Consumption of plant extract supplement reduces platelet activating factor-induced platelet aggregation and increases platelet activating factor catabolism: a randomised, double-blind and placebo-controlled trial

AbstractPlatelet-activating factor (PAF) is a potent mediator of inflammation that plays a crucial role in atherosclerosis. The purpose of this study was to evaluate the effect of a dietary supplement containing mainly plant extracts on PAF actions and metabolism in healthy volunteers. A double-blind, placebo-controlled, 8 weeks’ duration study was performed. Healthy volunteers were randomly allocated into the supplement or the placebo group and fifty-eight of them completed the study. The supplement contained plant extracts (Aloe gel, grape juice, Polygonum cuspidatum) and vitamins. The activities of PAF metabolic enzymes: the two isoforms of acetyl-CoA:lyso-PAF acetyltransferase, cytidine 5’-diphospho-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-cholinephosphotransferase) and platelet-activating factor–acetylhydrolase (PAF-AH) in leucocytes and lipoprotein associated phospholipase-A2 in plasma were measured along with several markers of endothelial function. Platelet aggregation against PAF, ADP and thrombin receptor activating peptide was measured in human platelet-rich plasma by light transmission aggregometry. No difference was observed on soluble vascular cell adhesion molecule-1, sP-selectin and IL-6 levels at the beginning or during the study period between the two groups. Concerning PAF metabolism enzymes’ activity, no difference was observed at baseline between the groups. PAF-AH activity was only increased in the supplement group at 4 and 8 weeks compared with baseline levels. In addition, supplement consumption led to lower platelet sensitivity against PAF and ADP compared with baseline levels. However, a trial effect was only observed when platelets were stimulated by PAF. In conclusion, supplementation with plant extracts and vitamins ameliorates platelet aggregation primarily against PAF and secondarily against ADP and affects PAF catabolism by enhancing PAF-acetylhydrolase activity in healthy subjects.

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EFFECTIVENESS AND TOLERABILITY OF CV-3988, A SELECTIVE PAF ANTAGONIST, AFTER INTRAVENOUS ADMINISTRATION TO MAN

10.1055/s-0038-1642878 ◽

1987 ◽

Author(s):

J Arnout ◽

A Van Hecken ◽

I Delepeleire ◽

Y Miyamoto ◽

I Holmes ◽

...

Keyword(s):

Light Transmission ◽

Platelet Rich Plasma ◽

Biological Activities ◽

Wide Spectrum ◽

Platelet Activating Factor ◽

Controlled Study ◽

Dependent Manner ◽

Double Blind ◽

Health And Disease

Platelet activating factor (PAF) is a naturally occurring phospholipid with a wide spectrum of biological activities. Although PAF has been ascribed a potential role in various conditions including inflammation, asthma, glomerulonephritis and thrombosis, its precise function in physiologic/pathophysiologic processes remains unclear. The introduction of selective PAF receptor antagonists could represent a useful tool to extend our knowledge of the role of this mediator in health and disease.We have investigated the efficacy and tolerability of (RS)-2-methoxy-3-(octadecylcarbomoyloxy)propy1 2-(3-thiazolio)-ethyIphosphate (CV-3988, Takeda Chem. Ind), a selective PAF antagonist with structural analogies with PAF, after intravenous infusion in man in a double-blind, placebo-controlled study. The compound, in doses from 750 to 2,000 pg/kg, significantly reduced platelet sensitivity to PAF. The threshold aggregating concentration (TAC) of PAF was defined as the minimal concentration causing an irreversible aggregation with a maximal amplitude of at least 50% of the difference in light transmission between platelet rich plasma and platelet poor plasma. It increased in a dose-dependent manner reaching 3.6 times the basal TAC (p<0.0005) at the end and 2.60 times the basal TAC (p<0.0005) 4 hours after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 hours after the end of the infusion.CV-3988 did not cause major side effects nor changes in blood pressure, pulse or respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and four hours after the end of the infusion, indicating a slight haemolysis probably by high local concentrations at the infusion site.Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can be safely administered to man and should be useful in elucidating the role of PAF in health and disease.

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PLATELET-ACTIVATING FACTOR (PAF)-INDUCED INTRACELLULAR Ca MOBILIZATION IN HUMAN PLATELETS.

