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)

Through immunohistochemical techniques, blood coagulation factors were identified in situ in fresh frozen sections of small cell carcinoma of the lung. Prothrombin/thrombin, factor VII, factor X, and antithrombin III were present in intercellular spaces and associated with tumor cells. Factor IX, factor XI, prekallikrein, and high molecular weight kininogen were identified as being associated with tumor cells but did not exist in intercellular spaces. Variable connective tissue staining but no tumor-related staining was observed for factor V, factor VIII-related antigen, factor XII, the B subunit of factor XIII, alpha 1-antitrypsin, alpha 2-macroglobulin, or alpha 2-antiplasmin. Neither consecutive tissue nor the tumor manifested platelet Ib and IIbIIIa surface glycoproteins. These divergent staining patterns suggested that the detected clotting factors had not merely diffused from permeabilized blood vessels, but were selectively localized in situ. While conditions may exist within tumor tissue that both retard and promote thrombin generation, we propose that interactions between the observed coagulation factors ultimately lead to local thrombin formation, which is responsible for the conspicuous fibrin deposits already described in small cell carcinoma of the lung. Thrombin formed locally might contribute to progression of this tumor. Inhibition of local thrombin formation by warfarin therapy could explain the beneficial effects of warfarin therapy in treating small cell carcinoma of the lung.
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PMID:Occurrence of blood coagulation factors in situ in small cell carcinoma of the lung. 282 13

A 7-day course of intravenous cefotetan disodium was given to nine patients. No significant changes were observed in haematological or biochemical parameters and serum vitamin K1 levels, prothrombin times, factor VII levels, thrombin times and activated partial thromboplastin times remained within the normal ranges throughout the treatment period in all patients. There was no evidence of clinical bleeding in any patient although in two the bleeding time was prolonged up to 13.0 min after 7 days' therapy. Notably, adenosine-5-diphosphate (ADP)-induced platelet aggregation responses were significantly increased (P less than 0.05) at the end of the treatment period. These data indicate that cefotetan disodium at a dose of up to 4 g daily can be used without risk of a bleeding diathesis. In situations associated with vitamin K1 deficiency, potential prolongation of the prothrombin time should be avoided by prophylactic vitamin K1 administration.
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PMID:The effects of cefotetan disodium on haemostasis. 288 12

Blood coagulation can be initiated when factor VII or VIIa, a plasma protease, binds to its essential cofactor, tissue factor (TF), and proteolytically activates factors IX and X, triggering a cascade of events which eventually leads to the formation of thrombin and a fibrin clot. Plasma contains a lipoprotein-associated coagulation inhibitor (LACI) which inhibits activated factor X (Xa) directly and, in a Xa-dependent way, inhibits VII(a)/TF activity, presumably by forming a quaternary Xa/LACI/VII(a)/TF complex. Sequence analysis of complementary DNA clones has shown that LACI contains three tandemly repeated Kunitz-type serine protease inhibitory domains. To investigate the relationship between these Kunitz structures and LACI function, we have used site-directed mutagenesis to produce altered forms of LACI in which the residue at the active-site cleft of each Kunitz domain has been individually changed. The second Kunitz domain is required for efficient binding and inhibition of Xa, and both Kunitz domains 1 and 2 are required for the inhibition of VIIa/TF activity; but alteration of the active-site residue of the third Kunitz domain has no significant effect on either function. We propose that in the putative inhibitory complex, Kunitz domain 1 is bound to the active site of VII(a)/TF and that Kunitz domain 2 is bound to Xa's active site.
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PMID:Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. 292 10

