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PubMed1976

Labile aggregation stimulating substance, free fatty acids, and platelet aggregation.

Labile aggregation stimulating substance (LASS), an intermediate produced during platelet biosynthesis of PGE2 and PGF2alpha, acts as a physiologic intercellular messenger to promote platelet aggregation and the release reaction. The activity is formed by intact cells after physiologic stimulation or can be generated from platelet membrane fractions after combination with arachidonate. In the present investigation, small amounts of polyunsaturated fatty acids added to an incubation mixture of platelet microsomes and arachidonate were found to significantly inhibit subsequent platelet aggregation. Saturated and mono-unsaturated fatty acids in the same concentrations were without effect. However, in higher concentrations mono-unsaturated fatty acids were found to be inhibitory and stearic acid was found to enhance subsequent platelet aggregation. The inhibition caused by the polyunsaturated fatty acid, linoleate, was shown to be the result of an effect on the production of LASS through an interaction with the platelet enzyme responsible for conversion of arachidonate to LASS. In contrast, stearic acid was found to enhance platelet aggregation by acting on the platelets and not directly on LASS production. The results suggest that small changes in the fatty acid composition of platelet phospholipids could significantly influence platelet reactivity.

Arachidonic Acids↗
PubMed1984

Platelet aggregation in poiseuille flow: I. A double infusion technique.

This paper describes the design of a double infusion microtube and its use to directly observe the aggregation of platelets undergoing Poiseuille flow immediately after the introduction of 1 microM ADP. Citrated human platelet-rich plasma flowed between two reservoirs through a 100-microns-diameter flow tube at the entrance of which ADP was simultaneously infused through the tip of a concentrically located micropipet . With the aid of microcinematography, the time course of platelet aggregation was followed by measuring the number distribution of single cells and aggregates across the median plane of the tube at various distances downstream of the micropipet . Preliminary studies covering a range of mean tube shear rates from 2 to 30 sec-1 showed that, for a given donor, the fraction of platelets in aggregates, both in control runs (infusion of Tyrodes ) and in experimental runs (infusion of ADP) was reproducible to within +/- 1%. Except at the lowest shear rate, the extent of aggregation increased with increasing distance down the tube.

Adenosine Diphosphate↗
PubMed2006

Expression of functional recombinant mosquito salivary apyrase: a potential therapeutic platelet aggregation inhibitor.

Excessive platelet activation and accumulation can lead to vessel occlusion and thus present major therapeutic challenges in cardiovascular medicine. Apyrase, an ecto-enzyme with ADPase and ATPase activities, rapidly metabolizes ADP and ATP released from platelets and endothelial cells, thereby reducing platelet activation and recruitment. In the present study, we expressed a 68-kDa recombinant mosquito (Aedes aegypti) salivary apyrase using a baculovirus/insect cell expression system and purified it to homogeneity using anion-exchange chromatography on a large scale. A yield of 18 mg of purified recombinant apyrase was obtained from 1 litre of the medium. Kinetic analysis indicated that the recombinant apyrase had a K(m) of 12.5 microM for ADP and a K(m) of 15.0 microM for ATP. The recombinant apyrase inhibited ADP-, collagen- and thrombin-induced human platelet aggregation in a dose-dependent manner, indicating that the recombinant protein retained nucleotidase activity in a whole cell system, which suggests that it may serve as a therapeutic agent for inhibition of platelet-mediated thrombosis.

Aedes↗
PubMed1998

Rhodocytin, a functional novel platelet agonist belonging to the heterodimeric C-type lectin family, induces platelet aggregation independently of glycoprotein Ib.

We isolated and characterized a functionally novel platelet agonist, designated as rhodocytin, from the Calloselasma rhodostoma venom. Rhodocytin was a disulfide-linked heterodimer consisting of 18- and 15-kDa subunits. The respective N-terminal amino acid sequences of both subunits were homologous to each other and to those of the carbohydrate-recognition domains (CRD) of C-type lectins. Rhodocytin alone induced platelet aggregation. Platelet agonists and antagonists constructed with CRD-like subunits from snake venoms bind to glycoprotein Ib directly or indirectly. However, rhodocytin induced platelet aggregation not by binding to glycoprotein Ib, because rhodocytin-induced platelet aggregation was not influenced by echicetin, a glycoprotein Ib-binding protein, that completely inhibits platelet agglutination by bovine von Willebrand factor. These findings indicate that rhodocytin is a novel protein structurally related to heterodimers of CRD-like subunits, but functionally distinct from venom proteins that induce platelet aggregation via glycoprotein Ib.

