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 plasma esterase inhibitors alpha2-macroglobulin, alpha1-antitrypsin, C1-inhibitor, antithrombin-heparin cofactor, and, as previously described, soybean trypsin inhibitor (Kunitz) and diisopropylphosphorofluoridate (9) enhance the response of guinea pig macrophages to migration inhibitory factor. To obtain this effect, macrophages are incubated with inhibitors prior to assay. The data suggest that (a) the enhancement of migration inhibitory factor response is due to the inhibition of esterases associated with the macrophage through a distinct active site on the inhibitors, and (b) that the active sites of antithrombin-heparin cofactor and soybean trypsin inhibitor, which interact with the macrophage enzymes, are different from the active sites of these inhibitors which interact with thrombin and trypsin respectively. Chemical modification of the active site of antithrombin-heparin cofactor for thrombin and of soybean trypsin inhibitor for trypsin does not affect their capacity to enhance the migration inhibitory factor response. From studies with thrombin, it was known that antithrombin-heparin cofactor has a heparin binding site. Addition of heparin was found to prevent the migration inhibitory factor-enhancing effect of antithrombin-heparin cofactor. The present results suggest that plasma esterase inhibitors may play a regulatory role in the response of macrophages to mediators of cellular immunity.
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PMID:Enhancement of migration inhibitory factor activity by plasma esterase inhibitors. 109 92

A highly purified factor XI (FXI) concentrate was prepared from human plasma by a process comprising a filter adsorption step and chromatography on a cation exchange resin. The freeze-dried FXI, which solubilized quickly, had high specific activity (130-150 U/mg protein), high potency (approx. 100 U/mL), and excellent stability for at least 24 hours at room temperature in the liquid state. The overall recovery was about 220 U of FXI per liter of plasma. Minor protein contaminants (C1-inhibitor, fibronectin, IgG, and alpha-2-macroglobulin) were found to be between 0.13 and 0.46 mg per 1000 U of FXI. Fibrinogen and relevant coagulation factors (factors II, V, VII, IX, X, XII, XIII, and VIII/von Willebrand factor) were undetectable, as evidenced by immunologic and immunoelectrophoretic data. Components of the kinin system were present in trace amounts or were undetectable. No evidence of activated factors such as factors Xa and IXa was found. Proteolytic activity, as assessed by S-2288 chromogenic substrate, was negligible and thrombin was undetectable. A solvent-detergent treatment was included prior to chromatographic purification to enhance viral safety against lipid-enveloped viruses. In vitro and in vivo animal studies demonstrated the absence of thrombogenic, hypotensive, or toxic effects. No thrombogenic activity was found in the Wessler model in rabbits at doses of 900 to 1100 U of FXI per kg of body weight. This FXI preparation could be beneficial in substitution therapy of congenital or acquired FXI deficiency, especially as a way to avoid the use of fresh-frozen plasma.
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PMID:A therapeutic, highly purified factor XI concentrate from human plasma. 147 Dec 51

The effect of burn wound size on the activation of fibrinolysis, coagulation, and contact factors was analyzed in 60 thermal injury patients. Blood samples from 47 male patients and 13 female patients, (average age 37 years; range 1.5-70 years) were collected within the first 36 hours and at 5-7 days following injury. The patient population was categorized by percentage of burn (second degree and/or third degree): less than 20%, n = 22; 20%-40%, n = 18; greater than 40%, n = 20. The average percentage of burn was 32% (range, 4%-95%). The mechanism of injury was by flame (25), explosion and flame (19), scald (12), electric (3), or chemicals (1). An associated inhalation injury was present in 12 patients. The overall mortality rate was 13% (8). Sepsis or serious infection occurred in 23% (14) of the patients. On admission, 83% of the patients had normal prothrombin times (PT) and activated partial thromboplastin times (APTT). However, specific hemostatic variables showed marked changes. Admission hemostatic markers that correlated with the severity of injury were: tissue-plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimer (D-di), plasminogen (Plg), proteins C and S (PrC and PrS), antithrombin III (ATIII), thrombin-antithrombin complex (TAT), kallikrein (Kal:c), kinin (Kin), C1 esterase inhibitor (C1Inh), and factor VII clotting and antigen (FVII:c, FVII:ag). These data suggest that during the early course following burn injury, thrombogenicity is increased (TAT increases) because of a decrease in ATIII, PrC, and PrS; and fibrinolysis activation (D-di increases) occurs via an increase in tPA with a p value increase in PAI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state. 163 6

