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PubMed1998

Cleavage of rhamnose from ristocetin A removes its ability to induce platelet aggregation.

Ristocetin A is used clinically as a tool for the measurement of von Willebrand protein due to its ability to induce the aggregation of platelets in plasma being proportional to the concentration of von Willebrand protein. The enzymatically induced cleavage of alpha-L-rhamnose from the tetrasaccharide of ristocetin A removes this ability to induce platelet aggregation in plasma, providing a possible insight into the structural basis for this effect.

Carbohydrate Conformation↗
PubMed1975

[The effect of bencyclan on shear induced platelet aggregation (author's transl)].

The platelet aggregation inhibiting effect of N-[3-(1-benzyl-cycloheptyloxy)-propyl]-N,N-dimethyl-amine (bencyclan, Fludilat) was studied by a new method for quantification of platelet aggregation in viscometric flow. In vitro-addition of bencyclan shows significant inhibition in a concentration of 1 mg/100 ml, total inhibition of platelet aggregation is found at a concentration of 5 mg/100 ml. Peroral application of bencyclan shows no significant effect on platelet aggregation. Intravenous application of bencyclan studied in three patients results in inhibition of platelet aggregation, however, no information about the duration of this platelet-inhibiting effect is yielded.

Adenosine Diphosphate↗
PubMed1995

Platelet aggregation at high shear is impaired in patients with congenital defects of platelet secretion and is corrected by DDAVP: correlation with the bleeding time.

Techniques measuring platelet aggregation in vitro under the high shear rate conditions that can be found in the microcirculation could reflect the status of primary hemostasis better than the turbidimetric technique. We studied platelet aggregation at high shear in patients with prolonged bleeding time caused by congenital platelet secretion defects such as delta-storage pool deficiency and primary secretion defect. Two different techniques were used: shear-induced platelet aggregation in a cone-and-plate viscometer and the filter aggregation test. With both techniques, platelet aggregation at high shear rate was defective in 14 patients with delta-storage pool deficiency and in 8 with primary secretion defect. There was a statistically significant correlation between platelet aggregation at high shear rate and the bleeding time. In patients with delta-storage pool deficiency, platelet aggregation at high shear rate and the bleeding time were significantly correlated with the platelet serotonin content. The intravenous infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) (0.3 micrograms/kg) increased the plasma concentration of von Willebrand factor (vWf), shortened the bleeding time, and potentiated platelet aggregation at high shear rate in all patients. Because platelet aggregation at high shear rate requires vWf, the effect of DDAVP is probably due to the induced increase in plasma vWf. Therefore, platelet aggregation at high shear rate is defective in patients with congenital defects of platelet secretion and is potentiated by DDAVP. Potentiation of platelet aggregation at high shear rate may be one mechanism by which DDAVP shortens the prolonged bleeding time of patients with congenital defects of platelet secretion.

Bleeding Time↗
PubMed2004

The effects of arm cranking exercise and training on platelet aggregation in male spinal cord individuals.

Platelet aggregation at rest and in responses to exercise and training were compared between spinal cord injured (SCI) individuals (N=5) and able-bodied subjects (N=7). All participants performed arm cranking exercise at 60-65% VO(2peak) for 30 min. Venous blood samples were obtained before and after sub-maximal exercise and measured for platelet aggregation using ADP and collagen. To assess the effects of arm cranking training, platelet aggregation was re-measured in all subjects at rest and in response to the sub-maximal arm cranking exercise after 12 weeks of individually supervised training programme. Before training, the resting mean values of platelet aggregation induced by ADP and collagen were not different (P>0.05) between SCI and able-bodied. However the SCI individuals, but not the able-bodied subjects, exhibited a significantly (P<0.05) higher maximal platelet aggregation induced by ADP and collagen following sub-maximal arm cranking exercise. Although VO(2peak) after training was significantly increased (P<0.05) in both groups, the resting mean values of platelet aggregation induced with ADP and collagen were not significantly different (P>0.05) from those observed before training and were not different (P>0.05) between SCI and able-bodied. Post-training, the SCI individuals, but not able-bodied individuals, exhibited a significant decrease (P<0.05) in platelet aggregation following sub-maximal arm cranking exercise and this occurred with both ADP and collagen. These results suggest that SCI individuals, but not normal subjects increase their platelet aggregation following sub-maximal arm cranking exercise. Furthermore, arm cranking training in SCI individuals, appears to diminish the percentage of platelet aggregation ex vivo.

