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PubMed1987

Protamine-induced platelet aggregation and clotting investigated by ultrasound.

Using high-resolution real-time ultrasound to monitor platelet aggregation and plasma clotting, the effect of protamine on platelets was evaluated in a dynamic system of plasma in vitro. Protamine induced platelet aggregation preceding plasma clotting at both low (1.6 s-1) and moderate (22.6 s-1) shear rates. The onset of aggregation and clotting was accelerated at the higher shear rate. Low-shear clots were heterogeneous on ultrasonic imaging, whereas moderate-shear clots were more densely homogeneous. Protamine-induced platelet aggregation was reversed by additional heparin. Pretreatment of plasma with prostacyclin prevented protamine-induced aggregation, but clot formation occurred. However, such clots were less echogenic. EGTA and hirudin inhibited both aggregation and clotting. Our ultrasonic aggregometry showed that platelet aggregation was induced by protamine before clots formed, and that not only shear rate but platelet activation might affect the rate and composition of plasma clots.

Adult↗
PubMed1983

Heparin counteracts the antiaggregating effect of prostacyclin by potentiating platelet aggregation.

It has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1 and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.

Adenosine Diphosphate↗
PubMed1979

Inhibition of platelet aggregation during hypovolemic hypotension by acetylsalicylic acid and artificial respiration.

In vivo measurement of platelet aggregation was performed by a previously described photoelectric method. It is shown that platelet aggregation induced by arterial hypotension can be inhibited by i.v. administration of ASA and by artificial respiration. The inhibition of platelet aggregation following artificial ventilation is significantly more pronounced than by ASA given 24 h prior to the beginning of the experiments. Different sources of platelet aggregation in venous and arterial blood are informative about the canine lung not only as a filter for aggregates but also as a source of aggregating substances.

Adenosine Diphosphate↗
PubMed1996

cAMP is not an important messenger for ADP-induced platelet aggregation.

In rat platelets, basal cAMP level did not vary significantly during ADP-induced aggregation. In the same conditions, no variation in the cAMP content was observed in platelets from rats treated with clopidogrel, whereas ADP-induced aggregation was totally inhibited. ADP decreased cAMP level in control prostacyclin- or forskolin-stimulated platelets whereas, in treated platelets, adenylyl cyclase down-regulation was strongly inhibited. SQ 22536 (500 microM), an inhibitor of adenylyl cyclase, strongly reduced the cAMP content of both control and treated platelets but did not reverse the anti-aggregating activity of clopidogrel, showing that inhibition of ADP-induced adenylyl cyclase down-regulation in treated platelets was not responsible for the anti-aggregating effect of clopidogrel. Similar results were obtained in rabbit platelets. These results therefore demonstrate that cAMP is not an important second messenger for ADP-induced platelet aggregation and suggest that another activating pathway, linked to the low affinity ADP receptor present on the platelet surface might be involved in the aggregation process.

Adenine↗
PubMed1992

The effect of dietary n-3 fatty acids on in vivo platelet aggregation in the cerebral microcirculation.

Diets enriched in n-3 fish oil have been suggested to decrease coronary artery disease in part through their ability to decrease cyclooxygenase-dependent platelet aggregation. However little is known concerning the effect of n-3 fatty acids on in vivo platelet aggregation. The purpose of these experiments was to determine whether dietary n-3 fatty acids affect the rate at which platelet aggregation occurs in cerebral arterioles. Fish oil (200 mg eicosapentaenoic acid + 143 mg docosahexaenoic acid/kg), corn oil or water was given daily by gavage to mice (n = 30) for six weeks and then in vivo platelet aggregation was induced by the light plus dye method, which injuries the endothelium. Two additional groups of mice were acutely treated with saline or indomethacin (0.5 mg/kg, ip), with the latter serving as a positive control for therapeutic inhibition of platelet aggregation. Serum thromboxane B2 was analyzed by RIA. All fed groups gained weight equally. Serum thromboxane B2 was decreased by 40% in the fish oil group (p = 0.05 vs. corn oil, p = 0.07 vs. water). The mean (+/- SE) time to first aggregate in pial arterioles was 101 +/- 6, 91 +/- 6 and 101 +/- 9 seconds in the fish corn oil and water groups, respectively. Indomethacin significantly increased the time to first arteriolar aggregate by 35% (p < 0.002) and caused an 80% reduction in serum thromboxane. These studies show dietary fish oil produces a moderate reduction in serum TxB2 level and does not affect arteriolar platelet aggregation whereas indomethacin produces a drastic TxB2 reduction and significantly slows platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

[Effects of Squama manitis on cardiac systolic function and platelet aggregation].