10.1055/s-0038-1643483 ◽

1987 ◽

Author(s):

K Matsuno ◽

F Katabami ◽

M Koyama ◽

K Abe ◽

K Sakurada ◽

...

Keyword(s):

Platelet Aggregation ◽

Light Transmission ◽

Platelet Rich Plasma ◽

Platelet Activating Factor ◽

Human Platelets ◽

Dependent Manner ◽

Platelet Suspension ◽

Fura 2 ◽

Intracellular Ca ◽

Specific Antagonist

PAF-induced intracellular Ca2+ mobilization and platelet aggregation were investigated in human platelets. Cytosolic free Ca2+ concentration ([Ca2+]cyt) was measured by using fluorescent 45Ca2+ probe quin2 and fura-2, and photoprotein aequorin. Ca2+ uptake was measured after stimulation by PAF. Platelet aggregation was studied by recording the change in light transmission with platelet rich plasma (PRP) or washed platelet suspension (WPS).These three Ca2+ -indicators could determine the elevation of [Ca2+ ]cyt that was stimulated by PAF in the presence of extra- cellular Ca2+ (quin2 method: 98.2nM to 289.7nM; fura-2 method: 102.OnM to 351.4nM; aequorin method: 4.1μM to 8.2μM). In the absence of extracellular Ca2+ , however, little elevation of [Ca2+ ]cyt was detected after stimulation by PAF. PAF could evoke the transient Ca2+ uptake.New PAF specific antagonist, ONO-6240 inhibited PAF-induced platelet aggregation at a concentration from lμM dose-dependently, whereas it didn’t inhibit collagen- and thrombin-induced platelet aggregation at a concentration of lOOyM. ONO-6240 inhibited PAF- induced increase in [Ca2+ ]cyt in a dose-dependent manner as deter mined by these Ca2+ -indicators, as well as platelet aggregation.These results suggest the increase in [Ca2+ ]cyt is responsible for platelet aggregation induced by PAF, and the increased Ca2+ is derived from external Ca2+ influx chiefly.

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Phospholipase C from Clostridium Perfringens Induces Human Platelet Aggregation in Plasma

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642761 ◽

1988 ◽

Vol 59 (02) ◽

pp. 236-239 ◽

Cited By ~ 2

Author(s):

Giovanna Barzaghi ◽

Chiara Cerletti ◽

Giovanni de Gaetano

Keyword(s):

Platelet Aggregation ◽

Receptor Antagonist ◽

Phospholipase C ◽

Clostridium Perfringens ◽

Human Platelet ◽

Ex Vivo ◽

Platelet Rich Plasma ◽

Platelet Activating Factor ◽

Inhibitory Effect ◽

Thromboxane Receptor Antagonist

SummaryWe studied the aggregating effect of different concentrations of phospholipase C (PLC) (extracted from Clostridium perfringens) on human platelet-rich plasma (PRP). PRP was preincubated with PLC for 3 min at 37° C and the platelet aggregation was followed for 10 min. The threshold aggregating concentration (TAG) of PLC was 3-4 U/ml.We also studied the potentiation of PLC with other stimuli on platelet aggregation. Potentiating stimuli, such as arachidonic acid (AA), ADP. Platelet Activating Factor (PAF) and U-46619 (a stable analogue of cyclic endoperoxides) were all used at subthreshold concentrations. We also studied the possible inhibitory effect of aspirin, apyrase, TMQ, a prostaglandin endoper- oxide/thromboxane receptor antagonist and BN-52021, a PAF receptor antagonist. Only aspirin and apyrase were able to reduce aggregation induced by PLC alone and PLC + AA and PLC + ADP respectively. TMQ and BN-52021 were inactive. In ex vivo experiments oral aspirin (500 mg) partially inhibited platelet aggregation induced by PLC alone, PLC + AA and PLC + ADP 2 and 24 h after administration. Aspirin 20 mg for 7 days also reduced aggregation induced by PLC + AA.