Adenosine Diphosphate↗
PubMed1993

Mechanisms of platelet aggregation by Streptococcus sanguis, a causative organism in infective endocarditis.

The ability of certain strains of Streptococcus sanguis to aggregate human platelets in vitro may be related to their virulence in the pathogenesis of infective endocarditis. We have studied the mechanisms of aggregation of human platelets by S. sanguis strain NCTC 7863. Platelet aggregation follows incubation of S. sanguis cells with platelet-rich plasma from normal, healthy adults, after a lag of 7-19 min. Platelet aggregation was accompanied by 5-hydroxytryptamine release and thromboxane B2 production. Aggregation was prevented by aspirin and by EDTA. Platelets from two patients with Glanzmann's thrombasthenia did not respond to bacteria. Fixed, washed platelets resuspended in normal plasma were not agglutinated by S. sanguis. Blocking the glycoprotein Ib receptor with a monoclonal antibody inhibited aggregation of PRP. However, S. sanguis did not induce von Willebrand factor (vWF) binding to platelets; nor did the bacteria prevent ristocetin-induced platelet agglutination or vWF binding. The aggregation response was not related to plasma vWF activity levels in normal subjects or in patients with von Willebrand's disease. The platelet response to S. sanguis therefore resembles true aggregation, requiring the cyclo-oxygenase pathway and the presence of glycoprotein IIb/IIIa. The mechanism also involves glycoprotein Ib, but not apparently through irreversible binding of vWF.

Agglutination↗
PubMed1980

Structure-activity relationships of novel 3-acylpyrrole derivatives: new inhibitors of platelet aggregation.

Several N-substituted-3-acyl-2, 5-dimethyl pyrrole derivatives were examined for their potency to inhibit aggregation of platelets in vitro and extra vivo in guinea pigs. A structure-activity relationship study showed that the substitution at 3 position of the pyrrole ring affected in vitro activity of inhibiting platelet aggregation. Compounds with 3-benzoyl or 3-thenoyl substituent had greater potency than those with 3-aliphatic acyl substituent. Modification of benzoyl, such as para substitution of phenyl group or reduction of carbonyl group, decreased the activity. There was no clear correlation between that N-substitution of the pyrrole ring and in vitro anti-platelet activity. However, compounds with a longer alkyl chain in the N-substituent had weaker activity. The in vitro inhibitory activity on prostaglandin synthetase of these compounds, though less potent compared with their antiplatelet activity, has a close correlation with the latter. N-substituents of the pyrrole ring had the effect on extra vivo activity. Compounds which have no N-alpha-methyl group and no hetero atoms such as oxygen or sulfur in the N-substituent diminished the extra vivo activity.

Animals↗
PubMed1998

The effect of different antithrombotic regimens on platelet aggregation after myocardial infarction.

Platelet aggregate ratio (PAR) was measured according to the method of Wu & Hoak in 143 patients after acute myocardial infarction (AMI) and in 54 controls. A PAR < 1 expresses the presence of platelet aggregates. The patients were randomized to aspirin 160 mg/d, or warfarin, or aspirin 75 mg/d + warfarin. In patients on aspirin, PAR was measured 24 h after aspirin intake, and in 76 patients also 2 h after aspirin. The median PAR in patients on warfarin was 0.85, on warfarin + aspirin 0.91 and on aspirin alone 0.94, all significantly lower than the median PAR of 0.97 in the controls. In 14 patients on aspirin the PARs were below a cut-off point of 0.82 (secondary aspirin non-responders). PAR increase significantly 2 h after aspirin intake. In two patients, however, PAR remained low (primary aspirin non-responders). It is concluded that some patients do not seem to respond to aspirin, the clinical implication of which has yet to be determined.