OBJECTIVE: To study the effect of Squama Manitis(S. M.) on cardiac function and platelet aggregation in vitro. METHOD: Isolated working rat hearts were prepared, and cardiac performance was measured before and after adding S. M. in the Krebs-Hensleit(K-H) perfusion buffer. Controls with K-H buffer were also investigated. Rich platelet plasma and Poor platelet plasma were centrifuged from the blood of 15 patients with coronary heart disease. Each sample was divided into three parts for use by three groups: control, group of S. M. and group of aspirin. Platelet aggregation was stimulated by adenosine diphosphate. RESULT: LVSP, +dP/dtmax and CO of isolated working rat hearts were significantly increased after treating with S. M. liquor. S. M. had no obvious effect on -dP/dtmax and LVEDP. These parameters did not change significantly in the control. Percentages of platelet aggregation were significantly lower in the group of S. M. and the group of aspirin as compared with the control. CONCLUSION: S. M. increases cardiac systolic function, has positive inotropic effect on myocardium and inhibits platelet aggregation.

Animals↗
PubMed2000

Glycoprotein IIb/IIIa receptor inhibitor attenuates platelet aggregation induced by thromboxane A2 during in vitro nonpulsatile ventricular assist circulation.

A recent development in antithrombotic research allows the inhibition of platelet aggregation via protection of the glycoprotein IIb/IIIa receptor on the platelet membrane. We hypothesized that a GP IIb/IIIa receptor inhibitor would inhibit thromboxane-induced platelet aggregation during circulation in our in vitro ventricular assist device (VAD) circuit and preserve long-term platelet function. Twenty-one in vitro nonpulsatile centrifugal VAD circuits were simulated for 4 days using 450 ml of fresh human whole blood with or without glycoprotein IIb/IIIa receptor inhibitor (tirofiban). Platelet aggregation and degranulation were measured in whole blood induced by ristocetin, collagen, ADP, and thromboxane A2 (TXA2). The tirofiban-treated group preserved the platelet count and tended to exert these beneficial effects by inhibiting pathologic platelet aggregation induced by TXA2, collagen, and ADP as well as degranulation. Tirofiban may be useful in preserving platelet number and function during clinical VAD use.

Adenosine Diphosphate↗
PubMed1992

Analogues of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) as potential anti-platelet-aggregation agents.

Dense granules of platelets contain a high content of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A). We have previously demonstrated an antithrombotic effect of this compound in a live rabbit model. In the present study we find that certain synthetic Ap4A analogues are superior to Ap4A in inhibiting ADP-induced aggregation of human platelets. Analogues having a P--C--P bridge located in the P2,P3 position of Ap4A are the most potent inhibitors. These analogues are also resistant to hydrolytic enzymes. Analogues having the above characteristics exhibit competitive inhibition with ADP in the ADP-induced platelet aggregation reaction. These compounds, such as AppCHFppA, may be useful as antithrombotic agents. The analogues ApSppSpA and ApSpCHFpSpA also showed good inhibitory effects on ADP-induced platelet aggregation. In addition, this action of Ap4A and its analogues provides an example of a dinucleotide inducing an antagonistic effect by occupying an extracellular mononucleotide binding site on platelets. It calls attention to the possibility that Ap4A and its analogues may act in a similar way in whole organisms, triggering effector or inhibitory responses in any one of a variety of cells.

Adenosine Diphosphate↗
PubMed1985

Plasma concentrations of platelet-specific proteins in different stages of essential hypertension: interactions between platelet aggregation, blood lipids and age.