High and low molecular weight kininogens (HK and LK) are able to bind to platelets to inhibit thrombin binding to and activation of platelets. The heavy chain domain on the kininogens that contains these functions has been determined. Domain 3 (D3) but not domains 1 or 2, completely inhibited 125I-HK binding to platelets (Ki = 24 +/- 7 nM, n = 4). 125I-D3 specifically bound to unstimulated platelets and human umbilical vein endothelial cells. On platelets, it was blocked by unlabeled D3 and HK but not prekallikrein, factor XII, C1s, or C1 inhibitor. Further, one monoclonal antibody (HKH13) directed to kininogens' D3 blocked 125I-HK and 125I-D3 binding to platelets. The binding of 125I-D3 to platelets was fully reversible by addition of 35 molar excess of unlabeled D3. D3 binding to platelets was saturable with an apparent Kd of 39 +/- 8 nM (n = 4) and 1227 +/- 404 binding sites/platelet. D3, like HK and LK, inhibited thrombin-induced platelet activation by preventing thrombin binding to platelets. Another monoclonal antibody (HKH12), directed to D3, which did not block HK binding to platelets, reduced HK's ability to inhibit 125I-alpha-thrombin binding. This result suggests that the region on D3 that inhibits 125I-alpha-thrombin binding to platelets is different from that which directly binds to platelets. These studies indicate that D3 of the kininogens contains both a binding region for platelets and endothelial cells and another region that inhibits thrombin-induced platelet activation.
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PMID:Domain 3 of kininogens contains a cell-binding site and a site that modifies thrombin activation of platelets. 174 Apr 22

Few data are available on the pathophysiology of the coagulation system during aortic surgery. Cross-clamping of the aorta, intestinal eventeration and circulatory shock in ruptured aortic aneurysms are thought to cause coagulation disturbances and hyperfibrinolysis. A prospective study of several parameters of the clotting system, i.e. standard clotting tests, platelet count, indicators of fibrinolysis, inhibitors of the clotting cascade and proteases were measured perioperatively in aortobifemoral bypass grafts. Ten patients undergoing elective procedures and two emergency cases with ruptured aortic aneurysms were included. The standard clotting tests reflected the use of heparin. A similar course of ATIII, C1-inhibitor, alpha 2-antiplasmin, plasminogen and fibrinogen with a decrease during the operation and a return to almost normal values postoperatively, were due to intra-operative blood loss, haemodilution and a slight activation of the clotting cascade, as well as, hyperfibrinolysis. This observation was supported by the increased levels of euglobulin lysis and PMN-elastase and the resultant increase in some fibrinogen degradation products, indicating non-specific proteolysis. These changes were more pronounced in the two emergency cases, except for the heparin induced changes in PTT and thrombin time. It is concluded that non-specific proteolysis may be an important factor in the pathogenesis of clotting disorders in surgery of the aorta. Further research is needed to discover the pathways of non-specific proteolysis and its prevention by protease inhibitors.
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PMID:Coagulation in aortofemoral bifurcation bypass grafting. 186 90