Adult↗
PubMed2003

The effect of plasma depletion of platelet concentrates on platelet aggregation and phosphatidylserine expression.

Plasma-reduced platelet concentrates are commonly administered to prevent febrile transfusion reactions and to avoid fluid overload in neonates. Because little is known about the influence of centrifugation and resuspension on functional aspects of platelets, we examined the effects of plasma-reduction on platelet aggregation and platelet-dependent thrombin generation. Our results show that plasma reduction and resuspension of the platelet pellet in saline or plasma results in a significant reduction in platelet aggregation to a combination of the platelet agonists adenosine diphosphate and epinephrine (p < 0.001). In contrast, when a combination of the more potent agonists collagen and thrombin was used, platelet aggregation was maintained. Likewise, no decline was observed in platelet-dependent thrombin generation as measured by the functional prothrombinase assay or Annexin V binding. We conclude that centrifugation and resuspension of platelets to render the concentrate plasma-free, as a routine procedure in blood banking, variably affects in vitro platelet aggregability but does not significantly affect platelet-dependent thrombin generation.

Annexin A5↗
PubMed1976

Increased sensitivity of in vivo platelet aggregation in rabbits after alloxan or streptozotocin.

In 14 rabbits previously injected intravenously with alloxan (dose 75-150 mg/kg) with subsequent hyperglycaemia, intra-arteriolar aggregation of platelets at the sites of small standardized electrical injuries to cerebral cortical vessels showed an increased sensitivity (P is less than 0.001) to application of adenosine diphosphate (ADP) in animals anaesthetized with either urethane or Pentothal. Intravenous injection of streptozotocin (10 rabbits, dose 30-200 mg/kg) was not followed so regularly by hyperglycaemia but even so many of these animals also showed increased sensitivity to ADP. After neither alloxan nor streptozotocin did the increased sensitivity correlate with the dose of agent used, the time between its injection and ADP testing, or changes in the rabbit's body weight. Again, ADP sensitivity did not correlate with the degree of hyperglycaemia, hyperketonaemia or hyperlactacidaemia. There was no rapid change in ADP sensitivity after i.v. injection of glucose to produce hyperglycaemia in normal rabbits, nor after parenteral or topical administration of insulin. Use of a removable skull capsule allowed serial observations on individual animals and these, together with observations on rabbits injected first with alloxan and later with daily insulin, showed reversibility of the increased ADP sensitivity by regular insulin injection for at least 5 days; this effect did not depend upon return of blood glucose levels to normal. In cross-perfusion experiments the increased ADP sensitivity was found to be dependent upon a blood factor for such sensitivity was shown by the head of a normal rabbit perfused with blood from a diabetic trunk. The results did not exclude a contribution of a mural factor to the results in intact animals after alloxan. The results are in keeping with in vitro observations of increased sensitivity to ADP of platelet aggregation in diabetic patients and demonstrate that such an effect holds within living blood vessels, as well as providing a model for further experiment.

Adenosine Diphosphate↗
PubMed1993

Species variation in the effect of glycoprotein IIb/IIIa antagonists on inhibition of platelet aggregation.