Plasma beta-thromboglobulin (beta TG) and platelet factor 4 (PF4) were significantly higher in a group of 116 hypertensive men than in a normotensive group of 142 men. They increased with the stage of hypertension but the level did not correlate with the age of the subjects. Platelet aggregation was similar in the two groups and positively correlated with the age of the subjects in the normotensive group but not in the hypertensive group. A strong positive correlation was observed between the levels of plasma beta TG and PF4 and between platelet aggregation to ADP and that to epinephrine in both the hypertensive and normotensive groups. However, there was no correlation between the level of plasma beta TG or PF4 and platelet aggregation. Plasma antithrombin III was lower in the hypertensive group than in the normotensive group. These studies suggest that plasma levels of beta TG and PF4 are closely related to the stage of hypertension and are better indicators than aggregation of in vivo platelet activation in hypertensive subjects. Enhanced platelet activation may be involved in the acceleration of hypertensive arteriovascular damage and atherosclerosis.

Adenosine Diphosphate↗
PubMed2000

Early detection of preeclampsia by determination of platelet aggregability.

Preeclampsia is still a leading cause of maternal and fetal morbidity and mortality. There is evidence for the involvement of platelets. Therefore, we investigated the suitability of corrected whole blood impedance aggregometry as an early predictor of preeclampsia in 71 consecutive, high-risk pregnancies. According to the occurrence of preeclampsia, defined postpartum by an independent investigator, and the stage of pregnancy (early and late, cutoff: 25 weeks of gestation), four study groups were defined. Platelet aggregation data were corrected for the influence of hematocrit and platelet count by a special purpose software package. Women developing preeclampsia showed significantly higher platelet aggregation response compared to controls in early and late pregnancy. In early pregnancy, all women developing preeclampsia had aggregation responses to collagen higher than the highest responses among the controls. Hence, this test had a 100% positive predictive value of subsequent preeclampsia. Despite being significantly increased, platelet aggregability was of minor predictive value in late pregnancy. We conclude that preeclampsia is accompanied by exaggerated platelet aggregability, particularly perceptible early in the course of pregnancy. We propose collagen-induced whole blood platelet aggregation with correction for the influence of hematocrit and platelet count for early detection of preeclampsia.

Adenosine Diphosphate↗
PubMed1997

Inhibition of platelet aggregation by L-arginine and polyamines in alloxan treated rats.

The antiaggregating effect of L-arginine and polyamines (putrescine, spermidine and spermine) was studied in platelets of normal and diabetic rats (120 mg/Kg alloxan, i.p.). This effect was compared with insulin. The assays of platelet aggregation were carried out using platelet-rich plasma (PRP) obtained from both groups of animals. The platelet aggregation test were first standardized by using PRP obtained from human health donors. 2.5 mumoles/ml ADP, 250 mumoles/ml epinephrine and 0.4 U/ml of thrombin were used as inductors of platelet aggregation. 60% of inhibition was observed with 10 microM of L-arginine or polyamines in PRP of normal rats, and 50% with PRP of diabetic rats when thrombin was used as an agonist. These results show that L-arginine and the polyamines putrescine, spermidine and spermine have an antagonist action in platelet aggregation. In addition, we demonstrated the platelet arginase activity not only in rat platelets but also in human, was less under hyperglycaemia. The activity of this enzyme has been associated with polyamine synthesis, required to regulate platelet function.

Animals↗
PubMed1996

Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists.

Recombinant thrombopoietin has been reported to stimulate megakaryocytopoiesis and thrombopoiesis and it may be quite useful to treat patients with low platelet counts after chemotherapy. As little is known regarding the possible activation of platelets by thrombopoietin, we examined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as an anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet aggregation induced by 2 micromol/L adenosine-diphosphate (ADP) in a dose dependent fashion. The enhancement was not affected by treatment of platelets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 micromol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 micromol/L), which does not induce platelet aggregation in hirudin platelet rich plasma (PRP), did so in the presence of thrombopoietin (10 ng/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggregation induced by collagen (0.5 micron.mL),. thrombin, serotonin, and vasopressin. Thrombopoietin does not induce any rise in cytosolic ionized calcium concentration nor activation of protein kinase C, as estimated by phosphorylation of preckstrin, indicating that the priming effects of thrombopoietin does not require those processes. The ADP- or thrombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm2)-induced platelet aggregation was also potentiated by thrombopoietin. The priming effect on epinephrine-induced platelet aggregation in hirudin PRP was unique to thrombopoietin, with no effects seen using interleukin-6 (IL-6), IL-11, IL-3, erythropoietin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functions may be necessary in the clinical trials of thrombopoietin.

