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)

Although the use of extracellular matrix proteins to precoat small-caliber vascular grafts before endothelial cell seeding has been shown to improve cell attachment, proliferation, and adherence, the effect of precoating on the thrombomodulatory properties of the seeded cells is unknown. The use of vascular prostheses lined with confluent endothelial cell monolayers expressing optimal thromboresistant properties may enhance patency rates. In this study human saphenous vein endothelial cells were seeded onto expanded polytetrafluoroethylene (ePTFE) graft material, both unmodified and precoated with fibronectin, type I collagen, or fibronectin and type I collagen (fibronectin/type I collagen). After 3 days of in vitro cultivation, endothelial cell production of prostacyclin, tissue plasminogen activator, and plasminogen activator inhibitor was evaluated under basal conditions and after stimulation with arachidonate or thrombin. Production of tissue plasminogen activator by endothelial cells cultured on fibronectin-ePTFE was significantly greater compared with production by endothelial cells grown on noncoated or fibronectin/type I collagen-ePTFE under basal conditions (p values less than 0.01 and less than 0.05, respectively) and in response to thrombin (p values less than 0.002 and less than 0.003, respectively). Plasminogen activator inhibitor-1 production was not detected in any of the four experimental groups. Endothelial cells cultured on fibronectin-ePTFE also synthesized significantly more prostacyclin than endothelial cells grown on type I collagen- or fibronectin/type I collagen-ePTFE, under basal conditions (p values less than 0.02 and less than 0.01, respectively) and in response to arachidonate (p values less than 0.03 and less than 0.002, respectively) and thrombin (p values less than 0.003 and less than 0.002, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Precoating expanded polytetrafluoroethylene grafts alters production of endothelial cell-derived thrombomodulators. 159 83

Plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of tissue-type plasminogen activator (t-PA) in plasma, is a serine proteinase inhibitor (serpin) that forms a 1:1 stoichiometric complex with its target proteinase leading to the formation of a stable inactive complex. The active, inhibitory form of PAI-1 spontaneously converts to a latent form that can be reactivated by protein denaturants. In the present study we have isolated another molecular form of intact PAI-1 that, in contrast with active PAI-1, does not form stable complexes with t-PA but is cleaved at the P1-P1' bond (Arg346-Met347). Other serine proteinases, e.g. urokinase-type plasminogen activator and thrombin, also cleaved this "substrate" form of PAI-1. Fluorescence spectroscopy revealed conformational differences between the latent, active, and substrate forms of PAI-1. This observation confirms our hypothesis that the three functionally different forms of PAI-1 are the consequence of conformational transitions. Thus PAI-1 may occur in three interconvertible conformations: latent, inhibitor, and substrate PAI-1. The identification of two distinct conformations of PAI-1 which interact with their target protease either as an inhibitor or as a substrate is a previously unrecognized phenomenon among the serpins. Conversion of substrate PAI-1 to its inactive degradation product may constitute a pathway for the physiological regulation of PAI-1 activity.
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PMID:Identification of a conformationally distinct form of plasminogen activator inhibitor-1, acting as a noninhibitory substrate for tissue-type plasminogen activator. 160 44

Widespread intravascular coagulation is common in patients with sepsis. Coagulation abnormalities may result from exposure to endotoxin, from tumor necrosis factor alpha or interleukin 1 release, or from the actions of a more specific mediator, such as vascular permeability factor. The result is marked activation of the contact and coagulation systems; simultaneously, there is decreased fibrinolysis and depressed levels of the inhibitors of the contact and coagulation systems. Multiple agents are being studied to correct these abnormalities. Antithrombin III holds promise because it inhibits a number of factors important in contact and coagulation activation, not just thrombin. Plasminogen activators may prove helpful in increasing fibrinolysis during sepsis; because they have been associated with rebound thrombin generation, however, plasminogen activators may be most effective if used in conjunction with hirudin or a synthetic hirudin analogue. Bradykinin may offset hypotension in sepsis. Protein C may inhibit thrombin formation and also complex with plasminogen activator inhibitor 1, thereby promoting fibrinolysis. Other agents that may prove effective include alpha 1-antitrypsin Pittsburgh, C1-esterase inhibitor, monoclonal antibodies to contact factors, soybean trypsin inhibitors, thrombomodulin, prostaglandin I2, and aprotinin. There are no data to support the use of heparin or fibronectin, except in limited circumstances.
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PMID:Modulators of coagulation. A critical appraisal of their role in sepsis. 162 18