Differences exist between platelets of different species in their reaction to pharmaceutical agents, such as inhibitors of platelet aggregation. Understanding these differences is critical in the interpretation of data from experimental animal models of thrombosis. Platelet aggregation, essential in the hemostatic process, requires that fibrinogen (fgn) bind to activated platelets. Analogs of Arginine-Glycine-Aspartic acid-Phenylalanine (RGDF), a peptide sequence of fgn, block fgn binding to its receptor known as glycoprotein (GP) IIb/IIIa on activated platelets and prevent aggregation. We studied the inhibition resulting from Arginine-Glycine-Aspartic acid-Serine (RGDS) and two analogs of RGDF, (SC-46749 and SC-47643) on aggregation of human, rat, guinea pig, dog, and rhesus monkey platelets in vitro using ADP as the agonist. The inhibitory potency of RGDS, SC-46749, ad SC-47643 was species dependent. The rank order of potency was rhesus monkey, dogs, and human followed by guinea pig and rat. In order to study the relative inactivity of the compounds in rat platelets compared to human, we diluted rat platelet-rich plasma (PRP) to yield platelet levels approximating that of humans. Platelet inhibition was not significantly changed in diluted rat PRP nor did changing concentration appear to affect activity in human PRP. Our data suggest that the platelet response of some species may better represent human response with regard to inhibition of GP IIb/IIIa by (RGDX) analogs.

Adenosine Diphosphate↗
PubMed1983

Inhibitory effect of imipramine on epinephrine-dependent platelet aggregation: "in vitro" studies on platelets from healthy and depressed people.

Inhibitory effect of imipramine on platelet aggregation in healthy and depressed people was studied. A different sensitivity was observed between healthy and depressed people. Two groups (D I and D II) were identified among depressed patients on the basis of sensitivity to imipramine effect. ID50 was calculated for healthy subjects (59.5 +/- 22 microM) and depressed patients (D I: 20 +/- 7 microM - D II: 117 +/- 49).

Adult↗
PubMed2002

The parasitic hematophagous worm Haemonchus contortus inhibits human platelet aggregation and adhesion: partial purification of a platelet inhibitor.

Blood sucking parasites elaborate mechanisms to counteract the hemostatic system of their victim. Haemonchus contortus worms use several mechanisms directed against the normal platelet hemostatic function. Platelet adhesion onto collagen and fibrinogen, and the ristocetin-mediated interaction of von Willebrand Factor with glycoprotein (GP) Ib were inhibited by the protein extract of adult worms. Also platelet aggregation induced by collagen, thrombin, ADP, ristocetin or A23187 was inhibited. Although we obtained evidence for interference with fibrinogen binding to GPIIb/IIIa, the strongest inhibition was seen when the agonists collagen or thrombin were used. A small multisubunit inhibitor of collagen-induced platelet aggregation was partially purified using anion exchange chromatography, gel filtration and RP-HPLC. The inhibitor has a pI between 4 and 6.5, elutes with a molecular weight of 23,800 Da after gel filtration, and is part of the elaborate broad-spectrum antiplatelet activity that results in the potent synergistic anti-hemostatic cocktail produced by H. contortus.

Animals↗
PubMed1991

Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse.

There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase), verapamil (calcium antagonist), forskolin (stimulator of platelet adenylate cyclase), and indomethacin (inhibitor of cyclooxygenase) were examined, alone and in combination, to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically, and the animals were divided into control, single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore, when these agents were combined, similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008), while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also, the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.

Adenocarcinoma↗
PubMed1992

[Effects of prolonged-action nitrates on platelet aggregation and prostaglandin formation].

Platelet aggregation and prostaglandin levels were examined in 50 patients with coronary heart disease concurrent with Functional Classes II-III angina who received nitroglycerin-retard (n = 20; Group 1), corovas (n = 20; Group 2), and placebo (n = 10; Group 3). Long-acting nitrates were found to exert a positive action on thrombocytic hemostasis as decreased platelet aggregation and reverse aggregation in 25% of the corovas-treated patients. Placebo failed to have the same action. Nitroglycerin-retard caused an increase in prostacyclin concentrations. Nitroglycerin-retard and corovas produced a clear-cut antianginal effect. They promoted the reduction in the number of anginal episodes and of nitroglycerin tablets used. No antianginal effect was absent when placebo was used.

