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PubMed1976

Lung responses and platelet release reaction following induced intravascular platelet aggregation in the cat.

Pulmonary microembolism secondary to intravascular platelet aggregation causes a rise in pulmonary vascular resistance and a decrease in dynamic lung compliance. The relationship between these lung responses and the platelet release reaction was investigated in the cat. Repeated episodes of platelet aggregation were induced by intravenous infusions of either ADP or collagen. Platelet release was evaluated by serial determinations of the plasma concentration of platelet factor 4 (PF-4). An increased plasma concentration of PF-4 was found after the initial episode of such induced intravascular platelet aggregation. Consecutive infusions of an aggregating agent still elicited vigorous lung responses, but no further increase in the plasma concentration of PF-4 was observed. There are different possible explanations for this lack of correlation between the lung responses and the PF-4 release. It may well be that the pattern of release for PF-4 does not reflect those release events which result in pulmonary smooth muscle contraction. Alternatively, but less likely, pulmonary smooth muscle constriction and platelet release could be fully independent phenomena.

Adenosine Diphosphate↗
PubMed1979

Experimental cerebral ischemia produces platelet aggregates.

Human studies indicate that transient platelet abnormalities accompany acute cerebral ischemia. Although these abnormalities may precipitate the ischemi process, ischemia could also alter platelet function. Platelets were therefore studied in gerbils subjected to 1 hour of unilateral carotid artery occlusion. Venous blood from five clinically affected gerbils contained more aggregated platelets (37.8% +/- 6.4) than did blood from eight unaffected animals (11.1% +/- 3.0; p less than 0.01). Platelets labeled with 3H-serotonin were increased in ischemic brain; the ratio of radioactivity in the ipsilateral versus contralateral hemisphere was greater in eight affected (1.09 +/- 0.03) than in 19 unaffected (1.00 +/- 0.01; p less than 0.02) animals. The radioactive serotonin was located predominantly within blood vessels. Cerebral ischemia thus stimulated the formation of platelet aggregates, a response which could contribute to the ischemic process.

Animals↗
PubMed1976

Alpha-tocopherol: its inhibition on human platelet aggregation.

Alpha-tocopherol inhibits human platelet aggregation induced by arachidonate sodium, collagen, epinephrine, adenosine diphosphate or thrombin - arachidonate sodium being the most susceptible. The second phase of the biphasic platelet aggregation induced by epinephrine or adenosine diphosphate is preferentially inhibited.

Adenosine Diphosphate↗
PubMed2001

Anagrelide metabolite induces thrombocytopenia in mice by inhibiting megakaryocyte maturation without inducing platelet aggregation.

OBJECTIVE: The mechanism for anagrelide's potent platelet lowering activity in human subjects is not well defined. Studies related to anagrelide function have been hampered by its lack of activity in nonhuman primates and water insolubility. In an effort to define the mechanism whereby anagrelide exerts its therapeutic effect, we identified a water-soluble metabolite (anagrelide.met). The availability of anagrelide.met allowed, for the first time, parallel in vitro and in vivo animal studies centered on the mechanisms by which anagrelide lowers platelet levels. MATERIALS AND METHODS: The effects of anagrelide.met on proliferation and maturation of mega-karyocytes (MKs) as well as platelet production were studied both in vitro and in vivo. RESULTS: Anagrelide.met is capable of blocking in vitro MK migration by 20% to 40%. At 100 ng/mL, anagrelide.met selectively blocked in vitro MK maturation, resulting in a 50% decrease in the total number of CD41a(+) MKs, corresponding with a 30% decrease in MK ploidy by day 10 and a 60% decrease by day 20. Daily intraperitoneal injections of anagrelide.met 100 microg into BALB/c mice was sufficient to significantly decrease platelet counts within 24 to 48 hours, stabilizing to 40 to 50% of normal levels by day 5. This was associated with a 45% decrease in the number of developing MKs and an increase in thrombopoietin levels. Anagrelide.met did not alter WBC counts, hematocrit, or bleeding time, or lead to any apparent signs of toxicity. Furthermore, unlike the parent anagrelide compound, anagrelide.met did not inhibit ADP-induced platelet aggregation even at high concentrations (10 microg/mL). CONCLUSIONS: We describe a cross-species reactive anagrelide metabolite that selectively inhibits MK maturation and migration, lowering platelet levels without influencing platelet aggregation.

Acetylcholinesterase↗
PubMed2004

Involvement of thromboxane A2 and tyrosine kinase in the synergistic interaction of platelet activating factor and calcium ionophore A23187 in human platelet aggregation.

