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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Z-D-Phe-Pro-boroMpg-OPin (9a)1,2 has been shown previously to be a highly specific inhibitor of thrombin in spite of lacking an arginine-like guanidino group at the P1 site. A range of compounds have been synthesized based upon this lead compound, varying the neutral side chain at the P1 site. Of the 20 examples based upon the structures at P2 and P3 of Z-D-X-Pro (X being Phe or beta,beta-diphenylalanine), all were found to be effective inhibitors of thrombin (Ki's between 10 and 100 nM). Furthermore all exhibited a high specificity toward thrombin having values for a Ki(trypsin)/Ki(thrombin) ratio of between 10- and 100-fold. High ratio values were found for a number of the compounds tested against a range of serine proteinases (plasmin, factor Xa, kallikrein, urokinase, protein Ca, chymotrypsin, elastase, and cathepsin G). As far as potency toward thrombin, compounds containing the methoxypropyl group at P1 were favored over those with a methoxy grouping on a shorter alkyl chain (8) or without the methoxy group (1-5). The compounds display potent anticoagulant activity with values for 18 in thrombin time of 0.63 microM and in activated partial thromboplastin time of 2.0 microM. 11B NMR has been used to confirm interaction of the boron atom with the active site. From the high specificity shown with all the compounds we propose that the compounds, constitute a new class of thrombin inhibitors.
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PMID:Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin. 773 10

In patients with liver cirrhosis a decrease of the coagulant potential is well-documented and has been linked to the high bleeding tendency among these patients. Whether the decrease of the coagulant potential is only due to a reduced hepatic synthesis of coagulation factors or also to its consumption by disseminated intravascular coagulation is debatable. We investigated hemostasis activation markers thrombin-antithrombin III complexes (TAT), fibrin degradation products (D-Dimer) and plasmin-alpha 2-antiplasmin complexes (PAP) in 41 outpatients with liver cirrhosis (Child-Pugh index 1 n = 18, 2 n = 15, 3 n = 8). Compared to controls similar in terms of age and sex, TAT, D-Dimer and PAP was elevated in the whole group of patients. A progressive increase of D-Dimer and PAP from Child 1 to 3 indicates a relationship between the severity of cirrhosis and the amount of hemostasis activation. Investigation of the natural anticoagulant potential showed significant decreases of antithrombin III (AT III), protein C, and protein S, most pronounced in Child 3 patients. Statistical analysis revealed significant negative correlations between levels of D-Dimer and both AT III and protein C, indicating that hemostasis activation is linked to the loss of anticoagulant potential.
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PMID:Hemostasis activation in patients with liver cirrhosis. 774 May 19

Plasma thrombin-antithrombin III complex (TAT), FDP-D-dimer, activated protein C (APC)-protein C inhibitor (PCI) complex, and tissue type plasminogen activator (t-PA), PA inhibitor-1 (PAI-I) were significantly increased in patients with acute myocardial infarction (AMI) at onset. These patients exhibited a hypercoagulable state and protein C activation at onset. The plasma PCI level at onset of AMI was within the normal range, but was significantly decreased after percutaneous transluminal coronary angioplasty (PTCA). After PTCA, plasma t-PA, FDP-D-dimer, and plasmin-alpha 2-plasmin inhibitor were increased but APC-PCI complex and TAT were not. The decrease in PCI after PTCA may have been caused by the activation of fibrinolysis. PCI may play an important role in the inhibition of fibrinolysis in stimulated or damaged endothelial cells. These findings suggest that the protein C pathway plays an important role in the onset of AMI and after PTCA.
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PMID:Decreased protein C inhibitor after percutaneous transluminal coronary angioplasty in patients with acute myocardial infarction. 774 Nov 29

The carbohydrate deficient glycoprotein (CDG) syndrome is a newly described disorder characterized by impaired glycosylated molecules. It has been reported that transient stroke-like episodes appear in half of the patients. We performed hemostatic studies on three CDG syndrome patients belonging to two unrelated families. The most characteristic findings were decreases in antithrombin III (AT III), protein C and alpha 2 plasmin inhibitor to nearly half normal levels. Protein S was reduced in two (siblings) patients. Isoelectric focusing of AT III in native plasma revealed decreased intensity of the major band and increased intensity of a minor cathodal band. These minor AT III molecules were considered to lack an oligosaccharide sidechain. A 12-year-old girl defective not only for AT III but also protein C and protein S developed disseminated intravascular coagulation accompanied by arterial thrombosis in her left hand following dyspnea associated with bronchial asthma. These findings suggest that thrombotic predisposition in patients with CDG syndrome is due to decreased levels of major coagulation inhibitors, particularly as a result of impaired glycosylation of AT III.
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PMID:Hemostatic studies in patients with carbohydrate-deficient glycoprotein syndrome. 786 68

