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PubMed2003

A new method to evaluate spontaneous platelet aggregation in type 2 diabetes by Cellfacts.

BACKGROUND: The alterations in the functional activities of platelets in diabetes produce an increase of spontaneous platelet aggregation (SPA) and release of platelet-derived microparticles. Platelet-derived microparticles are shed from platelets during activation by high shear stress, collagen and certain agonists. Although the physiologic role of microparticles has been difficult to assess, the characterization of their biological activity is of interest in view of a possible role in hemostasis and coagulation and their reported involvement in thrombotic disease. METHODS: We propose a new, simple method to evaluate spontaneous platelet aggregation and release of platelet-derived microparticles by the Cellfacts analyser (Microbial System Limited (MSL), Coventry, England) that uses electrical sensing flow impedance determination to detect the size particles and the cells in a conductive fluid. Platelet-rich plasma (PRP) from type 2 diabetes was employed for this study. The importance of platelet-activating factor (PAF) on spontaneous platelet aggregation was evaluated and the effect of vitamin E and WEB 2086-BS, an antagonist of platelet-activating factor, was measured. RESULTS AND CONCLUSIONS: Data presented show that Cellfacts could be an easy and fast instrument to check the state of platelets in patients with alterations in the functionality of platelets, and to follow the effect of pharmacological therapy on spontaneous platelet aggregation and the release of platelet-derived microparticles.

Adenosine Diphosphate↗
PubMed1996

Platelet aggregation in patients with primary pulmonary hypertension.

Platelet aggregation activity was investigated in patients with primary pulmonary hypertension in different stages of the disease. Platelets were activated with ADP and PAF. Spontaneous platelet aggregation was also measured. Spontaneous and low dose PAF-induced platelet aggregation in patients was greater than in healthy subjects and increased with the severity of the disease. It was concluded that the increased platelet activity can be related to unfavourable prognosis in these patients.

Adenosine Diphosphate↗
PubMed1994

Effects of MDL 28,133A, a 5-HT2 receptor antagonist, on platelet aggregation and coronary thrombosis in dogs.

We wished to characterize MDL 28,133A (1-(4-fluorophenyl)-2-[4-[(4-methanesulfonamidophenyl)carbonyl]-1- piperidinyl-ethanone HCl), a potent 5-HT2 receptor antagonist, on platelet aggregation and platelet thrombosis and determined its effect on thrombolysis with streptokinase (SK) in dogs with coronary thrombosis. MDL 28,133A and ritanserin, 0.3-1 microM, competitively inhibited 5-HT-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro. The pA2 values and slopes were 6.29 +/- 0.09, -0.96 +/- 0.14, and 6.58 +/- 0.09, =1.64 +/- 0.34 for MDL 28,133A and ritanserin, respectively, suggesting that both agents are similar in potency to 5-HT2 receptor antagonists. MDL 28,133A (0.01 mg/kg, p.o.) produced inhibition of arachidonic acid-induced platelet aggregation in whole blood from conscious dogs ex vivo for > or = 2 h, indicating oral bioavailability. The magnitude and duration of the effect of MDL 28,133A on platelet aggregation in whole blood was similar to that of ketanserin (2.5 mg/kg, p.o.). MDL 28,133A (0.001-0.03 mg/kg, i.v.) completely abolished cyclic flow reductions (CFRs) in stenosed and partially deendothelialized left anterior descending coronary arteries of anesthetized dogs for at least 120 min without affecting systemic blood pressure (BP) and heart rate, thus indicating that MDL 28,133A is a potent antithrombotic agent. Ketanserin (0.5 mg/kg, i.v.) also abolished CFRs, but produced a significant decrease in systemic BP as well. MDL 28,133A (0.001 mg/kg, i.v.) shortened time to reperfusion (15 +/- 1 vs. 36 +/- 8 min), prolonged time to reocclusion (112 +/- 6 vs. 85 +/- 6 min), and increased total volume reflow (20 +/- 2 vs. 10 +/- 2%) in dogs with coronary artery thrombosis undergoing thrombolysis with SK (1,000 U/min, i.a.). Reocclusion rate was not affected by MDL 28,133A (4 of 5 vs. 4 of 6). Treatment with heparin (150 U/kg, i.v. every hour for 2 h) alone or in combination with MDL 28,133A did not improve time to reperfusion but enhanced total volume reflow and prevented reocclusion. MDL 28,133A is a potent 5-HT2 receptor antagonist that inhibits platelet thrombosis and facilitates thrombolysis in vivo. The impeding effect of MDL 28,133A in coronary thrombosis and the lack of hemodynamic effects suggests that MDL 28,133A may be of benefit in treatment of hyperthrombotic conditions without having hemodynamic side effects.

