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PubMed1999

In vitro adhesion and platelet aggregation properties of bacteremia-associated lactobacilli.

Eight bacteremia-associated Lactobacillus strains were evaluated in vitro for the ability to adhere to human intestinal mucosa and to aggregate platelets. Adherence varied significantly among the strains, and platelet aggregation was induced by three strains. In conclusion, strong binding ability does not appear to be a prerequisite for the involvement of lactobacilli in bacteremia or to their ability to aggregate platelets.

Bacteremia↗
PubMed1978

Platelet monoamine oxidase and epinephrine-induced platelet aggregation.

Platelet MAO activity and the aggregation response to epinephrine, ADP, and collagen were measured in normal subjects. There was a direct correlation between the amount of platelet MAO activity and the per cent aggregation induced by 1 and 2 micrometer epinephrine. There were lesser correlations between platelet MAO and ADP or collagen-induced aggregation. These findings suggest that platelet MAO may play a role in determining the response of human platelets to epinephrine.

Adenosine Diphosphate↗
PubMed1982

The effect of polyunsaturated fatty acids on the n-3 and n-6 series on platelet aggregation and platelet and aortic fatty acid composition in rabbits.

Four groups of 6 New Zealand white rabbits were fed for 60 days on a commercial rabbit diet supplemented (60 g/kg) with 1 of 4 sources of fat: corn oil, linseed oil and fish oil, which respectively provided rich sources of linoleic acid (C18:2, n-6), alpha-linolenic acid (C18:3, n-3) and eicosapentaenoic acid (C20:5, n-3), and coconut oil, low in all polyunsaturated fatty acids (PUFA). Platelet-rich plasma was prepared and aggregation induced by ADP (final concentration 0.29-74.3 microM), collagen (2.5-20 micrograms/400 microliters, final concentration) and 2.5 U bovine thrombin, and recorded with a Peyton aggregometer. Platelet aggregation induced by both thrombin and collagen was significantly lower with either n-3 PUFA (fish or linseed oil) than with corn oil (n-6 PUFA) or the low PUFA coconut oil. ADP-induced platelet aggregation was significantly reduced only in animals fed fish-oil. Changes in platelet aggregation were accompanied by increased platelet lipid content of C20:5, n-3 and decreased content of C20:4, n-6, with little change in platelet total C20 fatty acids. Platelet levels of C20:5, n-3 were significantly increased with both the preformed C20:5, n-3 and its precursor C18:3, n-3 in the diet. However, aortic lipid accumulation of C20:5 only occurred with rabbits fed on fish oil. It was concluded that, for collagen and thrombin induced aggregation, C18:3, n-3 and C20:5, n-3 were equally antiaggregatory in rabbits. The implications of this in community nutrition programmes are discussed.

Adipose Tissue↗
PubMed1995

Shear-induced platelet aggregation is inhibited by in vivo infusion of an anti-glycoprotein IIb/IIIa antibody fragment, c7E3 Fab, in patients undergoing coronary angioplasty.

BACKGROUND: Elevated levels of shear stress such as those that occur in stenotic arterial vessels can directly activate and aggregate platelets and thus contribute to the pathogenesis of acute arterial thrombosis. This shear-induced platelet aggregation (SIPA) is mediated by von Willebrand factor binding to platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa. The chimeric Fab fragment of the monoclonal antibody 7E3 (c7E3 Fab) that binds selectively to GPIIb/IIIa is under clinical evaluation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA. METHODS AND RESULTS: Six patients received aspirin (325 mg) and boluses of heparin (12,00o U) followed by c7E3 Fab 0.25 mg/kg. Blood collected from each patient before and after heparin treatment and at various time points after c7E3 Fab administration was subjected to laminar shear stress in a cone-and-plate viscometer. Flow cytometry was used to quantify the extents of platelet aggregation and of antibody binding to GPIIb/IIIa. Results indicate that c7E3 Fab injection resulted in a rapid, extensive blockade of GPIIb/IIIa receptors (98.6 +/- 0.2%) and a 50% inhibition of ex vivo platelet aggregation induced by shear stress. c7E3 Fab also completely abolished the formation of large platelet aggregates ("large" refers to particles > 10 microns in equivalent sphere diameter), which are presumably the aggregates of greatest clinical significance. Partial reversibility of the inhibition was noted within 2 days after drug administration, but even after 1 week, platelet function had not been fully restored. CONCLUSIONS: This study demonstrates that c7E3 Fab is a potent inhibitor of SIPA, which may be an important mechanism of its beneficial effect in the treatment of arterial occlusive diseases and in the prevention of thrombotic complications of coronary artery disease after angioplasty.