The present study was carried out to examine the mechanisms of the synergistic interaction of PAF and A23187 mediated platelet aggregation. We found that platelet aggregation mediated by subthreshold concentrations of PAF (5 nM) and A23187 (1 mM) was inhibited by PAF receptor blocker (WEB 2086, IC50 = 0.65 mM) and calcium channel blockers, diltiazem (IC50 = 13 mM) and verapamil (IC50 = 18 mM). Pretreatment of platelets with PAF and A23187 induced rise in intracellular calcium and this effect was also blocked by verapamil. While examining the role of the down stream signaling pathways, we found that platelet aggregation induced by the co-addition of PAF and A23187 was also inhibited by low concentrations of phospholipase C (PLC) inhibitor (U73122; IC50 = 10 mM), a cyclooxygenase inhibitor (indomethacin; IC50 = 0.2 mM) and inhibitor of TLCK, herbimycin A with IC50 value of 5 mM. The effect was also inhibited by a specific TXA2 receptor antagonist, SQ 29548 with very low IC50 value of 0.05 mM. However, the inhibitors of MAP kinase, PD98059 and protein kinase C, chelerythrine had no effect on PAF and A23187-induced platelet aggregation. These data suggest that the synergism between PAF and A23187 in platelet aggregation involves activation of thromboxane and tyrosine kinase pathways.

Benzoquinones↗
PubMed1980

Carbacyclin--a potent stable prostacyclin analogue for the inhibition of platelet aggregation.

Carbacyclin is a chemically stable analogue of prostacyclin. As an inhibitor of platelet aggregation induced by ADP or collagen in vitro, carbacyclin is 0.03 times as active as prostacyclin in human, dog or rabbit plasma. Carbacyclin, like prostacyclin, reduces systemic arterial blood pressure (BP) in dogs, rabbits and rats and is not inactivated during passage through the pulmonary circulation. Further actions were investigated using a new ex vivo technique which allows rapid preparation of platelet-rich plasma and determination of platelet aggregation. In the dog, intravenous infusion of carbacyclin or prostacyclin inhibits platelet aggregation ex vivo with minimal effects on BP or heart rate. In the anaesthetised or conscious rabbit, carbacyclin and prostacyclin produces similar cardiovascular changes in doses producing an equivalent degree of platelet inhibition. In both rabbit and dog, carbacyclin is 0.1 times as active as prostacyclin in inhibiting ex vivo platelet aggregation. Platelet inhibition is maintained throughout the period of infusion of either compound (up to 3 h) yet is no longer apparent 10 min after terminating the infusion. Carbacyclin is thus a chemically-stable but metabolically-unstable analogue with a biological profile closely similar to prostacyclin.

Adenosine Diphosphate↗
PubMedDate not supplied

[Effect of diets of different isomer composition of fatty acids on the blood vessel wall, blood lipids and platelet aggregation].

It was established in rat experiments that prolonged (4.5 months) use of the diet with a high content of spatial (trans-) and positional isomers of fatty acids exerted an adverse effect on the laboratory animals. They showed the impairment of the hemostasis integrity; namely of the walls of blood vessels (aorta, intraorgan arteries of the heart and kidneys), blood lipids, fatty acid composition and aggregation properties of platelets. The animals developed alterations similar to those occurring with the use of the diets rich in saturated fatty acids. The vessels manifested dystrophic alterations of elasticity and smooth muscle cells, whereas blood an increase in the content of atherogenic lipoproteins associated with a high content of total lipids and cholesterol. The ADP-induced enhancement of platelet aggregation was observed in experiments in vitro.

Animals↗
PubMed1986

A new vasodilator 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (KC-404) has a dual mechanism of action on platelet aggregation.

3-Isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (KC-404) at a concentration of greater than or equal to 4.34 X 10(-5) M inhibited adenosine diphosphate-, arachidonic acid- and collagen-induced aggregation of rabbit platelets. In rabbit, KC-404 (0.5 and 2 mg/kg, i.v.) caused a decrease in weight of collagen strip extracorporeally superfused with arterial blood, because of a disaggregation of deposited platelet aggregates. This disaggregatory effect of KC-404 was markedly diminished by the pretreatment of animals with aspirin. KC-404 (greater than or equal to 4.34 X 10(-6) M) and its major metabolite diOH-KD-404 (greater than or equal to 3.78 X 10(-7) M) significantly potentiated the anti-aggregatory action of prostacyclin on rabbit platelets. KC-404 (greater than or equal to (4.34 X 10(-8) M) exerted a similar effect in rat platelets. KC-404 had no significant effect on 6-keto-PGF1 alpha and thromboxane A2 formation by rat aortic segment and rabbit platelets, respectively. KC-404 inhibited cyclic AMP phosphodiesterase (Ki = 91 microM). The present results indicate that KC-404 exhibits its anti-platelet effect via the inhibition of cyclic AMP phosphodiesterase activity in platelets and via the potentiation of anti-aggregatory activity of prostacyclin on platelets.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Inhibition of human platelet aggregation by GR91669, a prototype fibrinogen receptor antagonist.

