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)

We studied the activation of coagulation and fibrinolysis in the blood of patients with compensated (n = 25) and decompensated (n = 25) liver cirrhosis. We observed increased blood concentrations of thrombin-antithrombin III (TAT) complexes (p less than 0.001) and of D-dimer (p less than 0.001) in both groups of patients compared with healthy volunteers (n = 25). The blood levels of tissue-type plasminogen activator (t-PA) activity (p less than 0.001) and the concentrations of t-PA antigen (p less than 0.001) were also significantly raised in both groups of patients compared with controls, whereas plasminogen activator inhibitor did not deviate. There were no significant differences in the determined variables between the two groups of patients except that the concentrations of D-dimer were significantly higher (p less than 0.001) in patients with decompensated liver cirrhosis. The ratio between D-dimer and TAT did not deviate between patients with compensated liver cirrhosis and healthy volunteers but was significantly increased in patients with decompensated liver cirrhosis. These observations indicate that efflux from the extravascular space (for example, ascitic fluid) contributes to the high concentrations of fibrin degradation products (D-dimer) in patients with decompensated liver cirrhosis. In addition, we conclude that patients with liver cirrhosis have an enhanced activation of both coagulation and fibrinolysis but that the balance between these two systems is not significantly displaced compared with healthy volunteers.
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PMID:Increased levels of fibrinolysis reaction products (D-dimer) in patients with decompensated alcoholic liver cirrhosis. 175 53

A model system consisting of thrombin-stimulated bovine platelet releasates (PRthr) and bovine aortic endothelial cells (BAEs) was developed to determine if the interaction between platelets and endothelial cells regulates fibrinolysis. Zymographic analysis indicated that PRthr treatment of BAEs decreases urokinase and increases type 1 plasminogen activator inhibitor (PAI-1) activity. Although PRthr did not affect the overall rate of BAE protein synthesis, it increased PAI-1 biosynthesis within 6 hours. This increase was complete by 12 hours, with maximum stimulation at 10 to 15 micrograms/mL PRthr (1 microgram approximately 10(7) platelets). Neutralizing antibodies to transforming growth factor beta (TGF beta) reduced this effect by 75%. Treatments that activate latent TGF beta (eg, acidification or plasmin) increased this effect approximately fivefold, suggesting that TGF beta in PRthr exists in both a latent (approximately 80%) and an active (approximately 20%) form. In contrast to PRthr, adenosine diphosphate-prepared platelet releasates did not increase PAI-1 synthesis before acidification, indicating that they contain only the latent form of TGF beta. These results suggest that platelets can modulate the fibrinolytic system of the endothelium through the release of TGF beta, and that the mechanism by which the platelets are activated can influence the relative amount of active TGF beta.
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PMID:Platelets stimulate endothelial cells to synthesize type 1 plasminogen activator inhibitor. Evaluation of the role of transforming growth factor beta. 182 86

Human glomerular epithelial cells (GECs) in culture synthesize single-chain, urokinase-type plasminogen activator (SC-uPA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1) and possess specific membrane-binding sites for u-PA. Using purified 125I-alpha thrombin, we demonstrate here the presence of two populations of specific binding sites for thrombin on GECs (1.Kd = 4.3 +/- 1.0 x 10(-10) M, 5.4 +/- 1.4 x 10(4) M sites per cell, 2. Kd = 1.6 +/- 0.5 x 10(-8) M, 7.9 +/- 1.8 x 10(5) sites per cell). Purified human alpha thrombin promoted the proliferation of GECs and induced a time- and dose-dependent increase of SC-uPA, t-PA, and PAI-1 antigens released by GECs. Thrombin-mediated increase in antigen was paralleled by an increase in the levels of corresponding u-PA and PAI-1 messenger RNA. In contrast, thrombin decreased u-PA activity in conditioned medium. This discrepancy between u-PA antigen and u-PA activity was explained by a limited proteolysis of SC-uPA by thrombin, leading to a two-chain form detected by immunoblotting and that could not be activated by plasmin. Thrombin also decreased the number of u-PA binding sites on GECs (p less than 0.05) without changing receptor affinity. Hirudin inhibited the binding and the cellular effects of thrombin, whereas thrombin inactivated by diisopropylfluorophosphate had no effect, indicating that both membrane binding and catalytic activity of thrombin were required. We conclude that thrombin, through specific membrane receptors, stimulates proliferation of GECs and decreases the fibrinolytic activity of GECs both at the cell surface and in the conditioned medium. These results suggest that thrombin could be involved in the pathogenesis of extracapillary proliferation and persistency of fibrin deposits in crescentic glomerulonephritis.
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PMID:Thrombin increases proliferation and decreases fibrinolytic activity of kidney glomerular epithelial cells. 184 34

