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)

A number of tests are available to measure plasma fibrinogen. Of these, the determination of the thrombin induced rate of plasma clotting is the most widely used in a clinical laboratory. Quantitative fibrinogen assays are calibrated with commercially available standards. There exists no internationally recognized standard against which the manufacturers could calibrate their fibrinogen preparations and lyophilized normal plasmas. In the present study, the amount of clottable material was determined in ten commercially available fibrinogen standards. Following clotting with thrombin, the fibrin clots were extensively washed with citrated saline and subjected to nitrogen analysis. The proportions of intact and partially degraded fibrinogens in each standard were determined by SDS-polyacrylamide gel electrophoresis of the washed clots. Knowing the amino acid composition and the relative proportions of these fractions, the nitrogen contents of the clots were converted to fibrinogen. More than 30% deviation from the declared values was observed in three standards, in one of them even 80%. Our results indicate that fibrinogen standards of markedly differing quality are commercially available and that an accurate, international standard for fibrinogen assay should be established.
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PMID:How high is the true fibrinogen content of fibrinogen standards? 262 43

Platelets contain mitogenic activities for MCF-7 human breast cancer cells when assayed under serum-free chemically defined conditions. Purification from outdated human platelets identified insulinlike growth factor I (IGF-I) as the most potent breast cancer cell mitogen in lysates (Karey KP, Sirbasku DA: see accompanying article, this issue). In this study the release and subcellular localization of IGF-I was investigated. Degranulation of platelets by thrombin treatment caused release of lysosomal enzymes (beta-glucuronidase and N-acetyl-D-glucosaminidase), alpha-granule proteins (beta-thromboglobulin and fibrinogen) as well as mitogenic activity for MCF-7 cells and IGF-I as measured by radioimmunoassay (RIA) and radioreceptor assay. Release of mitogenic activity and immunologically identified IGF-I was induced tenfold over controls by thrombin and was nearly complete as compared to platelets disrupted by repeated freezing and thawing. Disruption of platelets by nitrogen cavitation followed by separation of the organelles by sucrose density gradient sedimentation showed that IGF-I and mitogenic activity localized predominantly to fractions containing alpha-granules rather than soluble cellular components, lysosomes, or dense granules. The morphology of MCF-7 cells in serum-free medium supplemented with supernatants from thrombin-treated platelets also indicated the release of important cell-adhesion factors for human breast cancer cells.
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PMID:Human platelet-derived mitogens. II. Subcellular localization of insulinlike growth factor I to the alpha-granule and release in response to thrombin. 275 54

We have identified and purified a platelet integral membrane protein (140,000 mol wt), using the KC4 monoclonal antibody specific for activated platelets, that is internal in resting platelets but exposed on activated platelets (Hsu-Lin S.-C., C.L. Berman, B.C. Furie, D. August, and B. Furie, 1984, J. Biol. Chem. 259: 9121-9126.). The expression of the protein on the platelet surface is secretion-dependent. This protein has been named platelet activation-dependent granule-external membrane (PADGEM) protein. PADGEM protein is distinct from the surface glycoproteins of resting platelets, but identical to the S12 antigen, GMP-140. Using immunofluorescent staining, resting platelets failed to stain for PADGEM protein with the KC4 antibody, but after permeabilization showed a punctate staining of the cell interior. Thrombin-stimulated intact platelets stained with a peripheral rim pattern thus demonstrating the translocation of PADGEM protein from an internal location to the cell surface. PADGEM protein expression on the platelet surface at varying thrombin concentrations correlated with alpha granule release, as measured by the secretion of platelet factor 4. Further evidence for an alpha granule localization of PADGEM protein was provided by nitrogen cavitation of resting platelets followed by metrizamide density gradient centrifugation; PADGEM protein codistributed with platelet factor 4. Using immunoelectron microscopy, the protein was localized to the alpha granule in frozen ultrathin sections of resting platelets labeled using rabbit anti-PADGEM protein antibodies, whereas in thrombin-activated platelets, the plasma membrane was labeled. These studies indicate that PADGEM protein is a component of the alpha granule membrane of resting platelets and is incorporated into the plasma membrane upon activation and secretion.
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PMID:A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein. 294 52

Cyclic amides of N alpha-arylsulfonylated 4-amidinophenylalanine are specific, highly potent inhibitors of thrombin. Introduction of amino acids between the arylsulfonyl blocking group and amino nitrogen influence particularly the antithrombin activity. By the use of glycine as spacer the compounds become tight binding thrombin inhibitors, while introduction of other omega-amino acids, Gly-Gly, L-Pro, Gly-L-Pro or L-Pro-Gly, reduces the specificity and potency of thrombin inhibition. Substitution of the arylsulfonyl blocking group for a heteroarylsulfonyl residue or an aryl residue causes a decrease in antithrombin activity, while substitution for a benzoyloxycarbonyl blocking group has only slight influence. It is concluded that the N alpha-moiety is of decisive importance for the antithrombin activity of derivatives of 4-amidinophenylalanine.
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PMID:[Synthetic inhibitors of serine proteinases. 32. Inhibition of trypsin, plasmin and thrombin by amides of N-alpha-substituted 4-amidinophenylalanine. Effect of various amino acids and blocking groups of the n-alpha residue on inhibitory activity]. 295 29

