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PubMed1992

Inhibitory effect of rhynchophylline on platelet aggregation and thrombosis.

Rhynchophylline (Rhy) inhibited rabbit platelet aggregation induced by arachidonic acid (AA), collagen, and ADP. The values of IC50 were 0.72, 0.74, and 0.67 mmol.L-1, respectively. Rhy reduced the thromboxane B2 (TXB2) generation in PRP induced by collagen but failed to reduce that induced by AA. Rhy suppressed malondialdehyde (MDA) formation in platelet suspension stimulated by thrombin, inhibited the platelet factor 4 (PF4) release. It did not alter intraplatelet cAMP concentration. Rhy 10-20 mg.kg-1 iv showed a significant inhibition of venous thrombosis and cerebral thrombosis in rats.

Alkaloids↗
PubMed1995

Inhibition of red blood cell-induced platelet aggregation in whole blood by a nonionic surfactant, poloxamer 188 (RheothRx injection).

RheothRx Injection, an aqueous solution of a nonionic block copolymer (poloxamer 188) formulated for intravenous administration, was investigated as an inhibitor of red blood cell (RBC)-induced platelet aggregation at plasma concentrations of 0.05-5mgmL-1. Platelet aggregation was determined by measuring the fall in single platelet counts after mechanical agitation of 2mL aliquots of citrated whole blood in a 37 degrees C shaking waterbath. Inhibition of RBC-induced platelet aggregation of > 95% was observed for poloxamer 188 at a concentration of 1mgmL-1, and 41% inhibition was observed at 0.05mgmL-1. Poloxamer 188 was observed to be a more effective inhibitor of RBC-induced platelet aggregation than 2-chloradenosine (2-ClAd) or phosphoenolpyruvate/pyruvate kinase (PEP/PK). Studies using platelet rich plasma (PRP) showed that platelet aggregation could not be induced by shaking in the absence of RBC, though aggregation was induced by the addition of exogenous adenosine diphosphate (ADP). Poloxamer 188 did not inhibit ADP-induced platelet aggregation. We propose that poloxamer 188 protects RBC from mechanical trauma by non-specific adsorption of copolymer to the RBC surface (via the hydrophobic polyoxypropylene moiety), and that this effect prevents mechanical damage and hence leakage of ADP from RBC. RheothRx Injection has been shown to have value in the treatment of acute ischemic disorders such as myocardial infarction. The observation of significant inhibition of RBC-induced platelet aggregation at clinically relevant concentrations suggests that RheothRx Injection may have antithrombotic properties in vivo, and may therefore have potential not only in acute ischemia but also to prevent thrombosis within vascular prostheses or to prevent rethrombosis after angioplasty or endarterectomy.

Adult↗
PubMed1997

Impact of eptifibatide on early ischemic events in acute ischemic coronary syndromes: a review of the IMPACT II trial. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

Formation of platelet-rich thrombus superimposed on ruptured atherosclerotic plaque has been implicated in the development of myocardial ischemia and its clinical manifestations. The platelet glycoprotein (GP) IIb-IIIa receptor is the final common pathway leading to platelet aggregation and thrombus formation. GP IIb-IIIa is therefore a logical therapeutic target for management of acute ischemic coronary syndromes and prevention of the ischemic complications of percutaneous coronary procedures. Of the pharmaceutical agents under development, the chimeric monoclonal antibody abciximab (ReoPro) and the cyclic peptide eptifibatide (INTEGRILIN) are the most studied. IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis), the phase III evaluation of eptifibatide in patients undergoing percutaneous coronary intervention, demonstrated the effectiveness and safety of this GP IIb-IIIa receptor inhibitor in reducing the acute adverse outcomes of invasive management of ischemic heart disease. GP IIb-IIIa receptor blockade provides an effective strategy for prevention of ischemic complications related to angioplasty in patients with coronary artery disease.

Clinical Trials, Phase III as Topic↗
PubMed2006

IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation.

Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke. A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling by cGMP-dependent protein kinase I (cGKI). However, the regulatory cascade downstream of cGKI mediating platelet inhibition is still unclear. Here, we show that the inositol-1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) is abundantly expressed in platelets and assembled in a macrocomplex together with cGKIbeta and the inositol-1,4,5-trisphosphate receptor type I (InsP3RI). cGKI phosphorylates IRAG at Ser664 and Ser677 in intact platelets. Targeted deletion of the IRAG-InsP3RI interaction in IRAGDelta12/Delta12 mutant mice leads to a loss of NO/cGMP-dependent inhibition of fibrinogen-receptor activation and platelet aggregation. Intracellular calcium transients were not affected by DEA/NO or cGMP in mutant platelets. Furthermore, intravital microscopy shows that NO fails to prevent arterial thrombosis of the injured carotid artery in IRAGDelta12/Delta12 mutants. These findings reveal that interaction between IRAG and InsP3RI has a central role in NO/cGMP-dependent inhibition of platelet aggregation and in vivo thrombosis.