The observation that urokinase infusion increases circulating levels of the anticoagulant activated protein C (APC) in baboons implies that APC might be elevated during thrombolytic therapy. Patients undergoing coronary thrombolysis showed an 11-fold increase (means from 6 to 69 micrograms/L) in APC during infusion of streptokinase. Thrombolytic therapy thus generates at least two potent antithrombotic factors in the circulation--the fibrinolytic enzyme, plasmin, and the anticoagulant enzyme, APC. APC may help prevent reocclusion during or after thrombolysis.
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PMID:Generation of activated protein C during thrombolysis. 790 87

Selected coagulation and fibrinolytic factors were evaluated in plasma and synovial fluid (SF) of 10 rheumatoid arthritis (RA) patients. Increased levels of fibrinogen were observed in plasma (p < 0.01), but only a trace amount of structurally intact fibrinogen was detected in the SF of RA patients, while immunostaining showed deposits of insoluble fibrin in their synovial membranes. Reduced levels of protein C, antithrombin III and coagulation factors II, V, VII, VIII, IX, XII and XIII (p < 0.01), and high levels of thrombin-antithrombin III (TAT) complexes (p < 0.01), were found in SF as compared to their corresponding plasma levels. The increased levels of fibrinogen, TAT complexes, B beta 15-42 peptide and plasminogen activator inhibitor-1 (PAI-1) in plasma (p < 0.01) are consistent with an enhanced fibrin turnover and endothelial perturbation due to a systemic inflammatory state. Plasminogen and alpha 2-plasmin inhibitor activity in SF were significantly reduced as compared to the plasma levels (p < 0.01), whereas an increase in PAI-1 activity was found in SF as compared to plasma (p < 0.01). The detection of D-dimer and B beta 15-42 peptide (p < 0.01) in SF suggests an involvement of plasmin in the degradation of fibrin generated in synovial tissue. The high levels of elastase-alpha 1-proteinase inhibitor complexes and of thrombin-increasable fibrinopeptide A, as well as the pattern of fibrinogen degradation as identified in SF by double-dimension immunoelectrophoresis, suggest that elastase released from exudated granulocytes may play an important role in fibrino(geno)lysis and tissue damage in RA joints.
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PMID:Elastase- and plasmin-mediated fibrinolysis in rheumatoid arthritis. 796 May 5

Because fibrin is commonly observed within arthritic joints, studies were undertaken to determine whether purified coagulation and fibrinolytic proteases degrade cartilage in vitro and to seek evidence for the activation of coagulation in arthritic joints through measurements of the levels of inhibitor-enzyme complexes and several other proteins associated with coagulation and fibrinolysis. The concentrations of 13 plasma proteins and complexes of thrombin and Factor Xa with antithrombin III were measured in synovial fluids recovered at the time of knee replacement surgery. All zymogens necessary to constitute the coagulation cascade were present. Thrombin and the combination of prothrombin plus prothrombinase induced proteoglycan release from both normal and arthritic cartilages. Factor Xa and plasmin induced release from diseased cartilage only, and urokinase, tissue plasminogen activator, and activated protein C were without effect at the levels used. At saturating levels of thrombin (> or = 2.0 microM) 80% of the proteoglycan content of normal cartilage was released within 24 h. Thrombin, which is cationic, reversibly binds cartilage with Kd = 7.0 +/- 1.0 microM and Bmax = 820 +/- 70 ng/mg of human cartilage. Levels of thrombin-antithrombin III complexes in synovial fluids and arthritis were 4-fold higher in osteo (OA) and 43-fold higher in rheumatoid (RA) than in controls (0.98 nM). Factor Xa-antithrombin III complex levels were threefold lower in OA and fivefold higher in RA than in controls (0.24 nM). These elevated levels of enzyme-inhibitor complexes imply a history of activation of coagulation within the joint, especially in RA. Since thrombin degrades cartilage in vitro and had been generated in vivo, as inferred by the existence of thrombin-antithrombin III complexes, intraarticular activation of coagulation may both contribute to the pathology of arthritis and comprise a target for therapy and diagnosis.
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PMID:Studies of thrombin-induced proteoglycan release in the degradation of human and bovine cartilage. 804 Mar