Increased thrombogenesis observed in systemic lupus erythematosus (SLE) is derived from multiple mechanisms, including: Enhanced coagulation factor VIII:VWf activity, lupus anticoagulants, anti-phospholipid antibodies, acquired deficiencies of natural anti-thrombotic mechanisms (protein C, protein S, anti-thrombin III), and impaired fibrinolytic mechanisms. We studied the fibrinolytic mechanisms of 18 patients with systemic lupus erythematosus, selected carefully to avoid other possible causes of abnormalities in the fibrinolytic activity. Despite the fact that the euglobulin lysis time in steady state was normal in all instances, disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system were found in all SLE patients: TPA activity was undetectable in all cases, whereas it was above 0.4 IU/ml in a control group. In 72 percent of patients, the undetectable TPA activity was correlated with abnormally high PAI activity; PAI levels were normal in all members of the control group, their mean value being 0.74 versus 8.63 IU/ml for SLE patients (P less than .01). Coagulation protein C deficiency was found in 3 patients (17%). Even though within normal range, fibrinogen levels were significantly higher in SLE than in normal controls (219 versus 192 mg/dl, P less than .01) and plasminogen levels were significantly higher in SLE than in controls (117 versus 78.2%, P less than .01). Cross-linked fibrin derivatives (D-D dimers) were negative in all patients with SLE. Sixty-eight percent of SLE patients had high levels of antiphospholipid antibodies, but no correlation with the disturbances of the TPA/PAI system was found. It is concluded that most patients with SLE display severe abnormalities in the TPA/PAI anti-thrombotic system and that these abnormalities may be related to the lupus thrombophilia, apparently multifactorial in its origin.
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PMID:Disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system in systemic lupus erythematosus. 190 23

Various thrombosis related parameters of the hemostatic system were evaluated in 11 patients who had had bone marrow transplantation (BMT). At 0, 1, 3 and 6 months after BMT, antithrombin III, heparin cofactor II, protein S (PS), factor VIII:C, von Willebrand factor (vWF:Ag, vWF:RiCof), tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin antithrombin III complexes (TAT), d-dimers (DD) and antiphospholipid antibodies (APA) were determined. A statistically significant rise in the levels of vWF was observed after BMT, with a similar trend for tPA. High TAT and/or DD were detected in 10/11 patients and positive APA only in 5/11. Of the other parameters only free PS was permanently low, with normal total PS and C4bBP. These findings suggest persistent thrombin generation peri- and post-BMT. The significantly high vWF and the low free PS could foster a procoagulant state.
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PMID:[Tendency to thrombosis following bone marrow transplantation?]. 190 84

Fifty-six pregnant women (gestational age 6-40 weeks) were evaluated for their coagulation activation (fibrin monomers and thrombin-antithrombin III complex) and for their fibrinolysis profile by determining tissue plasminogen activator, plasminogen activator inhibitor, plasminogen, alpha 2-antiplasmin and D-dimer. Fibrin monomers and thrombin-antithrombin III complexes were found to be significantly increasing with gestational age. All the fibrinolytic parameters showed a steady growth with the progress of the pregnancy, with the exception of tissue plasminogen activator which showed a significant decrease with gestational age, but mainly within the reference range. These results suggest a stimulation of the coagulation system and an activation of fibrinolysis with ongoing pregnancy, although the increasing alpha 2-antiplasmin and plasminogen levels and the decreasing tissue plasminogen activator concentrations do not conform to this trend.
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PMID:Blood coagulation and fibrinolysis during normal pregnancy. 190 79

Fifty-one patients with mild hypertension were evaluated in relation to the plasma concentrations of coagulation and fibrinolysis factors as well as for the aggregability of their platelets. In a considerable number of the patients (18/51), a significantly enhanced in vitro ADP (2 mumol/l)-induced aggregation was found. In the coagulation line significant increases could be demonstrated in fibrinogen, fibrin monomers and thrombin-antithrombin III. The fibrinolysis system showed significant increases for D-dimers, tissue plasminogen activator antigen and plasminogen activator inhibitor, whereas the tissue plasminogen activator activity was significantly diminished. Remarkably, there seems to be a discrepancy between the (low) tissue plasminogen activator activity and the (higher) plasminogen activator antigen concentration. Alterations in the plasma concentrations of the investigated coagulation and fibrinolysis factors and in the aggregability of the platelets are indicative of an involvement of coagulation, fibrinolysis and platelets in hypertension, which can be considered as partial risk factors for thrombophilia.
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PMID:Plasma concentration of coagulation and fibrinolysis factors and platelet function in hypertension. 191 85