Abciximab↗
PubMed1983

Comparative effects of phenylbutazone, naproxen and flunixin meglumine on equine platelet aggregation and platelet factor 3 availability in vitro.

Nonsteroidal anti-inflammatory drugs are commonly used in the treatment of inflammatory conditions, and have potential value in the treatment of thrombotic disease in the horse. This study compares the potency of three nonsteroidal anti-inflammatory drugs phenylbutazone, naproxen (equiproxen) and flunixin meglumine (banamine) with respect to their effects on equine platelets. Two functional responses of horse platelets were evaluated in vitro: their ability to aggregate and their ability to make available platelet factor 3 procoagulant activity. Flunixin at a concentration of 10(-6) M significantly depressed the maximum degree of adenosine diphosphate-induced (10(-6)M) aggregation while much higher concentrations of phenylbutazone and naproxen (5 X 10(5)M) were required to produce similar effects. None of the non-steriodal anti-inflammatory drugs significantly affected the duration of the lag phase or the initial velocity of adenosine diphosphate-induced aggregation within the range of drug concentrations used (10(-6)-10(-3)M). The lag phase and initial velocity of acid-soluble collagen-induced aggregation were significantly affected by 10(-6) M flunixin and 10(-4) M phenylbutazone or naproxen was required to produce equivalent effects. Concentrations of 5 X 10(-6) M flunixin and 5 X 10(-4) M phenylbutazone or naproxen were required to significantly depress the degree of collaen-induced aggregation of horse platelets. Although the effects of the nonsteroidal anti-inflammatory drugs were qualitatively similar, flunixin was a much more potent inhibitor of platelet aggregation than either of the other two drugs (which were equipotent). At very high drug concentrations (5 X 10(-4) M and greater), all three drugs produced the same degree of inhibition of equine platelet aggregation. Platelet factor 3 activity was made available by exposing horse platelets to 10(-5) M adenosine diphosphate or 1:800 acid-soluble collagen; but not by exposure to a suspension of kaolin particles. Only a small portion of the total platelet factor 3 activity was made available on stimulation with either adenosine diphosphate or collagen. Pretreatment of horse platelets with any of the nonsteroidal anti-inflammatory drugs (10(-4) M concentration) had no significant effect on adenosine diphosphate or collagen-induced platelet factor 3 availability.

Adenosine Diphosphate↗
PubMed1989

Thrombin-induced platelet aggregation involves an indirect proteolytic cleavage of aggregin by calpain.

5'-p-Fluorosulfonylbenzoyl adenosine (FSBA), a nucleotide analog of ADP, has been shown to inhibit ADP-induced shape change, aggregation and exposure of fibrinogen binding sites concomitant with covalent modification of a single surface membrane polypeptide of Mr 100,000 (aggregin). Since thrombin can aggregate platelets which have been modified by FSBA and are refractory to ADP, we tested the hypothesis that thrombin-induced platelet aggregation might involve cleavage of aggregin. At a low concentration of thrombin (0.05 U/ml), platelet aggregation, exposure of fibrinogen receptors and cleavage of aggregin in FSBA-modified platelets did not occur, indicating ADP dependence. In contrast, incubation of [3H]FSBA-labeled intact platelets with a higher concentration of thrombin (0.2 U/ml) resulted in cleavage of radiolabeled aggregin, aggregation, and exposure of fibrinogen binding sites. Under identical conditions, aggregin in membranes isolated from [3H]FSBA-labeled platelets was not cleaved by thrombin. Thrombin-induced platelet aggregation and cleavage of aggregin were concomitantly inhibited by a mixture of 2-deoxy-D-glucose, D-gluconic acid 1,5-lactone, and antimycin A. These results suggest that thrombin cleaves aggregin indirectly by activating an endogeneous protease. Thrombin is known to elevate intracellular Ca2+ concentration and thereby activates intracellular calcium dependent thiol proteases (calpains). In contrast to serine protease inhibitors, calpain inhibitors including leupeptin, antipain, and ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid (chelator of Ca2+) inhibited platelet aggregation and cleavage of aggregin in [3H]FSBA-labeled platelets. Leupeptin, at a concentration of 10-20 microM, used in these experiments, did not inhibit the amidolytic activity of thrombin, thrombin-induced platelet shape change, or the rise in intracellular Ca2+. Purified platelet calpain II caused aggregation of unmodified and FSBA-modified platelets and cleaved aggregin in [3H]FSBA-labeled platelets as well as in isolated membranes. The latter is in marked contrast to the action of thrombin on [3H]FSBA-labeled membranes. Thus, thrombin-induced platelet aggregation may involve intracellular activation of calpain which proteolytically cleaves aggregin thus unmasking latent fibrinogen receptors, a necessary prerequisite for platelet aggregation.