Adenosine Diphosphate↗
PubMed1980

The effects of prostacyclin (PGI2) on endotoxin shock and endotoxin-induced platelet aggregation in dogs.

Prostacyclin (PGI2) is a major metabolite of arachidonic acid and is synthesized in vascular endothelial cells. It is a potent inhibitor of platelet aggregation and a known vasodilator. Because of the effects of PGI2 on platelet function, this study was designed to determine the efficacy of prostacyclin in endotoxin shock and on endotoxin-induced platelet aggregation in dogs. Thrombocytopenia is characteristic of septic shock and is believed to be related to platelet clumping, and thereby, to participate in the pathophysiology of endotoxin shock. Twenty-four males dogs were given an LD50 dose of Escherichia coli endotoxin (1 mg/kg). Twelve of these animals were treated with PGI2 (20 ng/kg/min) by continuous infusion from 15 minutes before, and for 4 hours after the injection of endotoxin. Parameters determined were mean arterial pressure, cardiac output, pulmonary arterial pressure, heart rate, platelet and white blood cell counts, and arterial blood gases. In animals given endotoxin alone, only 42% (5/12) survived, whereas, with PGI2 treatment, 83% (10/12) survived (P < 0.05). Prostacyclin therapy did not alter the rise in pulmonary arterial pressure, but did further decrease the mean systemic arterial pressure. There was a transient attenuation of the thrombocytopenia, and minimal effects on the granulocytopenia. Despite the fact that the PGI2-treated animals had greater decreases in blood pressures, 83% of the animals did survive. These findings suggest that PGI2 may have some protective effects in endotoxin shock. Serratia marcescens endotoxin caused dose-dependent platelet aggregation in canine platelet-rich plasma in vitro. Antiaggregating agents such as indomethacin (0.2-1 microgram/ml), and aspirin (0.2-1 microgram/ml), PGE1 (0.1-1 microgram/ml) and PGI2 (0.1-1 microgram/ml), added 1 minute before endotoxin (1 microgram/ml), had no apparent effect on the endotoxin-induced platelet aggregation. These findings suggest that endotoxin-induced platelet aggregation may be caused by a mechanism that is unrelated to cAMP and/or the arachidonic acid prostaglandin system.

Animals↗
PubMedDate not supplied

Two inhibitors of platelet aggregation from a Panus species (Basidiomycetes).

Two inhibitors of platelet aggregation were isolated from fermentations of Panus sp. 9096. One inhibitor proved to be identical to naematolon (2), an antibiotic previously isolated by S. Backens et al. from several Hypholoma species. The other metabolite, panudial (1), is a new nordrimane (cis-annelation of the bicyclus) lacking the carbon atom in position 10 of the drimane skeleton. Panudial is a potent inhibitor of bovine and human platelet aggregation stimulated by different inducers.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1983

Inhibition of platelet aggregation by 5'-nucleotidase purified from Trimeresurus gramineus snake venom.