Animals↗
PubMed2004

Inhibitory activity of shiitake flavor against platelet aggregation.

Sulfuric-flavored compounds were extracted from shiitake (Lentinus edodes) and their inhibitory activity against platelet aggregation was investigated. Platelet aggregation induced by arachidonic acid and U-46619, the analog of thromboxane A(2), was inhibited by the essential oil from shiitake that contained lenthionine as a major sulfuric compound. This result indicates that the inhibitory site of the shiitake flavor compounds would be different from that of garlic-flavor compounds because the latter inhibits the passage between arachidonic acid and thromboxane A(2). The effect of the synthesized lenthionine was almost equivalent to that of the essential oil, which indicates that the inhibitory activity of the essential oil from shiitake would be mainly attributed to lenthionine.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors.

Thromboxane A(2) is a positive feedback lipid mediator produced following platelet activation. The G(q)-coupled thromboxane A(2) receptor subtype, TPalpha, and G(i)-coupled TPbeta subtype have been shown in human platelets. ADP-induced platelet aggregation requires concomitant signaling from two P2 receptor subtypes, P2Y1 and P2T(AC), coupled to G(q) and G(i), respectively. We investigated whether the stable thromboxane A(2) mimetic, (15S)-hydroxy-9, 11-epoxymethanoprosta-5Z,13E-dienoic acid (U46619), also causes platelet aggregation by concomitant signaling through G(q) and G(i), through co-activation of TPalpha and TPbeta receptor subtypes. Here we report that secretion blockade with Ro 31-8220, a protein kinase C inhibitor, completely inhibited U46619-induced, but not ADP- or thrombin-induced, platelet aggregation. Ro 31-8220 had no effect on U46619-induced intracellular calcium mobilization or platelet shape change. Furthermore, U46619-induced intracellular calcium mobilization and shape change were unaffected by A3P5P, a P2Y1 receptor-selective antagonist, and/or cyproheptadine, a 5-hydroxytryptamine subtype 2A receptor antagonist. Either Ro 31-8220 or AR-C66096, a P2T(AC) receptor selective antagonist, abolished U46619-induced inhibition of adenylyl cyclase. In addition, AR-C66096 drastically inhibited U46619-mediated platelet aggregation, which was further inhibited by yohimbine, an alpha(2A)-adrenergic receptor antagonist. Furthermore, inhibition of U46619-induced platelet aggregation by Ro 31-8220 was relieved by activation of the G(i) pathway by selective activation of either the P2T(AC) receptor or the alpha(2A)-adrenergic receptor. We conclude that whereas thromboxane A(2) causes intracellular calcium mobilization and shape change independently, thromboxane A(2)-induced inhibition of adenylyl cyclase and platelet aggregation depends exclusively upon secretion of other agonists that stimulate G(i)-coupled receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1976

Platelet aggregation, stroke, and transient ischemic attack in middle-aged and elderly patients.

Platelet aggregation was studied with optical density methods in a group of 39 patients with stroke or transient ischemic attacks (TIA) and in age, sex, and race-matched controls. The patients were divided at age 60 into young stroke patients and young controls (18 pairs) and old stroke patients and old controls (21 pairs). A semiquantitative measure of the threshold of phase II of platelet aggregation and distinct of disaggregation 3 minutes after peak aggregation were used as an index of platelet aggregability. Aggregability was significantly greater in young stroke patients than in young controls. Aggregability was similar in old stroke patients and old controls. Both old stroke patients and old controls were hyperaggregable compared with young controls, indicating that aggregability rises with age. This suggests that platelet aggregability is significant risk factor for stroke but is relatively more important in the younger than in the older stroke patient.

Adult↗
PubMed1998

Heterogeneity of platelet aggregation and major surface receptor expression in patients with acute myocardial infarction.