In order to produce more potent and specific fibrinogen receptor (GpIIb/IIIa) antagonists, the Arg-Gly of a chemical series based upon Arg-Gly-Asp was replaced by alkyl chains of varying lengths. The most potent in this series, GR91669, inhibited aggregation of human gel-filtered platelets (GFP) in vitro induced by ADP or the thromboxane A2 mimetic, U46619, with IC50 values of 200nM and 500nM respectively and was selected for further studies. Its inhibitory effects on GFP were reversed by addition of excess fibrinogen. The compound also inhibited ADP- or U46619-induced platelet aggregation in human whole blood (IC50 values of 700nM in both cases). 125I-Fibrinogen binding to ADP-stimulated platelets was inhibited by GR91669 with an IC50 (65nM) similar to that against platelet aggregation. GR91669 (1mM) did not inhibit U46619-induced platelet shape change or 14C-5HT secretion from platelets stimulated by collagen, U46619 or thrombin. Therefore GR91669 inhibits aggregation but has no significant effect on stimulus-response events, a profile consistent with fibrinogen receptor blockade. In addition, GR91669 (1mM), unlike echistatin or Gly-Arg-Gly-Asp-Ser, did not disrupt vitronectin recptor-dependent attachment of cultured HUVECS in vitro and similarly did not inhibit Mac-1 dependent adhesion of human granulocytes. Thus, of the integrins tested, GR91669 appears to be specific for GpIIb/IIIa. Following intravenous administration to marmosets of 1 or 10 mg/kg GR91669, ADP (10 microM)-induced platelet aggregation ex vivo was abolished for 15 and 60 minutes respectively. Greater than 50% inhibition was maintained for 30 minutes and 2 hours respectively. GR91669, therefore appears to be a potent, specific fibrinogen receptor antagonist in vitro and which is also active in vivo.

Amino Acid Sequence↗
PubMed1984

Synthesis and platelet aggregation inhibition activity of a series of enantiomeric bicyclo[3.2.0]heptane-6-oximinoacetic acids (1).

Opening of racemic epoxide (3) with (3S)- or (3R)-dimethyl-3-(dimethyl-t-butylsilyloxy)oct-1-ynyl aluminum gave two regioisomers, which were separated chromatographically. The separated regioisomers, themselves mixtures of chromatographically inseparable diastereoisomers, were converted into their dicobalthexacarbonyl complexes, which were easily resolved and isolated by chromatography. The individual diastereoisomers were deprotected to give bicyclo[3.2.0]heptan-3-ones, whose absolute stereochemistry was assigned using circular dichroism. One of these compounds, (1R,2R,3S,5R,3'S)-3-(3'-hydroxyoct-1'-ynyl)-bicyclo[3.2.0]++ +heptan-2-ol-6- oximinoacetic acid (11a) was 4.5 times more potent than PGE1 in inhibiting the ADP-induced aggregation of human platelets. The next most potent compound in this series was the "ent-15-epi" compound (11b), which was 0.034 times the potency of PGE1 in the platelet aggregation assay.

Adenosine Diphosphate↗
PubMed1992

Vascular occlusion of the retina--an experimental model. II. Platelet aggregates.

Using a new technique to mimic arteriolar occlusion syndromes, different microparticles were injected into the ophthalmic artery of pigs. These microparticles were platelet aggregates of various sizes ranging from 0.15 mm to more than 0.8 mm. Aggregation was induced using adenosine diphosphate and thrombin. In some experiments, acetylsalicylic acid and histamine were also applied. In a further series of experiments, mixed aggregates containing platelets and leukocytes were injected. The results were observed by indirect ophthalmoscopy and consisted of superficial and deep retinal infarction. Large platelet aggregates resulted in arterial branch occlusion, whereas mixed and small platelet aggregates produced occlusion of small arterioles. This technique seems to be valuable in studying retinal arteriolar occlusion syndromes.

Adenosine Diphosphate↗
PubMed1985

Increased platelet aggregation following splenectomy in patients with myeloproliferative disease.