Adenosine↗
PubMed1990

Endothelium-dependent vasorelaxations in response to aggregating platelets are impaired in reversed vein grafts.

The endothelium releases factor(s) that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses to aggregating platelets are altered in vein grafts. Segments of jugular veins were grafted in the reverse position into the carotid arteries in 16 rabbits. After 4 weeks the patent grafts (14 of 16) were removed, and the endothelium-dependent responses were examined in vitro. In control veins aggregating platelets, adenosine diphosphate, and serotonin caused endothelium-dependent relaxations. The platelet-induced relaxations were attenuated by apyrase (adenosine diphosphatase and adenosine triphosphatase) but not by methiothepin (serotonergic blocker). In vein grafts, endothelium-dependent relaxations in response to aggregating platelets were absent, and only contractions that could be attenuated by methiothepin were observed. In vein grafts, endothelium-dependent relaxations in response to adenosine diphosphate were reduced, and only endothelium-independent contractions were observed in response to serotonin. These contractions were attenuated by methiothepin. These results suggest that (1) the endothelium exerts an inhibitory effects mediated mainly by adenosine diphosphate in response to aggregating platelets in rabbit jugular veins and (2) endothelium-dependent relaxations in response to aggregating platelets are impaired in vein grafts because of reduced endothelium-independent contractions in response to serotonin. This impairment of endothelium-dependent responses in vein grafts may contribute to failure of the grafts.

Adenosine Diphosphate↗
PubMed1982

Anisodamine inhibits thromboxane synthesis, granulocyte aggregation, and platelet aggregation. A possible mechanism for its efficacy in bacteremic shock.

Anisodamine hydrochloride is a vasoactive drug produced in the People's Republic of China that appears efficacious in clinical and experimental bacteremic shock, and about whose mode of action little is known. Suspecting that the drug might work by inhibition of platelet or granulocyte aggregation, or both, we tested it in these systems. Anisodamine proved a modest inhibitor of granulocyte aggregation and a powerful inhibitor of platelet aggregation; thromboxane synthesis was inhibited in anisodamine-treated platelets, further suggesting that the biochemical mode of action might be inhibition of cyclo-oxygenase or thromboxane synthetase.

Animals↗
PubMed1979

Release of platelet fibronectin (cold-insoluble globulin) from alpha granules induced by thrombin or collagen; lack of requirement for plasma fibronectin in ADP-induced platelet aggregation.

Platelets lysed with Triton X-100 contain 3.44 +/- 1.27 (SD) microgram of fibronectin (cold-insoluble globulin) per 10(9) platelets. Fibronectin was partially released from washed whole platelets by collagen or thrombin, and its release by collagen was inhibited by aspirin. Analysis of subcellular fractions obtained by density-gradient centrifugation of disrupted platelets indicated that fibronectin was contained in the alpha granules. Fibrinogen depleted of fibronectin (less than 2 microgram/mg) supported ADP-induced aggregation as effectively as fibrinogen contaminated with this protein, thus reinforcing the generally held view that fibrinogen itself is the necessary protein cofactor in this reaction.

Adenosine Diphosphate↗
PubMed2004

Von Willebrand factor present in fibrillar collagen enhances platelet adhesion to collagen and collagen-induced platelet aggregation.