BACKGROUND: Platelets play an important role in the natural history of acute myocardial infarction (AMI). METHODS AND RESULTS: Platelet aggregation and receptor expression were studied in 23 patients with AMI before reperfusion therapy and compared with 10 healthy control subjects. Platelet aggregation was induced with 5 micromol/L adenosine 5'-diphosphate, 10 micromol/L ADP, 1 microg/mL collagen, 1 mg/mL thrombin, and 1.25 mg/mL ristocetin. Receptor expression was measured by flow cytometry with monoclonal antibodies to p24 (CD9), Ib (CD42b), IIb (CD41b), IIIa (CD61), IIb/IIIa (CD41b/CD61), very late antigen-2 (CD49b), P-selectin (CD62p), platelet/endothelial cell adhesion molecule-1 (CD31); and vitronectin (CD51/CD61). The percentage of platelet aggregation was higher in patients with AMI when induced by 5 micromol/L ADP (64.1+/-12.7 vs 52.0+/-6.7; P=.04), by 10 micromol/L ADP (71.7+/-13.0 vs 59.2+/-7.2, P=.003), by thrombin (75.8+/-10.9 vs 60.5+/-6.9, P=.01), and by ristocetin (92.5+/-7.8 vs 71.3+/-7.4, P=.0001). Collagen-induced platelet aggregation did not differ between groups. Expression of P-selectin (log amplification of fluorescence intensity) (31.5+/-5.0 vs 25.1+/-2.6, P=.003) and platelet/endothelial cell adhesion molecule-1 (56.8+/-17.7 vs 44.5+/-3.7, P=.04) were significantly increased in patients with AMI. The expression of IIb (28.4+/-2.5 vs 37.2+/-1.7, P=.0001) and Ib (103.6+/-29.9 vs 133.8+/-8.0, P=.007) were reduced in patients with AMI. CONCLUSIONS: Platelets are not necessarily systemically activated during the prereperfusion phase of AMI. For each agonist used and surface antigen measured, there was a cohort of patients with AMI within the normal or even below normal range of platelet status.

Adenosine Diphosphate↗
PubMed1989

Hypercholesterolemia impairs endothelium-dependent relaxations to aggregating platelets in porcine iliac arteries.

The purpose of the present study was to examine in peripheral arteries whether the endothelium plays a protective role against aggregating platelets and whether the responses to platelets are altered by hypercholesterolemia. Male Yorkshire pigs were fed either a normal diet or a 2% high-cholesterol diet for 10 weeks. Endothelium-dependent responses were examined in vitro. In isolated iliac arteries from control animals, aggregating platelets caused contractions that were significantly inhibited by the endothelium. In rings with endothelium from pigs fed a cholesterol diet, the contractions were augmented and no difference was noted between rings with and rings without endothelium. In rings taken from control pigs contracted with prostaglandin F2 alpha, aggregating platelets caused endothelium-dependent relaxations, which were attenuated by blockade of adenosine diphosphate or serotonin. Adenosine diphosphate and serotonin also caused endothelium-dependent relaxations. In arteries from cholesterol-fed animals, the inhibitory effects of the endothelium to aggregating platelets, adenosine diphosphate, and serotonin were impaired. These experiments indicate that in porcine iliac arteries the endothelium exerts inhibitory effects on the responses to aggregating platelets, which are mediated by adenosine diphosphate and serotonin released from platelets. Hypercholesterolemia impairs the endothelium-dependent relaxations to aggregating platelets caused by reduced relaxations to adenosine diphosphate and serotonin and unmasks the contractions evoked by aggregating platelets. This may increase the level of vascular tone, decrease blood flow and increase platelet aggregation, and eventually facilitate the occurrence of peripheral arterial occlusive disease.

Animals↗
PubMed2001

Dissociation of glycoprotein IIb/IIIa antagonists from platelets does not result in fibrinogen binding or platelet aggregation.

BACKGROUND: The primary mechanism of action of glycoprotein (GP) IIb/IIIa antagonists is inhibition of the final common pathway of platelet aggregation: fibrinogen binding to the GP IIb/IIIa complex. However, it has been reported that induction of fibrinogen binding and platelet aggregation is an intrinsic prothrombotic property of low-dose GP IIb/IIIa antagonists. These apparently paradoxical results have been extensively referenced in the cardiology literature. METHODS AND RESULTS: By platelet aggregation and flow cytometry, we demonstrate that (1) dissociation of GP IIb/IIIa antagonists (abciximab, tirofiban, eptifibatide, or xemilofiban) from platelets does not result in platelet aggregation; (2) tirofiban and eptifibatide can induce a fibrinogen-binding-competent conformation of the GP IIb/IIIa receptor, but stable fibrinogen binding does not occur without fixation; (3) the slow off-rate of abciximab exposes only a small proportion of unblocked GP IIb/IIIa receptors at any time, and these also fail to stably bind fibrinogen; and (4) the GP IIb/IIIa antagonist-induced fibrinogen binding in some previously reported experiments was probably the result of artifactual thrombin generation. CONCLUSIONS: Under physiological conditions, GP IIb/IIIa antagonists currently in clinical use do not have an intrinsic activating property that results in platelet aggregation or stable fibrinogen binding to GP IIb/IIIa.