Human umbilical vein endothelial cells were analyzed for the presence of prothrombin, factor VII, protein C, and protein S in culture supernatants and cell extracts using specific radioimmunoassays. Only protein S was detected. Conditioned medium from 24-hour cultures and cell lysates contained 21.7 ng/mL and 88.8 ng/10(7) cells of protein S, respectively. Intrinsic labeling and immunoprecipitation indicated that protein S was synthesized and secreted as a 75,000 molecular weight protein. Vitamin K, phorbol myristate acetate, and thrombin increased the production or specific activity (determined from activity/antigen ratios of 0.99 to 1.07, 0.93 to 1.04, and 0.90 to 1.04, respectively) of protein S. While untreated cells secreted a partially active protein S (activity/antigen = 0.40), warfarin greatly decreased the specific activity (less than 0.10) of this molecule, suggesting that endothelial cells contain the enzymes required for the carboxylation of selected glutamic acid residues. The production of protein S by these cells supports the hypothesis that cofactor production and expression by the endothelial cells may play a significant regulatory role in the initiation, propagation, and suppression of hemostasis and thrombosis.
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PMID:Human endothelial cells synthesize protein S. 293 70

Thrombin generation, as evidenced by plasma fibrinopeptide A (FPA) concentrations, was studied during blood collection from donors taking oral contraceptives (OC). 450 ml blood were drawn into Fenwal PVC bags from 26 OC users and 28 nonusers. Blood samples for determination of FPA, beta-thromboglobulin (BTG), thrombotest (TT), prekallikrein (PKK), antithrombin-III (AT-III) and factor VIII procoagulant activity (FVIII:C) were drawn from the bags immediately after ending blood donation and following storage for 24 h at 4 degrees C. The FPA concentrations following donation were significantly higher in the OC than in the control group (p less than 0.05). The levels of PKK were also higher in blood obtained from OC users (p less than 0.001), as was the FVIII:C level, the latter difference, however, was not significant (p = 0.06). No cold-promoted activation of factor VII, as evidenced from TT, was detected following storage at 4 degrees C, neither was any change observed in the FPA, PKK and AT-III levels. The BTG concentrations increased significantly during storage, most pronounced in the control group (p less than 0.05). The decay of FVIII:C was similar in the two groups, averaging 24.7%. No correlation was observed between the FPA levels and the other parameters determined. We conclude that thrombin generation is more pronounced during routine blood collection from donors taking OC.
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PMID:Thrombin generation during collection of blood from donors taking oral contraceptives. 295 72

Monocytes initiate coagulation through regulated surface expression of tissue factor and local assembly of a proteolytic enzymatic complex formed by tissue factor and factor VII/activated factor VII. We now show that, in the absence of these initiating molecules, monocytes and cell lines of monocytic/myeloid differentiation can alternatively initiate coagulation after exposure to ADP. The molecular basis for this procoagulant response consists of two distinct events. First, cell stimulation with ADP induces high-affinity binding of coagulation factor X to the surface-adhesive receptor Mac-1. Locally, Mac-1-concentrated factor X is then rapidly proteolytically cleaved to an active protease with size and activity characteristics of activated factor X, which supports the cell-associated formation of thrombin and the procoagulant response. We conclude that the monocytic/myeloid adhesive receptor Mac-1 has the unexpected, specifically inducible property to organize a molecular assembly culminating in rapid fibrin formation that is independently regulated from tissue factor and factor VII/activated factor VII.
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PMID:Adhesive receptor Mac-1 coordinates the activation of factor X on stimulated cells of monocytic and myeloid differentiation: an alternative initiation of the coagulation protease cascade. 297 72

The ability of tumor cells to initiate coagulation and subsequent platelet aggregation is believed to facilitate the metastatic process. The mechanism by which tumor cells initiate thrombotic alterations is unclear. We have purified a plasma membrane protein platelet aggregating activity/procoagulant activity (PAA/PCA) from several rodent tumors which initiates the coagulation of homologous plasma and aggregation of homologous platelets by a mechanism independent of factor VII. This protein does not possess any proteinase activity; however, its activity is dependent upon the presence of factor X. In addition, PAA/PCA requires reconstitution with phospholipid for expression of activity. These results suggest that tumor cells express a unique protein which possesses procoagulant activity resulting in thrombin generation. Thrombin is responsible for subsequent tumor-cell-induced platelet aggregation.
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PMID:Role of the coagulation system in tumor-cell-induced platelet aggregation and metastasis. 304 22