Administration, Oral↗
PubMed1990

Adenosine potentiates the inhibitory effects of calcium channel antagonists on human platelet aggregation induced by thromboxane A2 or U46619.

Calcium channel antagonists inhibit platelet function in vitro and ex vivo, but the mechanism responsible has not been clearly defined. The concentrations of these agents required to inhibit platelet aggregation in vitro are several fold higher than those attained in vivo. Adenosine, a known inhibitor of platelet function, is produced in large quantities in ischemic myocardium. In order to test the hypothesis that adenosine may potentiate the platelet-inhibitory effects of calcium channel antagonists, we studied the effect of adenosine plus nifedipine, verapamil or diltiazem on human platelet aggregation induced by thromboxane A2 or the stable endoperoxide/thromboxane A2 mimic, U46619 +/- epinephrine. Adenosine, in concentrations achieved in the plasma during myocardial ischemia (0.01-0.1 microM), enhanced the inhibitory effects of nifedipine, verapamil and diltiazem on platelet aggregation 5-100 fold. The same concentrations of adenosine alone did not inhibit platelet aggregation. In the presence of non-inhibitory concentrations of adenosine, nifedipine, in concentrations approaching those attained in vivo following standard therapeutic doses (as low as 0.29 microM), significantly inhibited thromboxane A2-induced platelet aggregation. Therefore, adenosine potentiates the in vitro inhibitory effects of calcium channel antagonists on platelet aggregation induced by thromboxane A2 or thromboxane A2 plus epinephrine. These results suggest that adenosine production by ischemic myocardium may augment the inhibitory effect of calcium channel antagonists on platelets.

Adenosine↗
PubMed1992

Detection of reversible platelet aggregates in the blood of smokers and ex-smokers with peripheral vascular disease.

OBJECTIVE: To demonstrate that smoking increases platelet aggregation in vivo, that smoking cessation reverses platelet aggregation and that this explains, in part, why smoking perpetuates the development of peripheral vascular disease. DESIGN: Prospective case-control study involving three groups of patients: smokers with peripheral vascular disease, ex-smokers with peripheral vascular disease and smokers with peripheral vascular disease who quit smoking during the study. SETTING/PARTICIPANTS: Fourteen smokers and seven ex-smokers, new patients with confirmed peripheral vascular disease, attending the vascular clinic at Fremantle Hospital between February and November, 1988. INTERVENTIONS: Blood samples taken weekly from all subjects for five weeks. Week 1 was taken as the baseline before smoking cessation in the six smokers who were assigned to stop smoking during the study. MAIN OUTCOME CRITERIA: Platelet aggregate ratio, an indicator of in-vivo platelet aggregability where an increase in platelet aggregate ratio suggests a decrease in platelet function. RESULTS: Only three of six smokers stopped smoking for the duration of the study. Median platelet aggregate ratios were: smokers = 0.85 (range, 0.79-0.92) v. non-smokers = 0.93 (range, 0.91-1.00). The difference was statistically significant P less than 0.0002. The difference in platelet aggregate ratios between smokers and quitters was not statistically significant. CONCLUSIONS: This study demonstrated an increase in platelet aggregability in smokers compared to ex-smokers but there was no clear evidence that platelet function was fully reversed after only four weeks cessation of smoking. The data suggested that platelet function of the ex-smokers had fully reversed to normal over a longer period. This could explain the decreased incidence of complications of peripheral vascular disease in ex-smokers. The small number of patients able to quit smoking impeded this study.

Adult↗
PubMed1994

SC-49992--a potent and specific inhibitor of platelet aggregation.

Fibrinogen binding is required for platelet aggregation and subsequent thrombus formation. SC-49992 (SC), an RGDF mimetic, is a potent and specific inhibitor of the binding of fibrinogen to its receptor on activated platelets, glycoprotein IIb/IIIa (IC50 0.7 microM). SC was more potent (1-5 microM) than either RGDS, RGDF or the gamma chain dodecapeptide in blocking platelet aggregation to a variety of agonists in both dog and human platelet rich plasma. SC was more potent as an inhibitor of GP IIb/IIIa on platelets than it was against other integrin and non-integrin receptors, including the RGD-dependent vitronectin receptor and other non-RGD-dependent integrins such as CDII/CD18. SC had little effect on ristocetin induced agglutination. SC blocked ex vivo collagen induced aggregation in dogs and collagen induced thrombocytopenia in rats. These data suggest that elimination of the Arg-NH2 and the Arg-Gly amide bond of RGDF provided increased inhibitory potency and specificity. This structural modification may be of value in the development of other more potent RGDF mimetics for the inhibition of platelet aggregation.