We examined the basis of the differences observed between different collagen preparations in their ability to aggregate platelets and support their adhesion under flow. As in previous studies, we found fibrillar collagen to be 10-fold more potent than acid-soluble collagen in inducing platelet aggregation and found that acid-soluble collagen did not support the adhesion of washed platelets under flow. Further, platelets in whole blood adhered to surfaces coated with either fibrillar or acid-soluble collagen, but thrombi formed faster and grew larger on fibrillar collagen. As a possible basis for this difference, we found that fibrillar collagen, but not acid-soluble collagen, contains a substantial quantity of von Willebrand factor (VWF), as demonstrated by enzyme-linked immunosorbent assay and by the ability of fibrillar collagen to support the adhesion of VWF antibody-coated beads and to agglutinate GPIb-IX-V complex-expressing Chinese hamster ovary cells. Supporting a role for VWF in collagen-induced platelet aggregation, aggregation induced by acid-soluble collagen was greatly enhanced by added VWF. Further, platelet aggregation by fibrillar collagen was partially blocked by a GPIbalpha antibody that inhibits the GPIb-VWF interaction. Taken together, these results suggest that much of the difference in prothrombotic potency of different collagens is directly related to their differences in VWF content. This probably accounts for the different conclusions made regarding the relative importance of different direct and indirect collagen receptors in collagen-dependent platelet functions and further emphasizes the close synergistic roles of the GPIb-IX-V complex and the collagen receptors GPVI and alpha2beta1 in supporting platelet adhesion.

Cells, Cultured↗
PubMed1991

The inhibition of platelet aggregation of metastatic H-ras-transformed 10T1/2 fibroblasts with castanospermine, an N-linked glycoprotein processing inhibitor.

A series of T24-H-ras-transformed 10T1/2 fibroblasts with varying metastatic potential was tested for the ability to aggregate platelets. Results indicate that although platelet activation was always detected in the highly metastatic cells, some non-metastatic cells also have the ability to cause platelet aggregation, suggesting that this is a necessary but not sufficient characteristic of the metastatic phenotype. Apyrase, an ADP scavenger, effectively inhibited platelet aggregation by metastatic cells, however, there was no significant increase in ADP secretion or relation to the ability of the tumor cells to activate platelets. Hirudin, a thrombin inhibitor, did not affect aggregation, suggesting that the pathway of activation is thrombin-independent. The glycoprotein processing inhibitor, castanospermine, which reduces glycosidase I activity and metastatic capability, inhibited the ability of metastatic cells to cause platelet aggregation. However, another inhibitor of oligosaccharide processing, swainsonine, which inhibits mannosidase II activity and does not reduce metastasis, had no effect on platelet aggregation. These results show that the integrity of N-linked oligosaccharide structure of glycoproteins is an important feature of the ability of ras-transformed fibroblasts to activate platelets.

Adenosine Diphosphate↗
PubMed2001

Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide.

A correlation exists between the ability of tumor cells to aggregate platelets and their tendency to metastasize. Tumor cell-induced platelet aggregation (TCIPA) facilitates the embolization of the vasculature with tumor cells and the formation of metastatic foci. It is well documented that matrix metalloproteinases (MMPs) play an integral part in tumor spread and the metastatic cascade. Therefore, we have examined the role of MMPs during TCIPA and its regulation by nitric oxide (NO) in vitro. Human HT-1080 fibrosarcoma and A549 lung epithelial cancer cells induced TCIPA in a concentration-dependent manner that was monitored by aggregometry. This aggregation resulted in the release of MMIP-2 from platelets and cancer cells, as measured by zymography. HT-1080 cells released significantly more MMP-2 than A549 cells and were more efficacious in inducing TCIPA. Inhibition of MMP-2 with phenanthroline (1-1000 microM), a synthetic inhibitor of MMPs, and by neutralizing anti-MMIP-2 antibody (10 microg/ml) reduced TCIPA induced by HT-1080 cells. TCIPA was abolished by simultaneous inhibition of platelet function with acetylsalicylic acid (100 microM; thromboxane pathway inhibitor), apyrase (250 microg/ml; ADP pathway inhibitor), and phenanthroline. NO donors such as S-nitroso-n-acetylpenicillamine and S-nitrosoglutathione (both at 0.01-100 microM) inhibited TCIPA and MMP-2 release from platelets and tumor cells. The inhibitory actions of S-nitroso-n-acetylpenicillamine and S-nitrosoglutathione were reversed by 1H-[1,2,4]oxadiazole[4,3]quinoxalin-1-one (0.01-30 microM), a selective inhibitor of the soluble guanylyl cyclase. We conclude that (a) human fibrosarcoma cells aggregate platelets via mechanism(s) that are mediated, in part, by MMP-2; (b) NO inhibits TCIPA, in part, by attenuating the release of MMP-2; and (c) these effects of NO are cGMP-dependent.

Adenosine Diphosphate↗