The authors have investigated the ability of platelets to enhance factor Xa-catalyzed activation of factor VII. Unstimulated platelets were without effect, whereas freeze/thawed platelets substantially enhanced activation. Antifactor V antibodies did not diminish the enhancement. Platelets activated by thrombin, collagen, or calcium ionophore A23187 also enhanced factor Xa-catalyzed activation of factor VII. In contrast to their lack of effect upon freeze/thawed platelets, antifactor V antibodies abolished augmented factor VII activation induced by activated platelets. Adding exogenous factor Va to unstimulated platelets failed to enhance factor Xa-catalyzed activation of factor VII, nor did adding exogenous factor Va to activated platelets augment activation beyond that observed with activated platelets alone. These observations can be interpreted as follows: (1) factor Va does not function as a cofactor for factor Xa-catalyzed activation of factor VII; (2) anionic phospholipids are a known cofactor for factor Xa-catalyzed activation of factor VII, and freeze/thawed platelets probably enhance activation by making anionic phospholipids on disrupted platelet membranes available to function as a cofactor; (3) the presumed binding of factor Xa to exogenous factor Va on unstimulated platelets is insufficient in itself to augment factor Xa-catalyzed activation of factor VII; (4) activated platelets augment factor Xa-catalyzed factor VII activation because activation allows both factor Xa to bind to released platelet factor V(a) and makes available a surface membrane component, probably anionic phospholipids, with which the bound factor Xa interacts.
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PMID:The effect of platelets upon factor Xa-catalyzed activation of factor VII in vitro. 313 57

Bismuth subgallate is an effective agent in preventing hemorrhage after adenotonsillectomy. The experiments described demonstrate that this may occur through the activation of Hageman factor by this agent. Bismuth subgallate shortened the clotting time of whole blood, an action localized to an effect on the early steps of the intrinsic pathway; bismuth subgallate did not accelerate the thrombin time or prothrombin time of normal plasma, but could be substituted for kaolin as an activator of coagulation in assays of the partial thromboplastin time. The action of bismuth subgallate was localized to an effect on Hageman factor. It did not induce coagulation of plasma samples deficient in any of the recognized factors participating in the intrinsic pathway of thrombin formation, but it shortened the clotting time of plasma deficient in factor VII, a component of the extrinsic pathway. Evidence was obtained that Hageman factor exposed to bismuth subgallate corrected the defect of Hageman factor-deficient plasma and acquired amidolytic properties in the absence of other clotting factors. These studies provide a rationale for the hemostatic properties of bismuth subgallate.
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PMID:Activation of Hageman factor (factor XII) by bismuth subgallate, a hemostatic agent. 317 56

As part of a controlled trial of the use of tamoxifen for the treatment of mastalgia, some of the metabolic and haematological effects of this agent were measured. A panel of haemostatic variables including prothrombin time, kaolin cephalin clotting time, fibrinogen, euglobulin lysis time, factor VII, factor VIII, protein C and anti-thrombin III were determined. In addition, levels of sex hormone-binding globulin and both total and free oestradiol were estimated. No alteration in clotting function was found during the administration of tamoxifen, although hepatic function did alter during this period with an increase in concentration of sex hormone-binding globulin. There was a significant increase in total oestradiol and free oestradiol although the percentage of biologically available free oestradiol fell slightly during the course of tamoxifen treatment. There was a slight reduction in low-density lipoprotein cholesterol with an increase in HDL2, a subclass of high-density lipoprotein (HDL) cholesterol, consistent with an oestrogen-agonist effect. These data suggest that tamoxifen administration does not adversely influence haemostatic mechanisms or lipoprotein metabolism in the short term.
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PMID:Effect of tamoxifen on oestrogen binding, lipid and lipoprotein concentrations and blood clotting parameters in premenopausal women with breast pain. 319 64


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