Amino Acid Sequence↗
PubMed1981

Properties of human asialo-factor VIII. A ristocetin-independent platelet-aggregating agent.

Human Factor VIII desialylated by treatment with Vibrio cholerae neuraminidase (ASVIII) aggregated human platelets in the absence of ristocetin in platelet-rich plasma and, to a lesser extent, in washed platelet suspensions. Aggregation is accompanied by thromboxane formation and is completely inhibited by EDTA. Aspirin blocks the second phase of aggregation and abolishes thromboxane production. Subaggregating doses of ASVIII and of either ADP, epinephrine, or collagen produce prompt and complete platelet aggregation. Bernard-Soulier syndrome platelets either did not aggregate with ASVIII (Two cases) or showed markedly decreased aggregation (one cases). Factor VIII complex was prepared from the plasma of two patients with variant von Willebrand's disease (sialic acid content 142 and 75 nmol/mg, respectively); neither protein generated platelet-aggregating activity upon desialylation. [3H]ASVIII binds rapidly to platelets and 37 degrees C, while tritiated, fully sialylated factor VIII binds to a negligible extent. As little as 1--2 micrograms ASVIII bound/10(9) platelets is capable of inducing platelet aggregation. ASVIII may be a useful tool for investigating platelet-Factor VIII interactions in the absence of ristocetin. Furthermore, desialylated Factor VIII might play a physiologic role in Factor VIII-mediated platelet reactions in vivo.

Asialoglycoproteins↗
PubMed2000

Porphyromonas gingivalis platelet aggregation activity: outer membrane vesicles are potent activators of murine platelets.

Recent evidence has established an association between chronic periodontitis and cardiovascular disease. Periodontitis is a chronic inflammatory disease caused by a small group of gram-negative bacteria, of which Porphyromonas gingivalis is considered an important causative agent. It has been proposed that dental plaque bacteria and their products can disseminate into the bloodstream from the site of infection and promote thromboembolic events associated with atherosclerosis and myocardial infarction. In this regard, Streptococcus sanguis and P. gingivalis have been shown to induce platelet aggregation in vitro. Here we report that P. gingivalis was able to induce platelet aggregation, and that oral strains of Actinobaillus actinomycetemcomitans, Bacteroides forsythus, Campylobacter rectus, Fusobacterium nucleatum, Prevotella intermedia and Trepenoma denticola failed to aggregate platelets when tested for platelet aggregation activity under similar conditions. Additionally, we show that vesicles (outer membrane evaginations that are shed into the environment by the bacteria) of P. gingivalis are potent inducers of mouse platelet aggregation in vitro. In summary, our data show that i) initial adherence of the bacterium to platelet may be facilitated by P. gingivalis fimbriae and ii) P. gingivalis vesicles possess platelet aggregation-inducing activity.

Animals↗
PubMed1971

A laboratory study of spontaneous platelet aggregation.

During studies on platelet aggregation using the EEL platelet aggregation meter, 8% of the individuals tested were found to have platelets which aggregated spontaneously when citrated, platelet-rich plasma was stirred at 37 degrees C. The EEL aggregation meter differs from other machines in that it incorporates a vertical stirrer which subjects platelets to greater mechanical force. When using this machine it is suggested that spontaneous platelet aggregation is related to increased mechanical fragility of the platelets and low levels of plasma ADP-inhibitor.

Adenine Nucleotides↗
PubMed1994

Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay.

