Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of plasmin treatment upon washed human platelets were studied in an attempt to elucidate the mechanisms underlying thrombin-induced platelet aggregation. At calcium concentrations of 10-20 muM, PLASMIN (0.2 CTA U/ml) inhibited thrombin-induced aggregation almost completely, but did not diminish the thrombin-induced release of adenine nucleotides, 5-hydroxytryptamine, or calcium. Increasing the calcium concentration partially antagonized plasmin's inhibition of aggregation. Studies utilizing calcium chelators and the Kunitz soybean trypsin inhibitor (SBTI) as a plasmin inhibitor indicated that in order to achieve maximal block of aggregation, plasmin must act upon a substrate made fully available only after an initial thrombin-platelet interaction has taken place. Moreover, the time course of this inhibition parallels the time course of the thrombin-induced release reaction. Plasmin inhibition of aggregation could not be mimicked by exposing the platelets to proteolytic digests of fibrinogen at concentrations as high as 17% total platelet protein. Nor could inhibitory activity be recovered from supernatants of plasmin-treated platelets, upon centrifugation and treatment with SBTI. With the use of a "cold initiation" technique, the release by thrombin of 46.7 plus or minus 6.7 (mean plus or minus SEM) mu-g of fibrinogen immunological equivalents per mg platelet protein could be demonstrated. Platelets in which thrombin-induced aggregation was abolished by plasmin treatment (and the plasmin subsequently inactivated by STBI) aggregated normally upon addition of as little as 10 mu-g human plasma fibrinogen per mg platelet protein. It is concluded that plasmin inhibition of aggregation most likely results from its attack upon a protein that is released or becomes fully available subsequent to interaction of thrombin with a platelet receptor mediating release. The results of this study are consistent with a cofactor role for fibrinogen in the aggregation of human platelets by thrombin.
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PMID:Plasmin inhibition of thrombin-induced platelet aggregation. 12 75

The influence of freshly purified ATP on the effects of aggregating agents on human platelets was studied. ATP inhibited aggregation induced by ADP competitively (Ki = 20 muM) and immediately without need for prior incubation. ATP had no effect on primary aggregation induced by adrenaline, thrombin, vasopressin, or 5-hydroxytryptamine (5HT). ATP inhibited the shape change and the consumption of metabolic ATP induced by ADP but did not inhibit these effects when induced by thrombin, vasopressin, or 5HT. ATP counteracted the inhibition by ADP of PGE1-stimulated cyclic AMP production in platelets but did not reduce inhibition by adrenaline. It is concluded that adrenaline, thrombin, 5HT, and vasopressin each can induce primary aggregation of human platelets by a mechanism independent of extracellular ADP.
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PMID:The effects of ATP on platelets: evidence against the central role of released ADP in primary aggregation. 16 88

Sodium L-ascorbate (ascorbate) and sodium D-ascorbate produced a dose-related rise of guanosine 3':5'-cyclic monophosphate (cGMP) in platelets with a maximum increment averaging 25-fold at 5 mM ascorbate. The ascorbate-induced increment in cGMP reached a peak after 1 min and was maintained for 1 h in the presence of ascorbate. 5-hydroxytryptamine (5-HT) also produced a dose-related rise of cGMP in platelets with a peak effect of approximately 25-fold at 16 micrometer 5-HT. The elevation of cGMP in platelets by both ascorbate and 5-HT did not require extracellular calcium and was blocked by inhibitors of cyclo-oxygenase such as aspirin or indomethacin. A maximum ascorbate-induced rise in platelet cGMP at the time of addition of epinephrine, collage or thrombin did not augment the release of [14C]5-hydroxytryptamine ([14C]5-HT) measured over 30 min. Although ascorbate appeared to increase platelet cGMP by modulation of endoperoxide formation, its failure to aggregate platelets or to influence the release reaction indicates that the ascorbate-stimulated rise in cGMP does not have a simple relationship to thromboxane formation.
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PMID:Elevation of the cyclic GMP concentration in human platelets by sodium ascorbate and 5-hydroxytryptamine. 20 83

