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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A sulfated polysaccharide fraction, obtained from the hot-water extract of the brown seaweed, Ecklonia kurome by removing laminaran and the major part of alginic acid, gave sulfated polysaccharides (B-I, B-II, C-I, and C-II) by both anion-exchange chromatography on a column of Ecteola-cellulose and by fractional precipitation with ethanol containing 0.3% calcium acetate, and then by gel-filtration chromatography on a Sepharose 4B column. B-I and B-II are composed of fucose, galactose, mannose, xylose, glucuronic acid, and ester sulfate in the approximate molar ratios of 1.00:0.36:0.48:1.08:1.85:2.35 and 1.00:0.81:0.18:0.45:0.61:2.00, respectively. C-I and C-II are composed of fucose, galactose, glucuronic acid, and ester sulfate in approximate molar ratios of 1.00:0.03:0.03:1.61 and 1.00:0.19:0.07:1.48, respectively. Blood-anticoagulant activities with respect to activated partial thromboplastin time (APTT) were approximately 24, 19, 81, and 85% of that of heparin for B-I, B-II, C-I, and C-II, respectively. All the polysaccharides showed slight antithrombin activity. No antifactor Xa activity was observed for any of the polysaccharides.
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PMID:Isolation, purification, and characterization of fucose-containing sulfated polysaccharides from the brown seaweed Ecklonia kurome and their blood-anticoagulant activities. 272 Jul 2

Synthetic peptides based on the COOH-terminal 21 residues of hirudin were prepared in order to 1) evaluate the role of this segment in hirudin action toward thrombin, 2) define the shortest peptide derivative with anticoagulant activity, and 3) investigate the role of tyrosine sulfation in the peptides' inhibitory activities. A hirudin derivative of 20 amino acids, Hir45-64 (derived from residues 45-64 of the hirudin polypeptide), was found to effect a dose-dependent increase in the activated partial thromboplastin time (APTT) of normal human plasma but to have no measurable inhibitory activity toward thrombin cleavage of a tripeptidyl p-nitroanilide substrate. Anticoagulant activity in hirudin derivatives was comparable in peptides of 20, 16, and 12 residues truncated from the NH2 terminus. Additional truncated peptides prepared by synthesis and carboxypeptidase treatment reveal that the minimal sequence of a hirudin peptide fragment with maximal anticoagulant activity is contained within the sequence: NH2-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-COOH. The 12-residue derivative thus identified was reacted with dicyclohexylcarbodiimide in the presence of sulfuric acid to yield a Tyr-sulfated peptide, S-Hir53-64. By comparison to unsulfated peptide, S-Hir53-64 was found to contain a specific inhibitory activity enhanced by one order of magnitude toward increase in APTT and to effect a dose-dependent increase in thrombin time of normal human plasma to yield a 4-fold increase in thrombin time with 2.5 micrograms/ml peptide using 0.8 units/ml alpha-thrombin. Comparison of S-Hir53-64 to hirudin in thrombin time and APTT assays reveals a 50-fold difference in molar specific activities toward inhibition of thrombin. Comparison of antithrombin activities of S-Hir53-64 using a variety of animal thrombins demonstrates greatest inhibitory activity toward murine, rat, and human enzymes and a 10-fold reduced activity toward bovine thrombin.
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PMID:Anticoagulant activity of synthetic hirudin peptides. 272 94

Gram-negative septicemia/endotoxemia remains a serious clinical disorder that is often complicated by disseminated intravascular coagulation (DIC). Plasma antithrombin-III (AT-III) levels usually decrease during gram-negative septicemia/endotoxemia, and even moderate decreases in this major inhibitor of the coagulation system are associated with serious DIC. We demonstrated in an earlier study that prophylactic treatment of rats with 250 U/kg of AT-III followed by endotoxin challenge markedly attenuates DIC, indices of organ damage, and metabolic dysfunction. The present study was to determine whether treatment with 250 U/kg AT-III 1 hr after endotoxin challenge would be similarly efficacious. Rats treated with 250 U/kg of AT-III inactivated by human sputum elastase (ATX) served as protein controls. Blood samples for analysis were obtained 4 hr after AT-III or ATX treatment (5 hr after endotoxin challenge). Rats in the ATX treatment group exhibited abnormalities characteristic of endotoxemia, i.e., decreased fibrinogen levels and platelet counts, increases in prothrombin time and activated partial thromboplastin time, elevated serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase (AKP), and hypoglycemia. Treatment with AT-III markedly and significantly (P less than .05) attenuated all of these abnormalities, although survival was not increased. This study strongly suggests that supplementation of plasma AT-III is efficacious after the development of sepsis, although not as efficacious as prophylactic treatment.
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PMID:Antithrombin-III treatment limits disseminated intravascular coagulation in endotoxemia. 273 21