The present study summarizes recent investigations in our laboratory, demonstrating that a number of organic nitrates, including glyceryltrinitrate, isosorbide dinitrate, isosorbide-2-mononitrate and the novel nitrate teopranitol stimulate the release of a prostacyclin (PGI2)-like antiplatelet activity from isolated bovine coronary arteries and veins. In bioassay experiments this increase amounted to 50 to 200% of control. Evidence for nitrate induced PGI2 stimulation is presented by inhibition of its formation by indomethacin and dexamethasone, the demonstration of inhibition of thrombin induced thromboxane generation of washed platelet suspensions by nitrate stimulated vessel incubates and an enhanced accumulation of the hydrolysis product of PGI2, 6-oxo-PGF1 alpha, in incubates of teopranitol stimulated vessels. This action is obtained at nanomolar, i.e. therapeutic concentrations of the compounds and requires the presence of free nitro group(s) at [exo] position of the isohexide molecule. There was no correlation between PGI2 release and the relaxing action of the nitrates on isolated vessel strips. The inhibitor of cyclic GMP accumulation, methylene-blue, also blocked the generation of the antiplatelet activity by glyceryltrinitrate and teopranitol. Recent evidence suggests that cGMP accumulation via intermediate nitrogen oxide (NO) production mediates the vascular effects of organic nitrates. Since NO is also a potent antiplatelet agent, it is concluded that a nitrate stimulated PGI2 release associated with or mediated by NO formation might explain the antiplatelet actions of organic nitrates in vitro and ex vivo.
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PMID:Stimulation of coronary vascular PGI2 by organic nitrates. 313 69

Clinical pathology is a valuable adjunct to physical examination of cases of colic. The present review considers evaluation of cases of colic for three main purposes: (1) making a prognosis, (2) deciding whether to operate, and (3) making a diagnosis. Blood tests noted to be useful for prognostication were hematocrit, lactate and urea nitrogen concentrations, pH, anion gap, fibrin/fibrinogen degradation products, antithrombin III activity, prothrombin time, and thrombin time. Horses with a poor prognosis often have relative polycythemia, marked lactic acidosis, high anion gap, azotemia, and coagulation abnormalities evidenced by increased fibrin/fibrinogen degradation products, decreased antithrombin III activity, and prolonged prothrombin and thrombin times. The decision to operate is usually a clinical one, supported by relative polycythemia, hyperglycemia, and, possibly, abnormal peritoneal fluid analysis. Diagnosis of the primary problem (causing the colicky signs) is also often based largely on physical examination. However, peritoneal fluid analysis provides worthwhile data, especially in cases of peritonitis or intestinal ischemia and infarction.
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PMID:Use of clinical pathology in evaluation of horses with colic. 332 25

In order to study factors which are involved in maintenance of phosphatidylserine (PS) asymmetry within the human red cell membrane, we measured the effect of ATP-depletion and of membrane skeleton/lipid bilayer uncoupling induced by sickling on the distribution of PS within the membrane bilayer of sickle cells. Trace amounts of radiolabeled PS were introduced into the outer membrane leaflet of both fresh and ATP-depleted reversibly sickled cells (RSCs), using a non-specific lipid transfer protein purified from bovine liver. The equilibration of the newly introduced PS over the two halves of the bilayer was monitored by treatment of the cells with phospholipase A2 which selectively hydrolyzes only those molecules present in the outer membrane leaflet. Within 1 h after insertion into fresh RSCs, only 10% of the labeled PS was accessible to the action of phospholipase A2. This fraction was markedly increased when the cells were subsequently deoxygenated. Prolonged deoxygenation of RSCs, deprived of their ATP after incorporation of radiolabeled PS, caused enhanced phospholipase A2-induced hydrolysis of radiolabeled PS. Similarly, phospholipase A2-induced hydrolysis of endogenous PS in intact RSCs was markedly enhanced when ATP-depleted, but not when fresh cells, were incubated under nitrogen for 3.5 h. Deoxygenated ATP-depleted RSCs markedly enhanced the rate of thrombin formation in the presence of purified coagulation factors Xa, Va, prothrombin and Ca2+. This enhancement appeared to be dependent on the duration of incubation under nitrogen. This phenomenon, indicating the presence of increasing amounts of endogenous PS in the outer membrane leaflet, was not observed when either fresh RSCs or ATP-depleted normal erythrocytes were incubated under nitrogen. Our present observations provide evidence that, in addition to the interaction of PS with the skeletal proteins, an ATP-dependent translocation of PS is required to maintain its absolute asymmetric distribution in the human erythrocyte membrane.
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PMID:Studies on sickled erythrocytes provide evidence that the asymmetric distribution of phosphatidylserine in the red cell membrane is maintained by both ATP-dependent translocation and interaction with membrane skeletal proteins. 333 4