The role of platelets in clot lysis has been investigated functionally with the use of dPRP clots formed at 4 degrees and shifted to 37 degrees. Clots handled in this manner lysed in 6 hr (+/- 1 hr), whereas clots formed at 4 degrees or at 37 degrees and held at those temperatures, or clots formed from dPPP did not lyse in less than 20 hr. dPRP clots having the shorter (6 hr) lysis time released 14C-5-HT at the time of the temperature shift. Preincubation of dPRP with antimycin A and 2-deoxy-D-glucose before addition of thrombin prolonged the clot lysis to 26 hr and inhibited release of 14C-5-HT at the time of the temperature shift. These studies demonstrate that metabolically active platelets are required to mediate the optimal clot lysis seen in the 4 degrees to 37 degrees system and that they continue to function (i.e., take up and release 5-hydroxytryptamine) after they have been incorporated into a clot. Thus the dPRP clot lysis system provides a model by which the timing and sequence of the interaction of metabolically active platelets with the fibrin framework of the formed clot can be studied.
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PMID:Role of platelets in lysis of dilute plasma clots: requirement for metabolically active platelets. 45 46

Platelets provide a procoagulant activity for the conversion of prothrombin to thrombin during normal hemostatis. This activity designated as platelet prothrombin-converting activity (PPCA) was monitored as rate of thrombin production in a two-stage assay using gel-filtered bovine platelets, factor Xa, and prothrombin. Expression of PPCA was not associated with ADP-induced release or platelet shape change but was associated with aggregation. Release of the contents of dense bodies, measured by release of 14C-5-hydroxytryptamine, was not required for expression of PPCA during platelet aggregation. During the PPCA assay, 5-hydroxytrypamine was released, but only after onset of thrombin production. Furthermore, the release of 5-hydroxytryptamine was retarded during the assay by the addition of 2 mM theophylline and 100 nM prostaglandin E1 without a comparable reduction in PPCA. In addition, 125I-factor-Xa was bound in greater amounts to platelets (aspirin-treated) after ADP-induced aggregation (without detectable release) than to unactivated control platelets. Finally, the PPCA of the ADP-activated platelets was saturated with respect to factors Xa and Va at less than 1 nM concentrations, indicating that the aggregation induced by ADP leads to the exposure of specific procoagulant sites by some process other than dense body secretion.
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PMID:The effect of aggregation and release on platelet prothrombin-converting activity. 46 34

Bleeding times of mink with the Chediak-Higashi (CH) syndrome was markedly prolonged. Platelet counts were normal but there was an impaired platelet aggregation response to collagen. The metabolic adenine nucleotide pool of platelets from normal and CH mink was labeled with 14C-adenine and the platelets were gel-filtered. Gel-filtered platelets (GFP) from CH mink contained only 37.9% of the adenosine triphosphate (ATP) and 9.6% of the adenosine diphosphate (ADP) found in normal platelets and the ATP/ADP ratio was similar to the 14C-ATP/14C-ADP ratio. Platelet content of Ca2+, Mg2+, and in particular 5-hydroxytryptamine was decreased. When GFP were incubated with thrombin to induce maximal secretion, only negligible amounts of ATP and ADP were released. The specific activity of the extracellular nucleotides approximated that within the platelet. These findings suggest that the stored nucleotide pool in CH platelets is virtually absent and that the abnormalities in platelet function may be due, in part, to the essential absence of secretable ADP and serotonin. The release of Ca2+ and Mg2+ by CH platelets was 56% and 27.8% of normal, respectively.
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PMID:Characterization of platelets from normal mink and mink with the Chediak-Higashi syndrome. 53 91

