced Platelet Aggregation, Release and Lysis.

1979 ◽  
Author(s):  
D. Heinrich ◽  
S. Beckmann
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Phospholipase A2 ◽  
Platelet Membrane ◽  
Membrane Phospholipids ◽  
Specific Antibodies ◽  
High Concentrations

Activation of washed platelets by exogenous phospholipase A2 (PIA2) purified from crotalus terrificus terrificus venom was studied. Platelets were labeled with 14C-serotonin and 51chromium and resuspended in Tyrode/albumin (TA). With 1-5 μg/ml (final conc.) of crotalus PIA2 no direct platelet alterations were observed. These platelets, however, were refractory to collagen - but not to thrombin or HLA-specific antibodies.10-50 μg/ml crotalus PIA2 rapidly induced platelet aggregation and release 100 μg/ml crotalus PIA2 induced platelet lysis.PIA2-induced platelet alterations were inhibited by EDTA, PGE1, ASS and apyrase. Crotapotin, an acid peptid isolated from crotalus venom, forms complexes with crotalus PIA2 and specifically inhibits PIA2-induced platelet alterations.Conclusion: PIA2-induced platelet alterations are due to liberation of arachidonic acid from phospholipids of the platelet membrane inducing prostaglandin and thromboxane synthesis. With high concentrations of PIA2 breakdown of membrane phospholipids will lead to platelet lysis.

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