BACKGROUND: As clinical diagnosis of heparin-associated thrombocytopenia (HAT) is often difficult, confirmation by sensitive laboratory assays is desirable. STUDY DESIGN AND METHODS: The sensitivity of the heparin-induced platelet activation (HIPA) test and the platelet aggregation test (PAT) was prospectively compared by using the sera of 209 patients with the putative diagnosis of HAT. Both assays were performed concomitantly with platelets of the same four donors using a different combination of donors from day to day. Further, all sera were assessed with a platelet factor 4 (PF4)/heparin enzyme-linked immunosorbent assay (ELISA). RESULTS: Positive results were obtained with 33 percent of sera in the PF4/heparin ELISA, with 33.5 percent of sera in the HIPA test, and with 11.5 percent of sera in the PAT. The PF4/heparin ELISA and the HIPA test showed no difference in sensitivity (p = 0.27 by McNemar's test) and were more sensitive than PAT (p < 10(-8) by McNemar's test). However, they recognized different patient cohorts. Nine HIPA-indeterminate and 12 HIPA-negative sera were positive in the PF4/heparin ELISA. Eight of the nine indeterminate sera caused platelet activation with high heparin concentrations in the HIPA test. Eleven of the 12 negative sera contained no IgG, but 9 contained IgM and 2 contained IgA HAT antibodies. Four sera that were indeterminate in the PF4/heparin ELISA and 18 sera that were negative were positive in the HIPA test. None of the sera that were positive in the PAT was missed in the HIPA test, but two of those were negative in the PF4/heparin ELISA. All sera were assessed with four low-molecular-weight heparins and a low-molecular-weight heparinoid in the HIPA test with platelets from the same four donors. Low-molecular-weight heparin caused platelet activation with positive sera in 98 percent of tests, and the heparinoid did so in 10 percent; in a further 12.8 percent, crossreactivity to the low-molecular-weight heparinoid could not be excluded. CONCLUSION: The majority of HAT antibodies react with a PF4/heparin complex, but there is strong evidence that other antigens are involved in some patients. The HIPA test and the PF4/heparin ELISA are sensitive for diagnosing HAT, and they complement one another.

Enzyme-Linked Immunosorbent Assay↗
PubMed1988

High affinity specific binding sites for tritiated platelet-activating factor in canine platelet membranes: counterparts of platelet-activating factor receptors mediating platelet aggregation.

In canine platelet membranes, tritiated platelet activating factor (PAF) labels in a saturable and reversible manner a single population (nH = 0.97) of binding sites. The affinity of this binding was high (Kd = 0.23 +/- 0.02 nM, n = 4, and 0.21 +/- 0.05, n = 8, determined by kinetics or saturation experiments, respectively), and the density of binding sites (Bmax) was 911 +/- 31 fmol/mg of protein (n = 8). [3H]PAF binding was entirely reversed by unlabeled PAF (10 microM). [3H]PAF exhibited stereoselective discrimination inasmuch as it was poorly displaced by enantio-PAF, the PAF enantiomer that does not occur naturally. Furthermore, the displacing potency of the (+)-enantiomer of the PAF antagonist 52770 RP against [3H]PAF was 45 times higher than that of the (-)-enantiomer. [3H]PAF binding displayed a remarkable specificity in that it was not affected by a variety of classical pharmacological agents. However, this binding was displaced by several PAF receptor antagonists such as 59227 RP, CV-6209, Ro 19-3704, 52770 RP, brotizolam, WEB 2086, SRI 63-441, L-652,731, alprazolam, triazolam, and BN 52021. The Ki of the 16 studied antagonists ranged from 7.9 nM (59227 RP, most potent) to 16.8 microM (BN 52021, least potent). The possible biological significance of our binding procedure was assessed by correlating the potencies of 16 PAF antagonists as [3H]PAF displacers in dog platelet membranes and as inhibitors of PAF-induced platelet aggregation in washed canine platelets. This analysis revealed the existence of a highly significant correlation (r = 0.82, p less than 0.001) between biochemical and functional tests. However, two compounds (Ro 19-3704 and BN 52021) were found to be located outside the confidence limits when the probability level of belonging to the regression line was set at 0.01. In conclusion, this study provides evidence that [3H]PAF binding in canine platelet membranes exhibits the required properties for a valid binding procedure. Furthermore, the labeled sites are likely to be the counterparts of platelet receptors that, when activated by PAF, induce aggregation.

Animals↗
PubMed2003

Increased platelet aggregation and production of platelet-derived microparticles after surgery for upper gastrointestinal malignancy.

BACKGROUND: Since platelet function is known to play a major role in arterial thrombosis, we investigated postsurgery alterations in platelet function that might predispose patients with upper gastrointestinal malignancy to postoperative thrombotic complications. SUBJECTS AND METHODS: Shear-induced platelet aggregation (SIPA) in platelet-rich plasma was measured in 23 patients who elected to undergo abdominal surgery. Measurement was done by cone-plate viscometer under low shear stress (12 dyn/cm(2)), a physiological condition, and under high shear stress (108 dyn/cm(2)), a pathological condition that simulates in vivo conditions such as those in stenotic arteries. Platelet microparticle (PMP) formation was analyzed by flow cytometry. Plasma von Willebrand factor (vWF) was also measured. RESULTS: SIPA under high shear stress was significantly enhanced from 44.0 +/- 13.4% preoperatively to 69.5 +/- 15.8% on postoperative day (POD) 1, and it returned to preoperative levels on POD 14. PMP formation under high shear stress was enhanced before surgery (140.8 +/- 38.7%) compared to that under a static condition, and the enhancement was further augmented on POD 1 (219.1 +/- 49.3%). The enhancement of SIPA and PMP formation had no association with disease stage. vWF levels increased significantly on POD 1. Exogenous vWF augmented SIPA and PMP formation under high shear stress, and this augmentation was inhibited by anti-vWF antibody. CONCLUSIONS: Because PMPs are highly procoagulant, increased SIPA and PMP formation induced by surgical intervention possibly contribute to thrombotic complications. Blockage of platelet interaction with vWF may prevent arterial thrombus formation perioperatively.