Size homogeneous heparin oligosaccharides were prepared from nitrous acid depolymerized heparin by means of repeated gel filtration chromatography. These oligosaccharides were then further separated with respect to affinity for antithrombin by means of affinity chromatography. All the high-affinity oligosaccharides thus obtained had a strong ability to potentiate factor Xa inhibition while their ability to inhibit factor IIa abruptly dropped below a chain length of 20 monosaccharides. In a rabbit stasis model, high-affinity oligosaccharides below a chain length of 20 units also showed a continuous decrease in antithrombotic effect with increasing degree of depolymerization. However, there was no distinct drop paralleling the thrombin inhibiting capacity. Low-affinity oligosaccharides also exhibited a weak antithrombotic effect, although they did not always contribute to an increased anti-factor Xa activity ex vivo. This was the case whether or not they were administered alone or in combination with high-affinity oligosaccharides. Low-affinity oligosaccharides may therefore exert an antithrombotic effect per se with a mechanism of action that is independent of antithrombin III.
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PMID:Antithrombotic effects of heparin oligosaccharides. 273 63

Abnormal antithrombin III (AT III) was found in the plasma of a 31-year-old female who suffered from recurrent thrombotic episodes. Heparin cofactor activity was 28% of normal and undetectable when measured by inhibition of thrombin and factor Xa (F.Xa), while both progressive antithrombin and antifactor Xa activities were normal. The concentration of plasma AT III antigen was 37 mg/dl. Analysis by crossed-immunoelectrophoresis (CIE) in the presence of heparin and affinity chromatography on heparin-Sepharose revealed that the propositus' AT III did not bind to heparin. When heparin cofactor II (HC II) was removed from propositus' plasma, heparin cofactor activity of AT III was not detected. Thus, HC II seemed to account for the plasma heparin cofactor activity found in the presence of thrombin. The patient's parents and three of her brothers demonstrated qualitative abnormality of AT III; heparin cofactor activity was 30-50% of normal levels in the presence of both thrombin and F.Xa. These findings indicate that the propositus' AT III lacks affinity for heparin and the mode of its inheritance seems to be autosomal dominant and, hence, the propositus would be a homozygote. For this variant, the name of AT III Kumamoto is proposed.
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PMID:Homozygous variant of antithrombin III that lacks affinity for heparin, AT III Kumamoto. 274 90

Addition of prothrombin to mouse peritoneal macrophages in vitro resulted in the formation of a thrombin-like enzyme, as demonstrated by use of the luminogenic peptide substrate S-2621. The prothrombinase activity was sedimented by high-speed centrifugation following homogenization of the cells and was abolished by treatment of the cells with the nonionic detergent Triton X-100 at 0.02% concentration. Moreover, the activity was drastically reduced by maintaining cultures in the presence of warfarin and, presumably due to competitive substrate inhibition, by adding S-2222, a chromogenic peptide substrate for Factor Xa. These findings suggest that prothrombin cleavage is catalyzed by Factor Xa at the macrophage surface. The generated thrombin was inhibited by antithrombin, and this reaction was accelerated by heparin with high affinity for antithrombin but not by the corresponding oligosaccharides composed of 8-14 monosaccharide units. Such oligosaccharides which are capable of accelerating the inactivation of Factor Xa by antithrombin, inhibited thrombin formation from prothrombin in the macrophage cultures, presumably by promoting inactivation by antithrombin of Factor Xa in a prothrombinase complex. Activation of the macrophage coagulation system, as proposed to occur in certain inflammatory conditions, thus may be modulated at various levels by heparin, or heparin oligosaccharides, released from mast cells.
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PMID:A prothrombinase complex of mouse peritoneal macrophages. 275 91

Two synthetic substrate assays (fluorometric and chromogenic) were used to measure antithrombin-III (AT-III) activity (residual thrombin activity) in non-medicated and heparin (sodium) treated horses. In 18 non-medicated horses the fluorometric substrate assay (FSA) values were similar to previous reports but they reflected inconsistent trends and larger deviations in the heparin-treated groups (Group 2: 40 and 100 U/kg IV, n = 6; Group 3: 240 U/kg IV, n = 5; Group 4: 80 U/kg IV followed by 160 U/kg SC, n = 8) when compared to the chromogenic substrate assay (CSA) values. The CSA values for the 18 non-medicated horses indicated a higher AT-III activity (lower residual thrombin activity) than the FSA. AT-III activity was quantified in 18 non-medicated horses (29 mg/dl) and compared well with values for humans (30 mg/dl) and dogs (40 mg/dl). Plasma heparin concentrations, determined by the FSA, correlated well with the 'therapeutic range' (1.5 fold to 2.5 fold prolongation of the activated partial thromboplastin time (APTT) normal value) and values reported for humans. The effect of heparin therapy on AT-III activity in four treatment regimens was evaluated. AT-III activity was not significantly affected (with one exception) by a single dose of intravenous (IV) heparin (40 and 100 U/kg) nor by repeated subcutaneous (SC) injections of heparin (240 U/kg). A transient increase in residual thrombin activity was measured 12 h after an intravenous (80 U/kg) injection of heparin. Large doses of heparin (80 U/kg IV followed by 160 U/kg SC) given every 12 h produced a progressive prolongation of the APTT. In this group the APTT remained prolonged 48 h after the last treatment.
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PMID:Antithrombin III activity (residual thrombin activity) in plasma from non-medicated or heparinized horses. 277 4