Binding, Competitive↗
PubMed2004

Combined effects of melagatran and eptifibatide on platelet aggregation inhibition but not thrombin generation inhibition.

The aim of our study was to investigate the combined in vitro effects of melagatran and eptifibatide on platelet aggregation and thrombin generation under low and high coagulant challenge in tissue-factor-activated, platelet-rich plasma. Increasing amounts of melagatran dose-dependently decreased prothrombin fragment 1.2 and activated factor X values, and dose-dependently prolonged the lag phase until the onset of platelet aggregation. Eptifibatide exerted a dose-dependent anti-aggregating effect under both high and low coagulant challenge. The combination of melagatran and eptifibatide resulted in significant additive prolongation of the lag phase until the onset of platelet aggregation, which was more pronounced under low coagulant challenge. Under low, but not under high, coagulant challenge, the combination of melagatran and eptifibatide had a significant additive inhibitory effect on platelet aggregation. No additive effects on decreasing prothrombin fragment 1.2 and activated factor X values were observed with combined administration of the drugs. The present study demonstrates the additive effect of melagatran and eptifibatide on platelet aggregation inhibition and on prolongation of the lag phase until the onset of platelet aggregation.

Azetidines↗
PubMed2006

Effects of IgG and its F(ab')2 fragments of some patients with idiopathic thrombocytopenic purpura on platelet aggregation.

OBJECTIVES: To make humanized monoclonal antibodies by phage surface display technology, we screened out the specific anti-platelet glycoproteins (GPs) IgG antibody from patients with chronic idiopathic thrombocytopenic purpura (ITP), which can inhibit platelet aggregation. METHODS: We studied plasmas from 68 patients with ITP for the presence of IgG antibodies specific for GPIIb/IIIa and/or GPIb/IX using modified monoclonal antibody immobilization of platelet antigen assays. The IgG antibody and its F(ab')(2) fragments of the positive plasmas which could inhibit platelet aggregation function were prepared and purified. Their immunoreactivity to platelet GPs and effects on platelet function were further analyzed. RESULTS: GPIIb/IIIa- and GPIb/IX-specific antibodies were found in 21 and 19 patients, respectively. Six of them had antibodies against both GP complexes. Among the 34 positive plasmas, four with positive anti-GPIIb/IIIa autoantibody showed significant inhibition of platelet aggregation induced by adenosine diphosphate (ADP), whereas one with GPIb/IX-specific antibody inhibited ristocetin-induced platelet aggregation. The purified IgG and its F(ab')(2) fragments from two patients not only retained the ability to bind to platelet GPs but also impaired the in vitro ADP-induced platelet aggregation. CONCLUSIONS: F(ab')(2) portion of the IgG is a functional fragment, which is responsible for the autoantibody interaction with platelet GPs in ITP, and some of them also affect platelet function, which can be used to develop completely humanized anti-GPIIb/IIIa small molecular phage antibody.

Adolescent↗
PubMedDate not supplied

Inhibition of intravascular platelet aggregation in the rat by adrenaline.

Intravascular platelet aggregation to adenosine diphosphate (ADP) was measured in anesthetized rats using 111indium-labelled platelets. Acute adrenalectomy increased the aggregatory effect of ADP in vivo, whereas infusions of low concentrations of adrenaline into adrenalectomized rats suppressed ADP-induced platelet aggregation. Similar antiaggregatory effects were seen with the alpha 2 agonist B-HT 933 and the alpha 1 agonist methoxamine, but not with isoprenaline. The effect of adrenaline was inhibited by phentolamine, yohimbine, the selective alpha 2 adrenoceptor antagonist WY 26392 and by indomethacin, but not by propranolol or prazosin. Adrenaline thus inhibits ADP-induced aggregation in vivo by a mechanism that may involve stimulation of an alpha 2 adrenoreceptor and may be dependent on activation of cyclooxygenase enzyme.

Adenosine Diphosphate↗
PubMed1978

Increase in platelet aggregation following a rise in plasma free fatty acids.

Platelet aggregation was studied following intravenous injection of heparin to nine healthy adults. Heparin is known to produce an increase in the concentration of free fatty acids (FFA) within 10 minutes of intravenous injection. A significant correlation was found between the intensity of primary platelet aggregation and changes in plasma FFA levels. No correlation was found between plasma FFA levels and the intensity of secondary platelet aggregation.

Fatty Acids, Nonesterified↗
PubMed1989

Platelet aggregating activity in the plasma of patients with established thrombosis.