Amino Acid Sequence↗
PubMed1976

Study of platelet aggregation in vivo i. Effect of bencyclan.

A 20mu diameter pore size screen was inserted into an arterio-venous bypass system in heparinized stumptailed monkeys. ADP and serotonin injection resulted in aggregation of platelets on the screen and consecutive increase in pre-screen pressure and decrease in post-screen pressure. From these changes an "aggregation index" was calculated. Bencyclan in doses of 0.5-15 mg/kg inhibited platelet aggregation in vivo. Doses of 20 mg/kg or above showed some hemolytic effect, no other undesirable effects were seen.

Adenosine Diphosphate↗
PubMed1990

Influence of hypercapnia and hypoxia on rabbit platelet aggregation.

The influence of changes in pCO2, pH and pO2 on the aggregation of rabbit blood platelets was studied in vitro, with emphasis on hypercapnia, acidosis and hypoxia. Hypercapnia combined with acidosis caused a reduction in rabbit platelet aggregation, as induced by collagen, thrombin and ADP; the effect being most pronounced with collagen and smallest with ADP. Hypoxia reduced thrombin induced platelet aggregation, but had no effect on ADP and collagen induced aggregation. Synergistic activation of rabbit platelets, as induced by the addition of serotonin to platelet rich plasma together with collagen or ADP, seemed to be equally sensitive to changes in pCO2 and pH as activation by the individual agents, and insensitive to changes in pO2.

Adenosine Diphosphate↗
PubMed1999

Fibrinogenolytic properties of natrahagin (a proteinase from cobra venom) and its effect on human platelet aggregation.

AIM: To study the fibrinogenolytic properties of natrahagin and its effect on platelet aggregation. METHOD: SDS-PAGE, fibrinogenolytic activity assay, platelet aggregation. RESULTS: Upon incubation of fibrinogen with natrahagin at the ratio of 50:1 (w/w), A alpha-chains of fibrinogen were almost completely hydrolyzed in 5 min; however, at least 6 h was needed for the complete degradation of gamma-chains. Fibrinogenolytic activity of natrahagin was 0.349 +/- 0.044 g.min-1.g-1 as determined by its ability to reduce the clottable fibrinogen. On the other hand, natrahagin concentration-dependently inhibited platelet aggregation induced by ristocetin in platelet-rich plasma and thrombin (80 U.L-1) in washed platelets with IC50 (95% confidence limit) of 56 (40-79) and 3.3 (1.4-8.0) mg.L-1. No inhibitory effect was found on collagen- and ADP-induced platelet aggregation even when the dose of natrahagin reached 200 mg.L-1. CONCLUSION: Natrahagin is an alpha, gamma-fibrinogenase with an inhibitory effect on platelet membrane glycoprotein Ib (GPIb)-dependent platelet aggregation.

Adult↗
PubMed1982

Reduction of plasma levels of betathromboglobulin and platelet factor 4 during hemodialysis: a possible role for a short acting inhibitor of platelet aggregation.

Plasma levels of the platelet markers betathromboglobulin and platelet factor 4 are elevated in patients with chronic renal failure, and their levels in hemodialysis patients increase further during exposure to the dialysis membrane. The effectiveness of a short acting inhibitor of platelet aggregation in reducing the blood levels of betathromboglobulin and platelet factor 4 was assessed by means of a double blind cross over study. A statistically significant reduction of betathromboglobulin and platelet factor 4 levels was observed during treatment with the platelet inhibitor.

Adult↗
PubMed1990

The platelet aggregating factor(s) of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is characterized by disseminated platelet aggregates throughout the microcirculation and a large body of clinical, experimental and pathological evidence implicates in vivo platelet aggregation as being pivotal in the disease. For this reason considerable energy has been spent by many investigators to identify a platelet aggregating factor. The understated reason for these studies is that the characterization of such a factor could lead to the subsequent identification of a medication or a plasma factor that could neutralize the aggregating factor. Although a platelet aggregating factor has been suspected to play a causal role in TTP for almost 50 years, only in recent years have investigators systematically attempted to identify such a factor. One group has identified a 37 kD protein in the plasma of TTP patients which can initiate platelet aggregation through a unique pathway of aggregation and this factor can be inhibited by normal IgG. The other group of workers (ourselves) have provided evidence that the platelet aggregating factor of TTP is calpain. Thus, the very nature of the aggregating factor, and by implication its inhibitors, is very different for the two groups, and it may take other investigators to resolve whether there are multiple platelet aggregating factors of TTP. Nonetheless, it is apparent that recent research has dramatically improved our understanding of this uncommon but important disorder and it is possible that such investigations will lead to more successful treatments of this condition.