Activated protein C (APC)-protein C inhibitor (PCI) complex and APC-alpha 1antitrypsin (alpha 1AT) complex levels were measured in 29 patients positive for lupus anticoagulant (LA). LA was considered positive if two of the following three criteria were fulfilled: (1) prolongation of the activated partial thromboplastin time, (2) prolongation of the kaolin clotting time (KCT) and KCT mixing test, and (3) prolongation of the dilute Russell's viper venom time (DRVVT) and DRVVT/DRVVT with high lipid concentration. Plasma thrombin-antithrombin III (AT-III) complex and plasmin-alpha 2-antiplasmin inhibitor complex levels in patients positive for LA were increased slightly, but not significantly, and FDP-D-dimer and t-PA levels were not markedly increased. Plasma PAI-1 level in the LA-positive patients was significantly increased compared with normal volunteers. AT-III activity, protein C antigen, PCI antigen, and protein S antigen levels in the LA-positive patients were virtually normal, while protein C activity was slightly, but not significantly, decreased. APC-PCI complex level was increased in all LA-positive patients, and was not detectable in patients with systemic lupus erythematosus and normal volunteers. APC-alpha 1AT complex was increased slightly, in only two LA-positive patients; it was not detectable in the other patients or in the normal volunteers. These findings suggest that patients positive for LA are in a hypercoagulable state and that protein C activity in such patients is decreased, due to the activation of this protein.
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PMID:Increased activated protein C-protein C inhibitor complex level in patients positive for lupus anticoagulant. 805 49

The effects of coronary thrombolytic therapy with urokinase on the intrinsic hemostatic and fibrinolytic states were investigated by determining several markers for hemostatic and fibrinolytic activities in 6 patients with acute myocardial infarction who underwent coronary thrombolysis with urokinase. The markers for hemostasis and fibrinolysis were: markers for plasmin generation [alpha 2-plasmin inhibitor (alpha 2-PI), plasminogen, plasmin alpha 2-PI complex (PIC)]; markers for fibrinolysis [fibrin/fibrinogen degradation products-E fragment (FDP-E), FDP D-D dimer (D dimer), fibrinogen]; markers for hemostatic activity (prothrombin time (PT), antithrombin III (AT-III), protein C); markers for thrombin generation [thrombin antithrombin III complex (TAT)]; markers for intrinsic fibrinolytic activity [tissue plasminogen activator plasminogen activator inhibitor complex (TPA PAI complex)]. These markers were measured before, at 1 to 2 hours intervals during first 6 hours, daily during the next 3 days, and subsequently on the 7th and the 14th day after urokinase therapy. Fibrinolysis (determined by increased D dimer) occurred only when alpha 2-PI became unmeasurable with 96 x 10(4) or more units of urokinase administration, then persisted for more than 2 hours. TAT increased from 13.1 +/- 15.4 to 70.8 +/- 65.8 ng/ml soon after fibrinolysis occurred, indicating that thrombin generation occurred at the same time as fibrinolysis. The TPA PAI complex level before urokinase administration (26.4 +/- 6.4 ng/ml) was greater than the normal upper limit, indicating increased intrinsic fibrinolytic activity, then decreased after urokinase administration. These findings suggested that urokinase administration might affect the intrinsic fibrinolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Serial changes in hemostatic and fibrinolytic states induced by coronary thrombolytic therapy]. 806 82

Potent active-site inhibitors of human tissue factor-Factor VIIa (TF.FVIIa) have been selected from Alzheimer's amyloid beta-protein precursor inhibitor (APPI) Kunitz domain libraries displayed on phage. Eight randomized positions on the extended primary binding loop (P5 through P4') and positions 34 and 39 were examined in three separate libraries. Libraries contained from 3.2 x 10(5) to 3.2 x 10(6) potential variants resulting from replacing up to 5 positions with all 20 amino acids. Following 4 rounds of selection against FVIIa associated with immobilized tissue factor (TF), 12 clones from each library were sequenced. Variants were purified by trypsin affinity chromatography and reverse-phase high performance liquid chromatography, and characterized for their ability to inhibit TF.FVIIa chromogenic activity. Measured apparent equilibrium dissociation constants (Ki*) ranged from about 10 to 500 nM. From sequence and activity data, an overall consensus sequence, TF7I-C, was constructed by site-directed mutagenesis. TF7I-C differed from APPI at 4 key residues, T11P, M17L, S19L, and G39Y, and inhibited TF.FVIIa with a Ki* = 1.9 +/- 0.4 nM, which represented an increase in binding affinity of more than 150-fold compared to APPI. At 40 microM, TF7I-C prolonged the clotting times 3.5-fold in a prothrombin time assay and > 10-fold at 7 microM in an activated partial thromboplastin time assay. Prolongation of the activated partial thromboplastin time correlates with potent inhibition of FXIa (Ki* = 0.8 nM) and plasma kallikrein (Ki* = 1.2 nM). TF7I-C also inhibited plasmin (Ki* = 40 nM) and FXa (Ki* = 55 nM), but not activated protein C, thrombin, or FXIIa (Ki* > 10 microM each).
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PMID:Kunitz domain inhibitors of tissue factor-factor VIIa. I. Potent inhibitors selected from libraries by phage display. 807 37


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