Adrenergic alpha-Antagonists↗
PubMed1999

Triflavin potentiates the antiplatelet activity of platelet activating factor receptor antagonist on activated neutrophil-induced platelet aggregation.

In this study, specific platelet activating factor (PAF) receptor antagonist ginkgolide B (BN52021) was tested for its antiplatelet activity in zymosan activated polymorphonuclear neutrophil-induced platelet aggregation. Triflavin was also tested for its antiplatelet activity compared with PAF receptor antagonist. Triflavin, an Arg-Gly-Asp-containing disintegrin purified from venom peptide inhibited platelet aggregation by interfering with the interaction of fibrinogen with the glycoprotein IIb/IIIa complex. Furthermore, we also report an efficient high resolution method for quantitative analysis of PAF using high-performance capillary electrophoresis (HPCE). The supernatant of polymorphonuclear neutrophils after their activation by opsonized zymosan induces the aggregation of washed rabbit platelets. In rabbit platelets, BN52021 (100-1000 microM) only partially inhibited activated polymorphonuclear neutrophil-induced platelet aggregation, and its maximal inhibition was estimated to be about 79%. Triflavin also partially inhibited platelet aggregation about 82% induced by activated polymorphonuclear neutrophils. Furthermore, after treatment with a combination of triflavin (0.26 microM) with various concentrations of BN52021 (4-1000 microM), the inhibitory effect of platelet aggregation was almost completely. This inhibition was greater than that produced by the individual drugs alone. These results indicate that a combination of glycoprotein IIb/IIIa complex and PAF receptor antagonist could completely inhibit activated polymorphonuclear neutrophil-induced platelet aggregation. In addition, the amount of PAF released from zymosan (6 mg/ml)-activated polymorphonuclear neutrophils was accurately calculated about 11.8+/-1.5 ng/10(6) cells, and did not further increase even at a high concentration of zymosan (10 mg/ml). These results suggest that PAF play a major role in the interaction between platelets and polymorphonuclear neutrophils. This interaction may be important in the pathogenesis of thrombosis and inflammatory diseases. Our present findings support the hypothesis that combination therapy with glycoprotein IIb/IIIa complex antagonists and PAF receptor antagonists may represent a new approach to the treatment of ischemic disorders.

Animals↗
PubMed1996

Losartan does not influence the blood platelet aggregation in normotensive rats.

Platelet aggregation was studied in PRP upon stimulation with ADP and collagen in normotensive rats treated with losartan (10 mg/kg). The acute and subchronic (5 days) losartan administration did not change the aggregating response of rat platelets. Similarly, in vitro study aggregation of platelets remained unaltered following incubation with losartan and its active metabolite EXP3174. In this study we presented the lack of influence of losartan and its main metabolite on rat platelet aggregation in normotensive rats.

Adenosine Diphosphate↗
PubMed2005

Transregulation of the alpha2-adrenergic signal transduction pathway by chronic beta-blockade: a novel mechanism for decreased platelet aggregation in patients.

Platelets play a pivotal role in the pathophysiology of acute coronary syndromes. Chronic beta-blockade has been shown to improve the long-term clinical outcome in coronary heart disease. Because platelets play a central role in thrombus formation, the aim of the present study was to investigate if chronic beta-blockade may transregulate the expression of alpha2-adrenergic receptors on human platelets and via this mechanism may modulate platelet activation. The densities of alpha2-adrenergic receptors of platelets were determined in healthy volunteers under chronic beta-blockade and as alpha2-adrenergic receptor-mediated function in catecholamine-induced platelet aggregation was determined. Chronic beta-blockade induced a time-dependent reduction of alpha2-adrenergic receptors. This reduction was accompanied by a decrease of the alpha-subunit of Gi proteins as demonstrated by Western blot analysis. This transregulation at both the receptor level and the G-protein level resulted in an almost complete loss of the alpha2-adrenergic receptor-mediated inhibition of adenylyl cyclase. The impairment of the alpha2-adrenergic receptor system correlated with a reduction of the catecholamine-induced activation and aggregation of human platelets. The functional transregulation of alpha2-adrenergic receptors by chronic beta-blockade in platelets and the consequent impairment of platelet activation may contribute to the therapeutic success of beta-blocker therapy.