In 30 patients with myeloproliferative disorders, decreased platelet aggregation in response to both ADP and collagen was demonstrated. The hypoaggregability was more drastic in patients with large spleens. Patients who had had splenectomy in the past showed normal platelet aggregation. In order to understand the role of the spleen in platelet function, platelet aggregation was studied in three patients with myeloproliferative disorders during the week following splenectomy and was compared to platelet aggregation in three control patients undergoing orthopedic operations. After splenectomy, platelet aggregation significantly increased, reaching a maximum after 3 to 4 days, but returned to presplenectomy values after 1 week. This is in contrast to the control patients, in whom no significant changes in platelet aggregation were observed. Our results suggest that the spleen retains or catabolizes the most hemostatically effective platelets.

Adult↗
PubMed1976

Evaluation of Mannich bases and related compounds as inhibitors of mitochondrial function in yeast and inhibition of blood platelet aggregation, blood clotting, and in vitro metabolism of 5-dimethylamino-1-phenyl-1-penten-3-one hydrochloride.

Dimethylamino-1-phenyl-1-penten-3-one hydrochloride (Ia) and 32 analogs were tested for inhibition of respiratory-dependent growth in Saccharomyces cerevisiae. Thirteen of the 33 compounds tested appeared to affect mitochondrial function, since the inhibition of respiratory-dependent growth was statistically greater than the inhibition of growth on fermentable energy sources. Inhibition of mitochondrial function in yeast and growth inhibition of an in vitro culture of human epidermoid carcinoma (KB) were positively correlated since 83% of the compounds tested either had mitochondrial-inhibiting properties and significant activity in the KB test or were inactive in both tests. Similarly, 78% of compounds tested showed murine toxicity and mitochondrial inhibition or had no effect on murine toxicity and yeast mitochondrial function. Injection of Ia into rats resulted in the appearance of blood in the urine and feces. Compound Ia inhibited adenosine diphosphate and collagen-induced aggregation of rat platelets but had no effect on blood clotting. TLC, following incubation of Ia with a rat liver extract, showed that the structure of Ia was not enzymatically modified and indicated activity per se on platelet aggregation and mitochondrial function.

Adenosine Diphosphate↗
PubMed1989

[Pharmacological deaggregation of platelet aggregation].

Antagonists of increasing concentrations were added to PRP which had exhibited irreversible aggregation and the extent of deaggregation was determined. Several classes of platelet antagonists with different mechanisms have been undertaken to reverse platelet aggregation induced by ADP, collagen, arachidonic acid, U46619 and PAF. The results indicate that maintenance of platelet aggregation is a complex phenomenon involving multiple mechanisms which depend on agonists. Maintenance of ADP induced aggregation requires exogenous calcium and active intracellular calcium mobilization. Active intracellular calcium mobilization appears to be essential for maintaining aggregation by PAF, U46619 and arachidonic acid. But additional pathway may be operative in maintaining collagen-induced aggregation. Calmodulin inhibitors with multiple actions are effective deaggregators. Calmodulin plays a role in maintaining platelet aggregation. The present study indicates that the ability of various antagonists to reverse platelet aggregation is closely related to three factors: 1) agonists used to stimulate platelet, 2) the time period following the initiation of platelet aggregation and 3) the kinds of antagonists used.

Calcium↗
PubMed1979

Effect of a single oral dose of aspirin on the platelet aggregation response to arachidonic acid.

1 The platelet aggregation response to arachidonic acid ex vivo was measured in six volunteers daily before and for 10 days after a single oral dose of 600 mg aspirin. 2 Arachidonic acid induced aggregation of platelets from all subjects before aspirin and aggregation occurred after an interval which varied inversely with the concentration of arachidonic acid. No aggregation occurred for 4 days after aspirin; a reduced response, compared with pre-aspirin values, was obtained on the 5th, 6th and 8th day. The values on days 7, 9 and 10 were not consistently different from the pre-aspirin values. In 6 subjects 24 h after aspirin ingestion the addition of 10--25% v/v normal platelets restored the aggregation response. 3 It is concluded that aspirin has an effect on the platelet precursors in the marrow in addition to its effect on circulating platelets.

Adult↗
PubMed1985

Identification of two proteins (actin-binding protein and P235) that are hydrolyzed by endogenous Ca2+-dependent protease during platelet aggregation.