The amantadine derivative 1.3-dimethyl-5-aminoadamantane, D 145, induces in high concentrations of 2-10 mM the release reaction. Adenine nucleotides and 5-hydroxytryptamine (5-HT) are liberated to the same extent and in the same ratio as found after thrombin-induced release. The time course of release is very slow; maximal release is reached in 15-20 min. The process is temperature-dependent and dependent on energy derived from glycolysis and oxidative phosphorylation. Extracellular Ca++ does not promote the release process. D 145, in accordance with the mother-substance amantadine, inhibits 5-HT uptake non-competitively, KI = 0.15mM. In concentrations of 0.1-1 mM D 145 triggers only the liberation of 5-HT, adenine nucleotides are not liberated. The ADP induced platelet aggregation is completely inhibited after preincubation with a 1 mM solution of D 145.
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PMID:Induction of the platelet release reaction by 1.3-dimethyl-5-aminoadamantane, a new adamantane derivative. 57 18

Halofenate--free acid (HFA), the major metabolite of the hypolipidemic drug, halofenate, inhibited platelet aggregation induced by collagen and sodium arachidonate and blocked the second phase of aggregation caused by ADP, thrombin and epinephrine in human platelet-rich plasma. The aggregation of washed platelets by thrombin and collagen was also blocked. HFA also inhibited the release by thrombin and collagen of 5-hydroxytryptamine from dense granules of platelets and the release by thrombin of beta-glucuronidase from platelet alpha-granules. These inhibitory effects were concentration and time-dependent. HFA decreased platelet factor 3 activity by 31% and also inhibited the incorporation of 14C-acetate and U-14C-glucose into platelet lipids by 89% and 56% respectively. Thrombin-induced lipid peroxidation and prostaglandin formation was investigated by measuring the by-product malonyldialdehyde, and this was found to be inhibited by HFA. It is suggested that the effect of HFA on aggregation is attributable to inhibition of the release reaction which may in turn be a consequence of the effects of the drug on platelet lipid synthesis.
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PMID:The effect of halofenate--free acid on aggregation--the release reaction, coagulant activity, and lipid metabolism of human platelets. 57 7

An abnormality of platelet aggregation has been detected in six family members with mild bleeding tendencies. In citrated platelet-rich plasma, primary aggregation induced by ADP or epinephrine and agglutination in response to ristocetin were present but second wave aggregation and aggregation in response to collagen suspension were absent or greatly reduced. Sodium arachidonate-induced aggregation was normal although aggregation in response to prostaglandin G2 was reduced and depended entirely on the presence of plasma or ADP. Further tests indicated that the platelets produced prostaglandins but did not release ATP in response to thrombin or sodium arachidonate. Platelets from the patients were found to contain reduced amounts of ADP and 5-hydroxytryptamine and to be unable to retain radioactivity during prolonged incubation at 37 degree C with radiolabeled 5-hydroxytryptamine. Although electron microscopy revealed an absence of very dense bodies, the platelets appeared otherwise normal. The findings are discussed in relation to previous studies of nucleotide storage pool deficiency and the light they shed on platelet physiology in general.
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PMID:Hereditary abnormality of platelet aggregation attributable to nucleotide storage pool deficiency. 66 60

Release of 14C-serotonin from human platelets prelabeled with 14C-5-hydroxytryptamine was measured during platelet aggregation induced by Staphylococcus aureus. Platelet-bacteria interaction (PBI) was as potent a stimulus of the platelet release reaction as collagen, thrombin, or epinephrine. Inhibitors which blocked platelet aggregation also prevented the release reaction of PBI. Sequential measurements of release, when correlated with nephelometry of aggregation, showed close correlation between the onset of release and the onset of platelet shape change and early aggregation. Ultrastructural studies with polylysine, an agent capable of polymerizing platelet granule contents, revealed that granule components are secreted to the region of the bacteria trapped between platelets in the forming aggregates. Platelet peroxidase activity remained localized within the dense tubular system of the platelets.
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PMID:Platelet interaction with bacteria. IV. Stimulation of the release reaction. 81 Nov 23


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