Adenylyl Cyclases↗
PubMed1984

[Platelet aggregation and coenzyme Q10 content in platelets in cancer patients].

Platelet aggregation, plasma beta-thromboglobulin (beta-TG) concentration and coenzyme Q10 content in serum and platelets were measured in 45 patients with unresectable carcinoma of the lung and in 7 patients with metastatic pulmonary tumor before and after receiving chemotherapy. A significant increase in the plasma beta-TG concentration in cancer patients (47.4 +/- 18.7 ng/ml) was observed (p less than 0.001) compared to the controls (30.3 +/- 9.2 ng/ml). Serum coenzyme Q10 content was lower in cancer patients (0.42 +/- 0.19 micrograms/ml) (p less than 0.05) compared to the controls (0.57 +/- 0.24 micrograms/ml). The reason of decrease in serum coenzyme Q10 content in cancer patients was difficult to explain. No significant difference of the coenzyme Q10 content in platelets (1 X 10(8) cells) was observed either cancer patients (12.5 +/- 2.8 ng) or the controls (12.6 +/- 2.1 ng). No significant correlation was noted among platelet aggregation, plasma beta-TG concentration and coenzyme Q10 content in serum and platelets. Administration of either vindesine or KW2083 did not influence the coenzyme Q10 content in platelets. These results suggest that ATP synthetic pathway by oxidative phosphorylation in platelet be maintained in cancer patients, although a significant increase of plasma beta-TG concentration appears to be associated with an acceleration in the metabolic turnover of platelet.

Adult↗
PubMed1988

The effect of exercise on platelet beta-adrenoceptor function and platelet aggregation in healthy human volunteers.

UNLABELLED: Plasma levels of adrenaline and noradrenaline, platelet cyclic-AMP (cAMP) content, platelet aggregation, platelet release of beta-thromboglobulin, and platelet factor 4 and serum content of thromboxane B2(TXB2) and 6-keto-PGF1 alpha were measured in 12 healthy male volunteers (age 38-72, mean 54.2 years) who were tested at rest and immediately after five min light cycle exercise. The plasma levels of adrenaline and noradrenaline increased significantly after exercise (P less than 0.01). The platelet cAMP level was not changed by exercise. The functional capacity of platelet beta-adrenoceptors, determined as cAMP production after beta-adrenoceptor stimulation in vitro, decreased highly significantly after exercise in all 12 volunteers (P less than 0.01). No alteration was observed in platelet aggregation induced by adrenaline or in platelet release of beta-thromboglobulin or platelet factor 4. No change was observed in the serum levels of TXB2 and 6-keto-PGF1 alpha. IN CONCLUSION: light cycle exercise results in a decreased functional capacity of platelet beta-adrenoceptors, but has no effect on platelet aggregation or platelet release. This might indicate a concomitant and equal decreased functional capacity of platelet alpha-adrenoceptors.

Adult↗
PubMed2005

Polyamines inhibit both platelet aggregation and glycoprotein IIb/IIIa activation.

Platelet aggregation is inhibited by the polyamines putrescine, spermidine, and spermine. To date, the mechanism of action has not been clearly identified. Evidence suggests that polyamines may interact with the fibrinogen receptor (GP IIb/IIIa), interfering with platelet-platelet attachment. The effect of polyamines on human platelet aggregation and GP IIb/IIIa activation was evaluated. For the aggregation experiments, platelets were obtained from heparin- or citrate-collected blood. Our results indicate that the polyamines putrescine, spermidine, and spermine cause a dose-dependent inhibition of ADP- or collagen-mediated platelet aggregation with an order of potency spermine>spermidine>putrescine. In addition, spermine arrests or inhibits thrombin-, epinephrine-, arachidonate-, or ristocetin-induced platelet aggregation. Expression of platelet membrane glycoproteins IIb, IIIa, and IX is not reduced by polyamines. However, spermine inhibits the ADP- or thrombin-induced activation of GP IIb/IIIa. It is concluded that the final step in aggregation, common to all agonists, ie, fibrinogen binding to GP IIb/IIIa, is inhibited by spermine through inhibition of the agonist-induced activation of GP IIb/IIIa that precedes fibrinogen-ligand binding.

Biogenic Polyamines↗