Angina Pectoris↗
PubMed1984

Platelet aggregation: its relation with ADP-induced fibrinogen binding to platelets and ADP-related membrane enzyme activities.

The receptor for ADP on the platelet membrane, which triggers exposure of fibrinogen-binding sites and platelet aggregation, has not yet been identified. Two enzymes with which ADP interacts on the platelet surface, an ecto-ATPase and nucleosidediphosphate kinase, have been proposed as possible receptors for ADP in ADP-induced platelet aggregation. In the present study, experiments were conducted with washed human platelets to examine if a relationship existed between platelet aggregation, fibrinogen binding and the enzymatic degradation of ADP. With 12 different platelet suspensions, a good correlation (P less than 0.01) was found between the extent of platelet aggregation and the amount of 125I-fibrinogen bound to platelets after ADP stimulation. No correlation was found between these parameters and the rate or extent of transformation of [14C]ADP to [14C]ATP or [14C]AMP. The binding of fibrinogen to platelets was inhibited in parallel with aggregation when ADP stimulation was impaired by the enzymatic degradation of ADP by the system creatine phosphate/creatine phosphokinase, or by the use of specific antagonists, such as ATP and AMP. These antagonists also influenced the enzymatic degradation of ADP. This effect occurred at lower concentrations of ATP or AMP than those required to inhibit ADP-induced platelet aggregation and fibrinogen binding. Our results demonstrate that ATP and AMP may be used as specific antagonists of the ADP-induced fibrinogen binding to platelets. They do not provide evidence to suggest that enzymes which metabolize ADP on the platelet surface are involved in the mechanism of ADP-induced platelet aggregation.

Adenosine Diphosphate↗
PubMed1993

An endogenous inhibitor of PAF-induced platelet aggregation, isolated from rat liver, has been identified as free fatty acid.

In an earlier study (Miwa, M., Hill, C., Kumar, R., Sugatani, J., Olson, M.S. and Hanahan, D.J. (1987) J. Biol. Chem. 262, 527-530) an inhibitor of PAF-induced aggregation of platelets was isolated from perfused rat liver. However, its structure was not established at that time. In this current investigation, the nature of this particular inhibitor was determined and found to be a mixture of long-chain unsaturated fatty acids. These acids ranged in chain length from 17 to 22. Individual chain length acids had IC50 values from 4.5 to 140 microM. Saturated fatty acids had no inhibitory properties even at concentrations well above their critical micellar concentrations. Hence, perturbation of membrane structure appears not to be the primary mode of action of these long-chain unsaturated fatty acids. These findings could have interesting connotations as regards modulation of PAF activity.

Animals↗
PubMed1999

Effects of docosahexaenoic and eicosapentaenoic acid on lipid metabolism, eicosanoid production, platelet aggregation and atherosclerosis in hypercholesterolemic rats.

Exogenously hypercholesterolemic (ExHC) rats were fed on an atherogenic diet supplemented with 1% each of either ethyl ester docosahexaenoic acid [EE-DHA, 22:6(n-3)], ethyl ester eicosapentaenoic acid [EE-EPA, 20:5(n-3)] or safflower oil (SO) for 6 months. The rats fed on the diets containing EE-EPA or EE-DHA, compared with those fed on SO, had lower serum cholesterol and triacylglycerol levels, less aggregation of platelets and slower progress of intimal thickening in the ascending aorta. Relative to the SO-fed rats, both of the (n-3) fatty acid-fed rats had a significantly reduced proportion of arachidonic acid in the platelet and aortic phospholipids, and lower production of thromboxane A2 by platelets and of prostacyclin by the aorta. These results suggest that EPA and DHA are similarly involved in preventing atherosclerosis development by reducing hypercholesterolemia and modifying the platelet functions.

Animals↗