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The Effect of Warfarin Sodium on the Duration of Platelet Aggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655087 ◽

1967 ◽

Vol 18 (03/04) ◽

pp. 766-778 ◽

Cited By ~ 2

Author(s):

H. J Knieriem ◽

A. B Chandler

Keyword(s):

Platelet Count ◽

Placebo Group ◽

Platelet Aggregation ◽

Prothrombin Time ◽

Platelet Rich Plasma ◽

Healthy Adults ◽

Double Blind Study ◽

Double Blind ◽

Warfarin Sodium

SummaryThe effect of the administration of warfarin sodium (Coumadin®) on the duration of platelet aggregation in vitro was studied. Coumadin was given for 4 consecutive days to 10 healthy adults who were followed over a period of 9 days. The duration of adenosine diphosphate-induced platelet aggregation in platelet-rich plasma, the prothrombin time, and the platelet count of platelet-rich plasma were measured. Four other healthy adults received placebos and participated in a double-blind study with those receiving Coumadin.Although administration of Coumadin caused a prolongation of the prothrombin time to 2 or 21/2 times the normal value, a decrease in the duration of platelet aggregation was not observed. In most individuals who received Coumadin an increase in the duration of platelet aggregation occurred. The effect of Coumadin on platelet aggregation was not consistently related to the prothrombin time or to the platelet count. In the placebo group there was a distinct relation between the duration of platelet aggregation and the platelet count in platelet-rich plasma.The mean increase in the duration of platelet aggregation when compared to the control value before medication with Coumadin was 37.7%. In the placebo group there was a mean increase of 8.4%. The difference between the two groups is significant (p <0.001). Increased duration of platelet aggregation also occurred in two individuals who received Coumadin over a period of 10 and 16 days respectively.

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The Effect of Collagen Mediated Platelet Release on Plasma Prekallikrein Activation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661014 ◽

1984 ◽

Vol 51 (01) ◽

pp. 037-041 ◽

Cited By ~ 2

Author(s):

K M Weerasinghe ◽

M F Scully ◽

V V Kakkar

Keyword(s):

Platelet Aggregation ◽

Healthy Volunteers ◽

Platelet Rich Plasma ◽

Age Groups ◽

Inhibitory Effect ◽

Age Group ◽

Platelet Factor ◽

Activated Platelets ◽

Platelet Release ◽

Collagen Treatment

SummaryCollagen mediated platelet aggregation caused -5.6 ± 6.7% inhibition and +39.1 ± 15.2% potentiation of prekallikrein activation in plasma from normal healthy volunteers between 20–40 and 50–65 years of age, respectively (n = 15, p <0.01). The amouns of platelet factor-four (PF4) released in the two groups were not significantly different. Collagen treatment in the presence of indomethacin caused +11.5 ± 3.6% and +59.6 ± 19.5% potentiation in the 20–40 and 50–65 age groups respectively (p <0.02). Adrenaline mediated platelet aggregation caused -55.2 ± 7.1% and -35.2 ± 8.3% inhibition in the 20–40 and 50–65 age groups, respectively. Collagen treatment of platelet-deficient-plasma and platelet-rich-plasma in EDTA also caused potentiation of prekallikrein activation.The results indicate that the observed degree of prekallikrein activation after platelet aggregation is a net result of the inhibitory effect of PF4 and the potentiatory effect of activated platelets. The potentiatory effect was greater after collagen treatment as compared to adrenaline treatment, and in the 50–65 age group as compared to the 20–40 age group.

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Commentary Author Reply to “Regarding ‘Platelet-Rich Plasma in Patients With Partial-Thickness Rotator Cuff Tears or Tendinopathy Leads to Significantly Improved Short-Term Pain Relief and Function Compared With Corticosteroid Injection: A Double-Blind Randomized Controlled Trial’”

Arthroscopy The Journal of Arthroscopic and Related Surgery ◽

10.1016/j.arthro.2021.03.022 ◽

2021 ◽

Vol 37 (5) ◽

pp. 1376

Author(s):

Andrew J. Sheean

Keyword(s):

Randomized Controlled Trial ◽

Platelet Rich Plasma ◽

Corticosteroid Injection ◽

Controlled Trial ◽

Rotator Cuff Tears ◽

Author Reply ◽

Short Term ◽

Double Blind ◽

Randomized Controlled ◽

And Function

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Use of platelet-rich plasma to suspend noncultured epidermal cell suspension improves repigmentation after autologous transplantation in stable vitiligo: a double-blind randomized controlled trial