We studied the changes of coagulation and fibrinolysis in bronchoalveolar lavage (BAL) and plasma obtained serially at intervals after the onset of adult respiratory distress syndrome (ARDS). BAL procoagulant activity was increased at 3 days and tended to decrease thereafter. Tissue factor associated with factor VII was the major BAL procoagulant. Fibrinopeptide A was increased, indicating increased thrombin-mediated conversion of fibrinogen to fibrin. Fibrinolytic activity was usually undetectable in BAL at 3 days post-ARDS and remained depressed for up to 14 days despite unchanged concentrations of urokinase and variably detectable tissue plasminogen activator. Depressed fibrinolytic activity was associated with increased antiplasmin activity and plasminogen activator inhibitor 1 (PAI-1) while PAI-2 concentrations approximated those of control samples and did not change during evolving ARDS. Evidence of systemic coagulopathy and increased systemic fibrin degradation were commonly found in serial ARDS plasma samples, consistent with accelerated vascular and/or extravascular fibrin deposition in these patients. The data indicate that intra-alveolar as well as systemic derangements of fibrin turnover are common features of evolving ARDS. Concurrent local abnormalities of both coagulation and fibrinolytic pathways favor persistence of alveolar fibrin for up to 14 days after clinical recognition of ARDS.
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PMID:Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. 192 57

Recent studies have suggested important roles for certain proteases and protease inhibitors in the growth and development of the CNS. In the present studies, inhibitors of urokinase or thrombin in cultured neural cells and serum-free medium from the cells were identified by screening for components that formed sodium dodecyl sulfate-stable complexes with 125I-urokinase or 125I-thrombin. Rinsed glioblastoma possessed two components that complexed 125I-urokinase. One was type 1 plasminogen activator inhibitor (PAI-1), because the 125I-urokinase-containing complexes were immunoprecipitated with anti-PAI-1 antibodies. The other component formed complexes with 125I-urokinase that were not recognized by antibodies to PAI-1 or protease nexin-1 (PN-1). Its identity is unknown. In addition to these cell-bound components, the glioblastoma cells also secreted two inhibitors that formed complexes with 125I-urokinase; one was PAI-1, and the other was PN-1. The secreted PN-1 also formed complexes with 125I-thrombin. It was the only thrombin inhibitor detected in these studies. Human neuroblastoma cells did not contain components that formed detectable complexes with either 125I-urokinase or 125I-thrombin. However, human neuroblastoma cells did contain very low levels of PN-1 mRNA and PN-1 protein. Added PN-1 bound to the surface of both glioblastoma and neuroblastoma cells. This interaction accelerated the inhibition of thrombin by PN-1 and blocked the ability of PN-1 to form complexes with 125I-urokinase. Thus, cell-bound PN-1 was a specific thrombin inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitors of urokinase and thrombin in cultured neural cells. 198 20

The influence of diacylglycerols, which are physiological activators of protein kinase C, on the production of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) by human umbilical vein endothelial cells (HUVEC) was studied in order to gain insight into the regulation of fibrinolysis by these cells. 1,2-dioctanoyl-sn-glycerol (diC8) stimulated tPA production in a dose- and time-dependent manner. The tPA antigen in cell supernatants increased from 0.9 ng/10(6) cells in unstimulated cells to 12.4 ng (10(6) cells after incubation with 400 microM diC8 for 24 hours. In contrast, PAI-1 production was not influenced by diC8, whereas phorbol 12-myristate 13-acetate (PMA) or thrombin stimulated both, tPA and PAI-1 production by HUVEC. Staurosporine and H7, which are inhibitors of protein kinase C, inhibited tPA synthesis by HUVEC. The degree of inhibition was dependent on the agonist used. While diC8-induced tPA production was inhibited to more than 80% by H7 (10 microM) and staurosporine (10 nM), higher doses of inhibitors were required to inhibit thrombin- and PMA-induced tPA production. Thrombin-induced PAI-1 production was inhibited to more than 80% by H7 (10 microM) and to about 50% by staurosporine, whereas PMA-induced PAI-1 production was not inhibited by staurosporine, and only to about 50% by higher doses of H7 (30 microM). These data suggest that activation of protein kinase C is a common intracellular trigger mechanism for the induction of tPA synthesis by HUVEC. Protein kinase C is most likely also involved in the regulation of PAI-1 synthesis by HUVEC.
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PMID:Regulation of endothelial tissue plasminogen activator and plasminogen activator inhibitor type 1 synthesis by diacylglycerol, phorbol ester, and thrombin. 211 75


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