Plasminogen activator inhibitor type 1 (PAI-1), the fast-acting inhibitor of tissue-type plasminogen activator (t-PA) and urokinase (u-PA), is a member of the serpin superfamily of proteins. Both in plasma and in the growth substratum of cultured endothelial cells, PAI-1 is associated with its binding protein vitronectin, resulting in a stabilization of active PAI-1. Recently, it has been demonstrated that the PAI-1-binding site on vitronectin is adjacent to a heparin-binding site (Preissner et al., 1990). Furthermore, it can be deduced that the amino acid residues, proposed to mediate heparin binding in the serpins antithrombin III and heparin cofactor II, are conserved in PAI-1. Consequently, here we have investigated whether PAI-1 also interacts with heparin. At pH 7.4, PAI-1 quantitatively binds to heparin-Sepharose and can be eluted with increasing [NaCl]. Binding of PAI-1 to heparin-Sepharose can be efficiently competed with heparin in solution (IC50, 7 microM). In the presence of heparin, the protease specificity of PAI-1 toward thrombin is substantially increased. This is shown by (i) quenching of thrombin activity of PAI-1 in the presence of heparin and (ii) induction of the formation of SDS-stable complexes between thrombin and PAI-1 by heparin. In a dose response curve, both effects reached a maximum at approximately 1 unit/mL and then diminished again upon further increasing the heparin concentration, strongly suggesting a template mechanism as an explanation for the observed effect. In contrast to vitronectin, heparin does not stabilize the active conformation of PAI-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional interaction of plasminogen activator inhibitor type 1 (PAI-1) and heparin. 170 36

Plasminogen activation on the cell surface is regulated by a variety of modulators which balance surface-bound plasminogen activators (PAs) and plasminogen activator inhibitors (PAIs). In this study, we developed as assay system to assess modulation of cell-associated plasminogen activation. Plasmin generation by endogenous plasminogen activators was measured with a combination of exogenously added plasminogen and a chromogenic substrate, S-2251, in the presence of living cells. A cell surface PA activity was quantitated by adopting a rate of plasmin generation. We used HT-1080, a human fibrosarcoma cell line, as representative of cells which have both PAs and PAIs on their cell surface. A basal level of cell surface PA activity was specifically reduced by anti-urokinase-type PA IgG and enhanced by anti-PAI-1 IgG, suggesting that the basal level is determined by a balance between uPA and PAI-1 on the cell surface. We examined effects of dexamethasone and thrombin on cell surface PA activity in the assay system. Dexamethasone appeared to suppress the cell surface PA activity by enhancing de novo synthesis of PAI-1, whereas thrombin suppressed it by inactivating single-chain urokinase-type plasminogen activators. These results indicate that our assay system can be adapted for the screening of various types of PA modulators.
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PMID:An assay system for the modulators of plasminogen activation on the cell surface. 189 67

Fluid cadaveric blood is generally known as a characteristic of sudden death. However, it has been reported that soft blood clots have been observed in a number of cases of sudden death after alcohol drinking. Such a tendency was also recognized on autopsy cases in our laboratory. This study was carried out to reveal the effects on clotting and fibrinolytic system in golden hamsters under acute alcohol intoxication. Furthermore, the influences of ether anaesthesia were also observed. Activities of clotting and fibrinolytic factors were measured with fluorogenic peptide substrate. Prothrombin and factor X activities began to decrease 1 hr after administration of alcohol. But thrombin-like and factor Xa-like activities significantly increased after 1 hr and then returned to the initial value 4 hr after administration. Plasminogen activity began to decrease 1 hr after administration, whereas plasmin-like and t-PA-like activities increased after 1 hr and returned to the initial values or decreased after 4 hr. These results show that under acute alcohol intoxication clotting and fibrinolytic factors (prothrombin, factor X and plasminogen) in golden hamsters were converted temporarily to their active forms (thrombin, factor Xa and plasmin). No influence of only ether anaesthesia on clotting and fibrinolytic activities was observed. At 1 hr after administration of alcohol some effects of ether anaesthesia on prothrombin, prekallikrein and kallikrein were observed and then were not observed after 4 hr. But it seems that the influence of ether anaesthesia on clotting and fibrinolytic activities was negligible in the process after alcohol consumption.
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PMID:[Clotting and fibrinolytic activities in acute alcoholic golden hamsters with or without ether anaesthesia]. 192 Sep 21

Plasminogen activator inhibitor activity and antigen were evaluated in plasma, serum and platelet lysate in patients with severe preeclampsia (n = 12), and in normal pregnant women (n = 21). Other parameters, including beta-thromboglobulin and platelet count, were also evaluated. A significant increase (p less than 0.05) in beta-thromboglobulin was observed in platelet poor plasma of preeclamptic women when compared with that of normal pregnant women, and the platelet count was lower in the preeclamptic group than in the normal pregnant group. A significant increase in plasminogen activator inhibitor activity and antigen was observed in platelet poor plasma of the preeclamptic group as compared with normal pregnant women, whereas platelet lysate from preeclamptic women showed a significant decrease in both plasminogen activator inhibitor activity and antigen as compared with that of normal pregnant women. No correlation between beta-thromboglobulin and plasminogen activator inhibitor type 1 antigen in platelet poor plasma was observed, but a significant inverse correlation (r = -0.78, p less than 0.05) between beta-thromboglobulin in platelet poor plasma and plasminogen activator inhibitor-1 antigen in platelet lysate was obtained in preeclamptic patients. However, in platelet poor plasmas obtained from normal platelet rich plasmas activated with thrombin (0.1 IU/ml, 37 degrees C, 1 min), an increase of about 300 ng/ml in beta-thromboglobulin was observed while the increase in plasminogen activator inhibitor was only 4 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of platelets to increased plasminogen activator inhibitor type 1 in severe preeclampsia. 214 18