Blood Coagulation Factors↗
PubMed2006

[The immunoreactivity of IgG and its fragments from ITP patients and their effects on platelet aggregation function].

OBJECTIVE: To prepare ITP plasma IgG and its F(ab')2 fragments and investigate their immunoreactivity to platelet GPIIb/IIIa and/or GPIb/IX and their effects on platelet aggregation function. METHODS: The ITP patients having inhibitory autoantibody to the platelet aggregation were selected by modified MAIPA and platelet aggregation test with turbidimetry. Plasma IgG and its F(ab')2 fragments were prepared by streptococcal protein A affinity column and pepsin digestion. The immunoreactivity and the effects on platelet aggregation function of the whole antibody and its fragments were detected by modified MAIPA and platelet aggregation test, respectively. RESULTS: (1) Anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies were detected in 34 of 68 (53.6%) ITP patients' plasmas and that from 5 patients significantly inhibited the platelet aggregation induced by ADP or ristocetin. (2) By using protein A column combined with protease digestion, pure IgG and its F(ab')2 fragments were successfully obtained. (3) The purified IgG and its F(ab')2 fragments retained the ability to bind to their respective glycoproteins and inhibited the platelet aggregation function, whereas the IgG depleted plasma lost the ability of binding to the platelet GPs. CONCLUSIONS: F(ab')2 fragment of the IgG antibody is a functional fragment, which not only has the binding ability to the platelet GPs but also inhibits the platelet aggregation function in a dose-dependent manner.

Adolescent↗
PubMed1975

The effect of ADP, calcium and some inhibitors of platelet aggregation on protein phosphokinases from human blood platelets.

A protein phosphokinase (ATP: protein phosphotransferase EC 2.7.1.37) which is stimulated by 3',5'-cyclic adenosine monophosphate (cyclic AMP) has been partially purified from both the cytoplasmic and membrane fractions of human platelets. The kinetics of both enzymes preparations are similar in respect to cyclic AMP, ATP, ADP and AMP. 5-10-minus 7 M cyclic AMP stimulated both preparations by approximately 100%. Both ADP and AMP at a concentration of 5-10-minus 5 M inhibited protein phosphokinase activity of the soluble and membrane preparation by between 50% and 70%. The response of the two enzyme preparations to calcium differed. 10 mM Ca-2+ inhibited soluble protein phosphokinase activity approximately 80% both in the presence and absence of 5-10 minus 7 M cyclic AMP whereas the same concentrations of Ca-2+ inhibited the membrane-bound enzyme by approximately 60% in the presence of 5-10-minus 7 M cyclic AMP and 40% in the absence of cyclic AMP. This observation may be of importance in understanding the mechanism of platelet aggregation.

Adenosine↗
PubMed1982

On the mechanism of heparin-induced potentiation of platelet aggregation.

The role of antithrombin III (AT III) in heparin-induced potentiation of platelet aggregation was investigated using purified AT III and AT III depleted plasma. When ADP or epinephrine was added to citrated platelet rich plasma (PRP) one minute after addition of heparin, marked enhancement of platelet aggregation was observed, compared with the degree of platelet aggregation in the absence of heparin. However, heparin exhibited no potentiating effect on ADP- or epinephrine-induced platelet aggregation when platelets were resuspended in AT III depleted plasma prepared by immunosorption using matrix-bound antibodies to AT III. When purified AT III was added to AT III depleted plasma at a concentration of 20 microgram/ml, potentiation of platelet aggregation by heparin was clearly demonstrated. These results suggest that the effect of heparin on platelet aggregation is also mediated by AT III.

Adenosine Diphosphate↗
PubMedDate not supplied

Spectrum of platelet aggregation abnormalities in myeloproliferative diseases.

Several platelet abnormalities have been described in myeloproliferative diseases. The present study deals with 81 patients with polycythaemia vera, chronic myelogenous leukemia, essential thrombocythaemia and idiopathic myelofibrosis, and reports the analysis of the findings in platelet-induced aggregation. Platelet abnormalities induced by ADP, adrenaline and collagen were found in 41.9% of the patients. A defect of primary aggregation was documented in 13 cases and one of them showed an aggregation pattern similar to that of Glanzmann's disease. Fifteen patients had an impairment of secondary aggregation, and in one case of this group the platelet malondialdehyde and serotonin findings were consistent with a defect resembling that of typical congenital storage pool deficiency. A disturbance of the arachidonic acid pathways associated with a storage pool deficiency was found in a third patient belonging to a group with abnormalities of primary and secondary aggregation. In conclusion, platelets in myeloproliferative diseases have several defects and in a few cases their combination is similar to those of congenital diseases.