The activity of the extrinsic pathway inhibitor (EPI), which is the factor-Xa-dependent inhibitor of the factor VIIa-tissue thromboplastin complex, was serially determined in 13 patients with postoperative/posttraumatic septicemia, and compared to the activity of antithrombin (AT), heparin cofactor II and protein C (PC). In the survivors (n = 8), initial low values for all the inhibitors normalized during recovery. In the demises (n = 5), a progressive increase in EPI activity was observed until death, whereas progressive decreases were observed for the other inhibitors. No correlation was found between the inhibitor values and the endotoxin concentration. We conclude that EPI activities are increased in the late course of fatal septicemia. Apparently, a large EPI-AT gap is a severe prognostic indicator in such patients.
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PMID:Extrinsic pathway inhibitor in postoperative/posttraumatic septicemia: increased levels in fatal cases. 280 38

We reported a rare case of triple cancers with acute lymphoblastic leukemia (ALL) associated with disseminated intravascular coagulopathy (DIC) after the operations of colon cancer and primary lung cancer. A 78-year-old Japanese male, who had been operated upon for colon cancer (adenocarcinoma) on March 1981, metastatic brain tumor (adenocarcinoma) on December 1986, and primary lung cancer (squamous cell carcinoma) on February 1987, was admitted to our hospital because of severe general malaise on December 6 1987. On admission, he had mild hepatosplenomegaly and hemorrhage diathesis such as purpura. Serum LDH increased to 2,515 mU/ml. The white blood cell count was 6,210/microliters with 53% leukemia cells, and the platelet count was 12,000/microliters. A bone marrow was infiltrated with 96.0% leukemia cells. The leukemia cells stained positively for PAS and negatively for peroxidase. Immunological examination of leukemia cells showed that HLA-DR, TdT, B1 and J5 were positive and cytoplasmic Igmu and surface Ig were negative, indicating common ALL. The coagulation studies revealed that the activated partial thromboplastin time was prolonged to 42.0 seconds, FDP increased to 79.9 micrograms/ml, and antithrombin-III decreased to 62%. Chromosome analysis showed a 48, XY, +2, +21q-, t(9;22) karyotype. He was diagnosed as having Ph1 positive ALL associated with DIC. He was treated with vindesine, prednisolone, L-asparaginase, and adriamycin and complete remission (CR) was achieved after two months. But on August 1988, 8 months after CR, ALL and brain tumor relapsed and he died of pneumonia on September 19, 1988.
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PMID:[Ph1 positive acute lymphoblastic leukemia with DIC after operation of colon and lung cancer]. 281 Jul 93

Unfractionated and low molecular weight (LMW) heparins with good antithrombotic activity invariably catalyze thrombin inhibition and inhibit the appearance of thrombin activity in contact-activated plasma. Conversely, the antithrombotic efficacy of LMW heparins decreases as their ability to catalyze thrombin inhibition and to inhibit the appearance of thrombin activity in plasma decrease. The activated partial thromboplastin time (APTT) has proven a reliable test for assaying unfractionated heparin. We therefore compared 2 unfractionated and 3 LMW heparins on the basis of the minimum concentrations required to double the APTT of normal plasma and by then determined how this anticoagulant effect was achieved. The amount of unfractionated and LMW heparin which doubled the APTT was found to be equivalent to approximately 0.25 antithrombin units. This concentration of each glycosaminoglycan completely inhibited prothrombin activation for 45 s after CaCl2 was added to contact-activated plasma; accelerated thrombin inhibition by purified antithrombin III by approximately 50-fold; and accelerated thrombin inhibition equally by antithrombin III in undiluted plasma. This concentration of the three LMW heparins increased, by approximately 70-fold, the rate of factor Xa inhibition by purified antithrombin III compared to the 50-fold increase seen with the two unfractionated heparins. These results thus suggest that tests based on the inhibition of prothrombin activation and/or on the catalysis of thrombin inhibition provide a useful basis for assigning in vitro potency to both unfractionated and LMW heparins.
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PMID:An approach to assigning in vitro potency to unfractionated and low molecular weight heparins based on the inhibition of prothrombin activation and catalysis of thrombin inhibition. 285 Nov 91


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