Components of coagulation and fibrinolysis reactions were identified in situ by immunohistochemical staining in fresh frozen sections of small cell carcinoma of the lung tissue. Tumor cells stained positively for tissue factor, a protein that is capable of activating the extrinsic pathway of coagulation (the components of which have been seen within small cell carcinoma of the lung [SCCL] tissue), and for proteins C and S antigens. Fibrin was seen in a focal distribution at the host-tumor interface, indicating that thrombin had acted upon the fibrinogen found throughout the tumor stroma. Staining with a neoepitope-specific antibody, which does not discriminate between fibrinogen fragment D and fibrin fragment D-dimer, was similar to that of the fibrin antibody. High molecular weight urokinase-type and tissue-type plasminogen activators were seen in vascular endothelium, but neither existed within the tumor. Low molecular weight urokinase was found in rare isolated foci of tumor cells primarily adjacent to areas of necrosis. Plasminogen activator inhibitor-3 occurred in tumor cell cytoplasmic blebs and in necrotic tumor cells, but plasminogen activator inhibitors 1 and 2 were not seen. Our data suggest a mechanism for thrombin generation and fibrin formation within SCCL tissues that could support cell proliferation, stroma formation, and preservation. These features could be conductive to perpetuation of this tumor and conceivably could form the basis of the beneficial effects of antithrombotic therapy seen in SCCL.
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PMID:Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. 215 29

Patients with acute myeloid leukemia have multiple hemostatic and thrombotic complications, which may or may not result from disseminated intravascular coagulation. Previous studies incorporating routine coagulation analyses failed to detect any clinically useful information in most of these patients. In this study, the first comprehensive evaluation of the various aspects of the hemostatic system in a population of patients with acute myeloid leukemia was performed. Eighteen patients (23-71 years of age) were studied at either diagnosis or relapse. Hemostatic studies were performed at onset and on days 3, 7, and 30 after initiation of therapy. The bone marrow blast counts ranged from 8% to 98%; prothrombin time and activated partial thromboplastin time showed only minor prolongations in a few of these patients. However, in all patients measurement of platelet-associated markers revealed elevated platelet factor 4 and thromboxane B2 and normal 6-keto-prostaglandin F1 alpha levels. Fibrinolytic markers showed an increase in D-dimer and tissue plasminogen activator and a decrease in alpha 2-antiplasmin levels. Plasminogen, plasminogen activator inhibitor, and fibrinogen levels were normal. Coagulation markers demonstrated a decrease in protein C and antithrombin III levels and an elevation of the thrombin-antithrombin complex. The pretreatment values for all hemostatic markers studied were similar to the values obtained on days 3, 7, and 30 during treatment. This investigation demonstrated a subclinical activation of the components of the hemostatic system possibly leading to a hypercoagulable state. Although only six patients (33%) experienced hemorrhagic complications, the risk of bleeding and/or thrombosis was strongly evident in all patients. The significance of finding abnormal levels of specific molecular markers of hemostasis will be established in the future application of such markers in clinical evaluations of leukemic patients known to be at risk for coagulation disorders.
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PMID:Global and molecular hemostatic markers in acute myeloid leukemia. 222 Jun 67

Although the mechanisms involved in the pathophysiology of primary pulmonary hypertension have not yet been delineated, thrombosis has been implicated. This study was designed to determine whether thrombin activity as reflected by plasma concentrations of fibrinopeptide A (FPA), a marker of the action of thrombin on fibrinogen, is increased in patients with primary pulmonary hypertension. To evaluate fibrinolytic activity, we measured plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and cross-linked fibrin degradation products. We studied 31 patients with primary pulmonary hypertension. Plasma FPA concentrations measured by radioimmunoassay, were elevated to 87.4 +/- 36.9 ng/ml (mean +/- SEM). Fifteen minutes after administration of heparin (5,000 U), FPA concentrations decreased to 6.8 +/- 1.4 ng/ml (p less than 0.001 compared with preheparin levels). In 21 of 30 patients (70%), FPA concentrations after heparin administration were less than half the preheparin levels, a response consistent with inhibition of thrombin by heparin and the short half-life of FPA. Despite evidence for marked thrombin activity, plasma concentrations of cross-linked fibrin degradation products were normal in all but four patients. Plasminogen activator inhibitor-1 activity was elevated in 19 of the 27 patients in whom it was measured, potentially limiting the fibrinolytic response. The elevations of FPA indicate that thrombin activity is increased in vivo in patients with primary pulmonary hypertension. Thus, sequential assays of plasma markers of thrombosis and fibrinolysis in vivo may help identify those patients who may benefit from treatment with anticoagulants.
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PMID:Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. 239 5


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