Our previous research has shown that the Ca2+-dependent protease within platelets is activated when platelets aggregate, resulting in the production of three polypeptides (Mr = 200,000, 100,000, and 91,000). We have now shown that these three polypeptides arise from the hydrolysis of actin-binding protein. An antibody against actin-binding protein raised in rabbits was shown to be specific for actin-binding protein on immunoblots of total platelet proteins. This antibody reacted with additional polypeptides of Mr = 200,000, 100,000, and 91,000 on immunoblots of the proteins of thrombin-activated platelets. Actin-binding protein was purified from fresh, human platelet concentrate and hydrolyzed with platelet-derived Ca2+-dependent protease; hydrolysis resulted in the appearance of three polypeptides with molecular weights and isoelectric points identical to those of the three polypeptides generated within intact, aggregating platelets. Production of these polypeptides was inhibited by leupeptin and by the chelation of Ca2+. Hydrolysis of actin-binding protein was observed at micromolar Ca2+ concentrations, demonstrating that the level of Ca2+ in aggregated platelets is sufficient to account for the hydrolysis of actin-binding protein by the Ca2+-dependent protease. P235 was also purified and tested for its susceptibility to the protease. It was hydrolyzed by the Ca2+-dependent protease, and two polypeptides (Mr = 200,000 and 46,000) were produced. Antibodies against P235 raised in rabbits reacted only with P235 on immunoblots of total platelet proteins. These antibodies also reacted with polypeptides of Mr = 200,000 and 46,000 on immunoblots of thrombin-activated platelets. These data show that both actin-binding protein and P235 are cleaved during thrombin-induced platelet aggregation and suggest that the activation of the Ca2+-dependent protease may permit reorganization of the platelet cytoskeleton in aggregating platelets.

Antibody Specificity↗
PubMed2004

A laboratory method for parallel determination of platelet aggregation and thrombin generation.

Optimal use of combinations of antiaggregating and antithrombotic drugs in vivo requires improved methods for testing of possible synergistic drug effects. Therefore, we developed an in vitro model that allows parallel evaluation of the influence of drugs on the time course of platelet aggregation inhibition and on thrombin generation inhibition. Platelet rich plasma samples were incubated with different amounts of antiaggregating and/or antithrombotic agents and the effects on thrombin generation, lag phase until the onset of platelet aggregation, and on inhibition of platelet aggregation were detected. Plasma activation was performed by addition of high (29 nM final concentration, "high coagulant challenge") or low (5 pM final concentration, "low coagulant challenge") amounts of tissue factor. Thus, platelet activation is initiated in our model by endogenously generated thrombin and not by exogenously added agonists, as usual in conventional evaluation of platelet aggregation. The combination of glycoprotein IIb/IIIa inhibitors (eptifibatide or abciximab) and anticoagulants (unfractionated heparin, low molecular weight heparin, or recombinant hirudin) used in this study exhibited an additive effect on prolongation of the lag phase until the onset of platelet aggregation. Under high but not under low coagulant challenge the combination of eptifibatide and anticoagulants had a synergistic inhibitory effect on platelet aggregation. Combination of abciximab and anticoagulants had no additive inhibitory effects on platelet aggregation under both high and low coagulant challenge. Under low coagulant challenge combination of eptifibatide but not abciximab with low molecular weight heparin significantly reduced the thrombin generation. We suggest that our laboratory method might be useful for pre-clinical testing of in vitro effects of glycoprotein IIb/IIIa inhibitors and anticoagulants.

Anticoagulants↗
PubMed2005

Inhibitory effect of aqueous extracts of some herbs on human platelet aggregation in vitro.

Effect of aqueous extract of several herbs on human platelet aggregation in vitro was investigated. Out of 28 herbs/nutriceuticals investigated, camomile, nettle alfalfa, garlic and onion exhibited most significant anti-platelet activity (>or=45% inhibition). Aqueous extracts of alfalfa, fresh nettle, and camomile inhibited ADP induced-platelet aggregation by 73, 65 and 60%, respectively, compared with control (P < 0.05). Camomile and alfalfa inhibited collagen-induced platelet aggregation by 84 and 65%, respectively, but nettle could not inhibit collagen-induced aggregation. In contrast, nettle was the most potent inhibitor (66%) of whole blood aggregation induced by collagen, followed by alfalfa (52%), and camomile (30%) compared with control (P < 0.05). None of these three herbs however could inhibit arachidonic acid or thrombin induced platelet aggregation. Camomile and alfalfa strongly inhibited thromboxane B2 synthesis induced by ADP or collagen, but nettle had no effect. Alfalfa and nettle increased cGMP levels in platelets by 50 and 35%, respectively, compared with the control (1.85 +/- 0.23 nM) (P < 0.005). All these data indicate that camomile, nettle and alfalfa have potent anti-platelet properties, and their inhibitory actions are mediated via different mechanisms.

Blood Platelets↗