This paper describes the successful therapy of cavernous and capillary haemangiomata by inducing thrombosis with Tissucol homologous fibrinogen and thrombin. After angiography, infants and small children were injected with Tissucol directly into the vascular convolution at two weekly intervals, resulting in complete thrombosis with subsequent fibrosis, leading to diminution of the haemangioma until it finally disappeared. Histological examination showed fibrosis and sclerosis, with granular tissue rich in fibrinoblasts as a manifestation of a partially organised thrombosis. There were no traces of inflammation. In a large number of adults, reduction of the haemangioma was successfully achieved by injections of Tissucol, leading to thrombosis, followed by immediate surgical removal of the entire haemangioma. Treatment of small haemangiomata by cryosurgical measures with liquid nitrogen, as recommended by Lexer in 1921, was likewise successfully applied.
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PMID:[New aspects in the treatment of hemangioma]. 387 49

The behavior of direct fibrinolytic (non-plasmin) proteinase activity and plasminogen-activator activity in the lung and spleen was investigated in rats after a single intravenous injection of bacterial endotoxin, and the influence of thrombin inhibitors on the effects of the endotoxin was assessed. The non-plasmin fibrinolytic activity was markedly increased following a decrease of plasminogen-activator in the lung. In addition, variations in hematological parameters, i.e. a decrease of platelet count, fibrinogen level and antithrombin III, and an increase of blood urea nitrogen and euglobulin fibrinolytic activity, were induced by the injection, indicating the occurrence of disseminated intravascular coagulation. In comparative studies on the effects of the endotoxin injection and thrombin infusion, in the lung and spleen an increase of fibrinolytic proteinase activity was induced in a similar manner; the plasminogen-activator activity in the lung was decreased by the endotoxin injection but not decreased by the thrombin infusion. In prevention studies with heparin and MD-805, the latter was found to prevent the decrease of either fibrinogen or platelet count. However, the former failed to prevent the decrease of platelet count although that of the fibrinogen level was prevented. Heparin and MD-805 exerted no preventive effect on the endotoxin-induced variations of proteinase activity and plasminogen-activator activity in the lung.
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PMID:Variation in activities of non-plasmin fibrinolytic proteinase and plasminogen-activator in the lung and spleen induced by bacterial endotoxin in rats with special reference to the effects of MD-805. 390 90

Platelets can release a variety of inflammatory mediators. These formed elements have been shown to accumulate early in acute inflammation, often prior to fibrin and thrombus formation. Polymorphonuclear leukocyte (PMNL) infiltration is also an early event and is linked to protein exudation and hyperemia. The relationship between PMNL and platelet accumulation was studied. Inflammation was induced in rabbits by intradermal injection of stimuli, and 51Cr-labeled leukocytes and 111In-labeled platelets were used to quantitate the rates of leukocyte and platelet accumulation in the dermal reactions. A temporal association between the rates of leukocyte infiltration (greater than 95% PMNL) and of platelet deposition at skin sites was observed when killed Escherichia coli, E. coli-derived chemotactic factors, zymosan-activated plasma, f-met-leu-phe, or endotoxin were injected intradermally. A linear correlation (r = 0.96; p less than 0.001) between these parameters was observed. 59Fe-labeled red cells did not accumulate in these lesions. Platelet deposition in response to inflammatory stimuli did not occur in PMNL-depleted (nitrogen mustard treatment) but platelet-sufficient rabbits, in spite of normal platelet deposition in thrombin-injected sites. Platelet responses to inflammatory stimuli were normal when neutropenia, after nitrogen mustard treatment, was prevented. In contrast, in situ PMNL reconstitution of the skin sites in neutropenic rabbits did not cause local platelet accumulation. Intravenous infusion of the synthetic chemotactic factor, f-met-leu-phe, induced transient neutropenia and thrombocytopenia (30% of control) with platelet sequestration primarily in the lung. This is also the known site of PMNL sequestration during f-met-leu-phe infusion. It is concluded that platelets selectively deposit in acutely inflamed tissues primarily during PMNL margination in, and emigration across, the microvasculature. Platelets and PMNLs likely coassociate on the vessel wall, and this interaction may influence the course of inflammation.
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PMID:Role of neutrophils in the deposition of platelets during acute inflammation. 636 76


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