Adenosine Diphosphate↗
PubMed1982

The role of platelet membrane potential in the initiation of platelet aggregation.

The membrane potential of human platelets, and the role of this potential in platelet aggregation, was assessed using the noncovalent, fluorescent probe DiS-C3-5. High K+ and Gramicidin depolarised the cells, whereas valinomycin in standard (4 mMK+) solution produced a hyperpolarisation. Very small changes in potential were observed when choline Cl replaced NaCl. These findings indicate that platelets possess a relatively K+-perm-selective membrane. The resting potential calculated from the "valinomycin null point" (the K+ concentration gradient at which valinomycin did not change the potential) was approximately -60 mV. Other factors that contribute to the platelet membrane potential include a significant Cl- permeability, demonstrated by replacing Cl- with methylsulphate, and an electrogenic Na+ pump, demonstrated using strophanthidin. Little or no change in potential was observed upon addition of ADP, collagen, U44069 or thrombin. Neither strong depolarisation with high K+ or gramicidin nor hyperpolarisation with valinomycin induced platelet aggregation or altered platelet responses to agonists. It is concluded that the information transduction mechanisms involved in platelet activation do not include changes in platelet membrane potential.

Benzothiazoles↗
PubMed2001

Leptin does not play a major role in platelet aggregation in obesity and leptin deficiency.

OBJECTIVE: A recent study suggested that high concentrations of leptin enhance platelet aggregations. Therefore, the aim of this study was to investigate whether platelet aggregation is altered in patients with leptin gene mutations compared with obese subjects or controls. RESEARCH METHODS AND PROCEDURES: Four men (one homozygous man and his three heterozygous brothers) carrying a leptin gene mutation; 20 age-matched, healthy, unrelated men; and 18 age-matched obese men were enrolled in the study. Adenosine diphosphate (ADP)-, collagen-, and epinephrine-induced platelet aggregation were evaluated in all individuals. RESULTS: Our results show that patients with the leptin gene mutation (both the homozygous and heterozygous patients) had significantly higher ADP-induced (78.3 +/- 3.4% vs. 57.9 +/- 9.3%, p = 0.001), collagen-induced (78.1 +/- 2.9% vs. 56.7 +/- 9.3%, p = 0.007), and epinephrine-induced (76.5 +/- 9.2% vs. 59.5 +/- 7.70%, p = 0.003) platelet aggregation compared with controls. However, ADP-, collagen-, or epinephrine-induced platelet aggregations were similar to those in obese patients. Platelet aggregation responses to a combination of pretreatment with leptin at concentrations of 20, 50, 100, or 500 ng/mL for 5 minutes and ADP at concentrations of 2 micromol/liter also were evaluated. However, we did not find significant increases in platelet aggregation even at high concentrations of leptin (100 or 500 ng/mL) in leptin-deficient patients, obese subjects, or controls. DISCUSSION: Our data show that similar to findings in obese humans, homozygous or heterozygous leptin deficiency is associated with increased platelet aggregation compared with controls, and that higher concentrations of leptin do not increase platelet aggregation.

Adenosine Diphosphate↗
PubMed1997

L-arginine infusion decreases platelet aggregation through an intraplatelet nitric oxide release.

Nitric Oxide (NO) inhibits platelet aggregation via activation of an intraplatelet soluble guanylate cyclase which induces an increase in cyclic GMP (1). It has been also demonstrated that platelets contain a constitutive, calcium-dependent, NO synthase which is activated by collagen-induced platelet aggregation. This leads to a NO synthesis from L-Arginine (L-Arg), which in turn increases cyclic GMP and down-regulates platelet aggregation (2). In vitro administration of supraphysiological concentrations of L-Arg enhances platelet cyclic GMP levels by increasing NO production and reduces platelet aggregation. This effect is reversed by pre-incubation with NO-synthase inhibitors (3). These results indicate that the L-Arg: NO pathway plays an important role in the modulation of human platelet aggregation (4). In vivo L-Arg, when administered i.v., induces hypotension (5) and vasodilatation (6,7) in humans, and when orally supplemented reduces platelet aggregability both in hypercholesterolemic rabbits and healthy men (8,9).

Adenosine Diphosphate↗