Orthotopic liver transplantation is frequently associated with a complex coagulation disorder, influencing the outcome of the procedure. In this respect, disseminated intravascular coagulation (DIC) had been suggested to be of causative importance for bleeding complications after reperfusion of the liver graft. In 10 consecutive patients undergoing orthotopic liver transplantations, we studied the occurrence of two phagocyte proteinases of different origin in the graft liver perfusate and in systemic blood during the operation, as well as their effects on hemostasis. As compared with plasma samples taken at the end of the anhepatic phase, highly significant increases of cathepsin B and thrombin-anti-thrombin III complexes (TAT), as well as highly significant decreases in antithrombin III, protein C, and C1-inhibitor were observed in graft liver perfusate. Von Willebrand factor and fibrinogen were slightly decreased, whereas the elastase-alpha 1 proteinase inhibitor complexes (EPI) were elevated. In plasma the activity of cathepsin B remained unchanged during the prereperfusion phases, but immediately after revascularization of the graft this cysteine proteinase increased. The EPI showed a gradual increase in plasma during the preanhepatic and anhepatic phases but a more pronounced increase in the reperfusion phase. In parallel with the rise in these two proteinases TAT increased and the activities of antithrombin III and C1-inhibitor in plasma decreased after reperfusion. At 12 hr after revascularization plasma levels of TAT, antithrombin III, and C1-inhibitor had returned to the prereperfusion ranges, whereas cathepsin B and EPI were significantly above the baseline levels. These observations are consistent with the hypothesis that extracellularly released lysosomal proteinases may play a role in the development of a DIC-like constellation, including thrombin formation after revascularization of the liver graft. For the first time we could prove the occurrence of phagocyte proteinases in graft liver perfusate and evaluate the importance of these proteinases for the understanding of the pathophysiology leading to bleeding complications in patients undergoing orthotopic liver transplantation.
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PMID:Possible role of extracellularly released phagocyte proteinases in coagulation disorder during liver transplantation. 189 20

Formation of the covalently stabilized complex of alpha 1-antitrypsin (alpha 1-AT) with neutrophil elastase, the archetype of serine proteinase inhibitor serpin-enzyme complexes, is associated with structural rearrangement of the alpha 1-AT molecule and hydrolysis of a reactive-site peptide bond. An approximately 4-kDa carboxyl-terminal cleavage fragment is generated. alpha 1-AT-elastase complexes are biologically active, possessing chemotactic activity and mediating increases in expression of the alpha 1-AT gene in human monocytes and macrophages. This suggested that structural rearrangement of the alpha 1-AT molecule, during formation of a complex with elastase, exposes a domain that is recognized by a specific cell surface receptor or receptors. To test this hypothesis, the known three-dimensional structure of alpha 1-AT and comparisons of the primary structures of the serpins were used to select a potentially exteriorly exposed and highly conserved region in the complexed form of alpha 1-AT as a candidate ligand (carboxyl-terminal fragment, amino acids 359-374). We show here that synthetic peptides based on the sequence of this region bind specifically and saturably to human hepatoma cells and human monocytes (Kd = 4.0 X 10(-8) M, 4.5 X 10(5) plasma membrane receptors per cell) and mediate increases in synthesis of alpha 1-AT. Binding of peptide 105Y (Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val-Tyr-Leu-Ile) is blocked by alpha 1-AT-elastase complexes, antithrombin III (AT III)-thrombin complexes, alpha 1-antichymotrypsin (alpha 1-ACT)-cathepsin G complexes, and, to a lesser extent, complement component C1 inhibitor-C1s complexes, but not by the corresponding native proteins. Binding of peptide 105Y is also blocked by peptides with sequence corresponding to carboxy-terminal fragments of the serpins AT III and alpha 1-ACT, but not by peptides having the sequence of the extreme amino terminus of alpha 1-AT. The results also show that peptide 105Y inhibits binding of 125I-labeled alpha 1-AT-elastase complexes. Thus, these studies demonstrate an abundant, relatively high-affinity cell surface receptor which recognizes serpin-enzyme complexes (SEC receptor). This receptor is capable of modulating the production of at least one of the serpins, alpha 1-AT. Since the ligand specificity is similar to that previously described for in vivo clearance of serpin-enzyme complexes, the SEC receptor may also be involved in the clearance of certain serpin-enzyme complexes.
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PMID:Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes. 216 76