International Journal of Dermatology ◽

10.1111/ijd.14286 ◽

2018 ◽

Vol 58 (4) ◽

pp. 472-476 ◽

Cited By ~ 5

Author(s):

Nimitha Parambath ◽

Vinod K. Sharma ◽

Anita S. Parihar ◽

Kanika Sahni ◽

Somesh Gupta

Keyword(s):

Randomized Controlled Trial ◽

Cell Suspension ◽

Epidermal Cell ◽

Platelet Rich Plasma ◽

Controlled Trial ◽

Autologous Transplantation ◽

Double Blind ◽

Randomized Controlled

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Enhanced platelet aggregation and activation under conditions of hypothermia

Thrombosis and Haemostasis ◽

10.1160/th07-03-0189 ◽

2007 ◽

Vol 98 (12) ◽

pp. 1266-1275 ◽

Cited By ~ 41

Author(s):

Ruben Xavier ◽

Ann White ◽

Susan Fox ◽

Robert Wilcox ◽

Stan Heptinstall

Keyword(s):

Cardiac Surgery ◽

Platelet Aggregation ◽

Platelet Function ◽

Whole Blood ◽

Platelet Rich Plasma ◽

Baseline Levels ◽

Spontaneous Aggregation ◽

High Concentrations ◽

Induced Aggregation ◽

P2y12 Antagonist

SummaryThe effects on platelet function of temperatures attained during hypothermia used in cardiac surgery are controversial. Here we have performed studies on platelet aggregation in whole blood and platelet-rich plasma after stimulation with a range of concentrations of ADP, TRAP, U46619 and PAF at both 28°C and 37°C. Spontaneous aggregation was also measured after addition of saline alone. In citrated blood, spontaneous aggregation was markedly enhanced at 28°C compared with 37°C. Aggregation induced by ADP was also enhanced. Similar results were obtained in hirudinised blood. There was no spontaneous aggregation in PRP but ADP-induced aggregation was enhanced at 28°C. The P2Y12 antagonist AR-C69931 inhibited all spontaneous aggregation at 28°C and reduced all ADP-induced aggregation responses to small, reversible responses. Aspirin had no effect. Aggregation was also enhanced at 28°C compared with 37°C with low but not high concentrations of TRAP and U46619. PAF-induced aggregation was maximal at all concentrations when measured at 28°C, but reversal of aggregation was seen at 37°C. Baseline levels of platelet CD62P and CD63 were significantly enhanced at 28°C compared with 37°C. Expression was significantly increased at 28°C after stimulation with ADP, PAF and TRAP but not after stimulation with U46619. Overall, our results demonstrate an enhancement of platelet function at 28°C compared with 37°C, particularly in the presence of ADP.

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Computerized Platelet Aggregation Analysis: A New Method

10.1055/s-0039-1687281 ◽

1979 ◽

Author(s):

J.A. Zeller ◽

R.E. Dayhoff ◽

R.S. Ledley ◽

Y.G. Kulkarni

Keyword(s):

Platelet Aggregation ◽

Light Transmission ◽

Platelet Rich Plasma ◽

Aggregate Size ◽

Size Group ◽

Mean Values ◽

Minute Period ◽

Size Groups ◽

Platelet Aggregates ◽

Aggregation Analysis

Computerized Platelet Aggregation Analysis (CPAA) is a new direct, microscopic methedo-logy using image analysis to quantitate thousands of free platelets and aggregates in platelet rich plasma suspensions and determine the percentage of platelets present in discrete aggregate size groups. CPAA is sensitive to the earliest stages of platelet aggregation which are not recognized by light transmission aggregometry (0% change in light transmission). Platelets of ten normal irxiividuals aged 20-40 years were stimulated by a spin bar (SB) (1100 rpm) for a one minute and a ten minute period. The mean values are shown below for different aggregate size groups.There is no significant increase in the number of aggregates between one and ten mirais of stimulation except for size group 9-40, which shows a minimal increment (P .025). All platelet suspensions contained aggregates of size group 3-8 platelets/aggregate and 4 of 10 specimens had aggregates of size 9-40,No aggregates larger than 41 platelets were found. CPAA can also be applied to the study of larger sized platelet aggregates induced in abnormal individuals.

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