This study examines the incidence and significance of novel plasma derived platelet aggregating activity (PAA) in 190 consecutive patients admitted to the medical wards of a general hospital. Seventy five patients (39%) demonstrated this activity. The incidence was highest in patients with a history of thrombosis (52%) or in those with a heightened thrombotic tendency, for example, patients with diabetes or hypertension. In contrast, platelet aggregating activity was observed in six out of 62 patients (approximately 10%) in whom a current or past medical history of thrombosis could not be elicited and in only two out of 72 healthy volunteers examined (3%). A high frequency of PAA was also noted in a small group of patients with idiopathic thrombocytopenia and patients who had previously received platelet transfusions. In these patients, this activity presumably reflects the presence of antiplatelet antibodies. A good correlation between the presence of plasma derived platelet aggregating activity and the phenomenon of spontaneous platelet aggregation was observed. The platelet aggregating activity was not heparin dependent, but was completely abolished by EDTA (5 mM) and benzamidine (8 mM), or by pretreating the platelets with aspirin. A synergistic response was observed with subaggregatory concentrations of thrombin and adrenalin. Our results suggest that the presence of this platelet aggregating activity may provide a marker for vascular thrombosis. Furthermore we postulate that this plasma derived activity may be partly responsible for platelet hyperactivity previously observed in patients with thromboembolic disorders.

Adult↗
PubMed1989

[Platelet aggregation in diabetes mellitus in children].

Platelets-endothelial cells interaction appears to cause vascular damage in diabetes. Platelet aggregation was studied in 24 diabetic children and adolescents (mean age: 12.2 years, mean duration of diabetes: 3.3 years), with only one presenting microangiopathy complications (retinopathy). Platelet aggregation was found to be normal, suggesting that there is usually no platelet hyperactivity in diabetic children.

Adenosine Diphosphate↗
PubMed1990

Exercise-induced platelet aggregation in angina and its possible prevention by beta 1-selective blockade.

Moderate exercise increased platelet aggregability of 12 middle-aged men with stable angina pectoris: the mean ADP threshold fell from 4.58 +/- 0.63 to 3.18 +/- 0.41 microM, P less than 0.01. Exercise did not, however, alter platelet aggregability in 12 healthy matched controls. Physical effort approximately doubled the plasma levels of adrenaline and noradrenaline in patients as well as in controls. Under the same conditions the cAMP content of platelets fell in the angina group from 20.86 +/- 1.86 to 17.78 +/- 1.71 pmol 10(-9) platelets, P less than 0.01, while there was no change in control levels. The fall of cAMP could account for the observed increase in platelet aggregability. We speculate that the increased aggregability of platelets in the exercising anginal subjects represents an imbalance between prostacyclin release and haemodynamic changes. The beta 1-selective blocker metoprolol, in usual therapeutic dosages, prevented the observed platelet changes probably by minimizing the haemodynamic disturbances and stimulating release of prostacyclin.

Adrenergic beta-Antagonists↗
PubMed1991

Inhibition of platelet aggregation by a fibrinogenase from Naja nigricollis venom is independent of fibrinogen degradation.

Fibrinogenases, proteinases which release peptides from the carboxy-terminal end of fibrinogen, are classified as alpha-fibrinogenases or beta-fibrinogenases, based on their ability to preferentially attack the A alpha or B beta chain, respectively, of fibrinogen. alpha-Fibrinogenases have been shown to inhibit platelet aggregation whereas beta-fibrinogenases do not. We have studied the inhibition of platelet aggregation by proteinase F1, an alpha-fibrinogenase from Naja nigricollis venom. This proteinase inhibits whole blood aggregation in a dose-dependent manner, with an IC50 value of 145 micrograms. However, the proteinase fails to inhibit aggregation in washed platelet suspensions. Thus, proteinase F1 appears to require a plasma factor to cause inhibition. Since fibrinogen acts as an adhesive protein which links platelets during aggregation, and since proteinase F1 cleaves fibrinogen, we investigated the role of fibrinogen in the inhibition of platelet aggregation by proteinase F1. The degradation products of fibrinogen formed by the proteinase did not cause significant inhibition. Thus, the inhibition of platelet aggregation appears to be independent of the formation of fibrinogen degradation products. We also studied the effect of proteinase F1 on aggregation of platelets that were reconstituted with defibrinogenated plasma. The proteinase inhibited aggregation of platelets even in the absence of plasma fibrinogen. Proteinase F1 was about 4-fold more potent in inhibiting platelet aggregation in defibrinogenated blood. From these results, we conclude that the inhibition of platelet aggregation by proteinase F1 from N. nigricollis venom is independent of its action on fibrinogen.

Animals↗