Plasminogen activators (PA) in the euglobulin fraction of dextran sulfate activated plasma (DS-EF) were assayed on fibrin plates. Activity related to tissue plasminogen activator (t-PA) or urokinase (u-PA) was quantified by antiserum inhibition. The DS-EF contained 30% t-PA, 30% u-PA and 40-50% activity unrelated to t-PA or u-PA. The latter was completely inhibited by 1.7 mumol/1 C1-inhibitor (C1INH), the two former were less sensitive. Addition of flufenamate to the DS-EF (DS-EF/Fluf) from normal and two factor XII (F XII)-deficient plasmas increased their activities to the same high level. More than 50% of the activity was unrelated to t-PA or u-PA, 30-40% was u-PA and 5-10% t-PA related. After addition of fibrinogen to DS-EF/Fluf and clotting with thrombin, the remaining solution contained only about 30% of the total activity, including less than 10% u-PA. The epsilon-aminocaproic acid inhibition pattern obtained with the DS-EF was uniform, and thus different from the biphasic pattern obtained with the low fibrin affinity PA, two-chain urokinase. Thus, both the plasma u-PA and the major unidentified PA in plasma have affinity for fibrin.
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PMID:Assay characteristics and fibrin affinity of plasminogen activators of the intrinsic fibrinolytic system. 242 31

Since intravascular and endoparietal fibrin deposition is thought to be involved in the development of atherosclerosis, we measured factor XIII activity and its subunit 'a' and 'b' concentrations against a background of other haemostasis parameters in diabetics with angiopathy and in 2 control groups (healthy subjects and diabetics without vascular complications). Diabetics with angiopathy revealed a significant increase of factor XIII activity as well as its subunit concentrations. They also had significantly elevated anti-thrombin III, alpha 2 macroglobulin, alpha 1 antitrypsin, C1 inhibitor, fibrinogen, FDP concentrations and prolongation of euglobulin lysis time. The highest factor XIII levels were found in diabetics with renal failure. We suppose that increased factor XIII level and other observed changes of haemostasis in patients with diabetic angiopathy might promote intravascular and endoparietal fibrin deposition and contribute to the development of atherosclerotic complications of diabetes.
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PMID:Plasma factor XIII and some other haemostasis parameters in patients with diabetic angiopathy. 243 83

Oxidative inactivation of alpha-1-proteinase inhibitor (A1-P1) and plasminogen activator inhibitor-1 (PAI-1), both members of the serine protease inhibitor (serpin) superfamily, using mild oxidation conditions has been already demonstrated. The oxidation mechanism has been shown to involve conversion of methionine to methionine sulfoxide in the reactive center of the inhibitors. In this study evidence is presented that alpha-2-antiplasmin (A2-PI) and antithrombin III (AT III) can also be inactivated by means of oxidation. For total inactivation of 50 pM A1-PI about 10 nM chloramine T (CT) and for the same molar concentration of A2-PI and AT III about 250 nM CT were found necessary. C1-inhibitor (C1-INH) showed some resistance to oxidation that could be overcome only by increasing CT to an amount (greater than 2000 nM) already beginning to inactivate the corresponding C1-esterase. As target enzymes for A2-PI, AT III, and A1-PI plasmin, thrombin and elastase, respectively, were used. Their activity was not impaired by the oxidation conditions applied. As there is no methionine in the reactive center of AT III an additional mechanism for oxidative inactivation of serpins has to be taken into consideration. Oxidation seems to be a general mechanism for altering the balances between serine proteases and their inhibitors in favour of the protease.
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PMID:Oxidative inactivation of purified human alpha-2-antiplasmin, antithrombin III, and C1-inhibitor. 245 61


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