By means of DEAE-Sephadex A-50 column chromatography and gel filtrations on Sephadex G-75, Sephacryl S-300 and Sephadex G-100, successively, a potent 5'-nucleotidase was purified from Trimeresurus gramineus venom. The venom 5'-nucleotidase is a single polypeptide chain and homogeneous as judged by SDS-polyacrylamide gel electrophoresis. It is a thermostable glycoprotein consisting of 589 amino acid residues. Its molecular weight was estimated to be 74,000 by SDS-polyacrylamide gel electrophoresis. It possessed nucleotidase activities toward adenosine monophosphate and adenosine diphosphate. The specific activities toward AMP and ADP were 504 +/- 28 and 101 +/- 8 micrograms Pi/min per mg, respectively. Pre-incubation of this venom's 5'-nucleotidase with ADP resulted in the cleavage of ADP and formation of adenosine. The 5'-nucleotidase activity was inhibited by EDTA. Both Zn2+ and Co2+/- reversed the inhibitory effect of EDTA. In rabbit platelet-rich plasma, it inhibited completely the ADP (2 x 10(-5) g/ml)-induced platelet aggregation. It also inhibited the platelet aggregations induced by sodium arachidonate (100 microM), collagen (20 micrograms/ml) and ionophore A-23187 (5 microM)-induced platelet aggregations were not affected significantly by this venom 5'-nucleotidase. In ADP-refractory platelet-rich plasma, the venom 5'-nucleotidase inhibited the platelet aggregations induced by collagen (20 micrograms/ml) or sodium arachidonate (100 microM). The venom 5'-nucleotidase showed a more pronounced inhibitory effect on sodium arachidonate-induced platelet aggregation than creatine phosphate/creatine phosphokinase and apyrase did. No lactate dehydrogenase was released by this venom 5'-nucleotidase, indicating that no platelet lysis occurred. It is concluded that removal of ADP, which is released by these platelet aggregation inducers, and the subsequent accumulation of adenosine are responsible for the inhibitory effect of the venom 5'-nucleotidase on platelet aggregations.

5'-Nucleotidase↗
PubMed2001

Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil.

The aim of this study was to investigate if the phospodiesterase type 5 inhibitor sildenafil inhibits collagen- or ADP-induced human platelet aggregation and bleeding time. To investigate this, two studies were designed. In the first, a single oral dose of sildenafil, 100 mg, was administered to healthy men. Bleeding time was determined and agonist (ADP and collagen)-induced platelet aggregation (ex vivo in platelet rich plasma) was measured 0, 1, and 4 h after application. In the second, a single oral dose of sildenafil, 50 mg, was administered and, in addition to the parameters in the first study, we also determined the platelet aggregation after 24 h and measured the effect of a nitric oxide donor (S-nitroso-N-acetylpenicillamine [SNAP]) in combination to mimic a physiologic nitric oxide release from the endothelium. The bleeding time of 1 h after sildenafil medication (100 mg) was significantly prolonged but recovered toward control values after 4 h, whereas application of sildenafil at a lower dose (50 mg) did not alter the bleeding time. Sildenafil (100 and 50 mg) did not inhibit the ADP-induced aggregation, whereas the collagen-induced aggregation (100 mg) was markedly reduced after 1 h and significantly inhibited 4 h after application. This inhibitory effect was overcome by higher concentrations of collagen. SNAP (0.5 microM) induced an inhibition of platelet aggregation that was potentiated after taking sildenafil (50 mg, 1 and 4 h afterward) and abrogated after 24 h. These data indicates that sildenafil may inhibit collagen-induced platelet aggregation ex vivo. After co-administration of nitric oxide, collagen- and ADP-induced platelet aggregation was significantly inhibited, which may reflect physiologic conditions of an in vivo system.

Adenosine Diphosphate↗
PubMed1988

Inhibition of platelet aggregation and thromboxane production by low concentrations of aspirin in vitro.

1. The aspirin concentrations previously reported to inhibit platelet aggregation in vitro (40-500 mumol/l) are much greater than those required in vivo in man (5 mumol/l). 2. Human platelet-rich plasma was incubated with buffer or various aspirin concentrations at 37 degrees C for up to 4.5 h. Platelet aggregation and thromboxane generation were measured in response to collagen (0.4-6.3 micrograms/ml) and adenosine 5'-pyrophosphate (0.5-4 mumol/l). 3. The concentration of aspirin needed to inhibit platelet aggregation in response to a critical concentration of aggregating agent (lowest concentration to cause greater than 50% aggregation) was lower than that required for higher concentrations of aggregating agent. 4. With more prolonged incubation times with aspirin, lower concentrations of aspirin inhibited platelet aggregation. 5. Inhibition of platelet aggregation and thromboxane formation by 10 mumol/l aspirin was maximal by 90 min. There was progressive inhibition by 3 mumol/l aspirin during incubation for 270 min. By the end of this time there was also significant inhibition by 1 mumol/l aspirin. 6. The apparent discrepancy between inhibitory aspirin concentrations in vivo and those observed in vitro in previous studies appears to have been resolved by extending the incubation time of platelets with low aspirin concentrations, thus mimicking the conditions in vivo.

Aspirin↗