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)

Thromboembolic complications associated with prothrombin complex concentrate treatment may be related to the high levels of factors II and X in these products. We report here results from preclinical safety studies with a human coagulation factor IX product (AlphaNine; Alpha Therapeutic Corp., Los Angeles, Calif.) that contains no detectable factor II or VII and less than 10 units of factor X/100 units of factor IX. This product was manufactured from virally inactivated factor IX complex with a barium citrate adsorption step followed by affinity chromatography yielding factor IX concentrate with a specific activity of about 86 factor IX units/mg protein. Electrophoresis and immunoblot analysis indicated that the factor IX represents about 65% of the protein in this product. The virus inactivation step incorporated into the manufacturing process (incubation with n-heptane at 60 degrees C for 20 hours) was shown to inactivate at least 8.6 logs of type 1 human immunodeficiency virus. The barium citrate adsorption and affinity chromatography steps were found to remove 2.0 logs of the marker virus, vaccinia, and the DEAE ion-exchange chromatography used to produce factor IX complex was found to remove 1.4 logs of the marker virus, Sindbis. Analysis of three separate manufacturing lots with the polymerase chain reaction revealed no evidence of hepatitis C virus. The purified factor IX was nonthrombogenic when tested at doses of 450 units/kilogram in a rabbit stasis (Wessler) model, whereas the prothrombin complex concentrates were found to be thrombogenic at doses of less than 50 units/kg. There was no evidence of DIC in a porcine model after infusion of 200 units/kg of coagulation factor IX, as manifested by negative fibrin monomer tests, the absence of fibrin in blood vessels at autopsy, little or no change in prothrombin times and partial thromboplastin times, and only moderate decreases in platelet levels after infusion.
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PMID:Human coagulation factor IX: assessment of thrombogenicity in animal models and viral safety. 844 88

We evaluated the antithrombotic effects of DX-9065a, a specific factor Xa inhibitor, using tissue thromboplastin-induced DIC (TP-DIC) and the arterio-venous shunt (AV shunt) in rats. Intravenous TP injection reduced the platelet counts and fibrinogen concentrations in blood. In the TP-DIC model, an intravenous dose of DX-9065a 0.23 mg/kg 1 min before TP injection suppressed the consumption of platelets and fibrinogen to 57% and 66%, respectively, and the production of FDP almost completely. In the AV shunt model, DX-9065a inhibited thrombus formation to 51% on intravenous administration of 0.23 mg/kg and to 60% when given orally at 23.3 mg/kg. Intravenous administration of 2.33 mg/kg of DX-9065a did not affect the bleeding time. These results suggest that Xa inhibition may be an appropriate approach for suppressing thrombosis without impairing haemostasis.
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PMID:DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. 858 99

Severe coagulation defects often develop in neonates undergoing cardiac surgery, both as a result of the surgical intervention, and as pre-existing defects in the hemostatic mechanisms. The following case report describes a newborn patient with complex congenital heart disease and respiratory failure whose pre-operative coagulopathy was aggressively managed prior to surgical correction. A 5-day-old, 2.5 kg child presented with interrupted aortic arch, ventricular septal defect, atrial septal defect, and patent ductus arteriosus. On admission, he was in respiratory arrest suffering from profound acidemia. In addition, the child was hypothermic (30.1 degrees C), septic (Streptococcus viridans), and coagulopathic (disseminated intravascular coagulation-DIC). The patient was immediately intubated and initial coagulation assessment revealed the following: prothrombin time (PT) 48.9 s (international normalized ratio (INR) 15.7), activated partial thromboplastin time (aPTT) >106 s, platelet count 30,000 mm(3), fibrinogen 15 mg dL(-1) and antithrombin III (AT-III) 10%. Before cardiac surgery could be performed, the patient's DIC was corrected with the administration of cryoprecipitate (15 ml), fresh frozen plasma (300 ml), and platelets (195 ml). In spite of the large transfusion of fresh frozen plasma, the AT-III activity, measured as a percentage, remained depressed at 33. Initial thromboelastographic (TEG) determination revealed an index of +2.02, and following 100 IU administration of an AT-III concentrate, declined to -2.32. Sequential TEG profiles were performed over several days, with the results used to guide both transfusion and medical therapy. The congenital heart defect correction was subsequently performed with satisfactory initial results, but the patient developed a fungal infection and expired on the 16th post-operative day. The present case describes techniques of coagulation management for a newborn with both a severe hemostatic defect and congenital heart disease.
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PMID:Pre-operative coagulopathy management of a neonate with complex congenital heart disease: a case study. 1078 72

This study evaluated hemostatic data in 28 patients with newly diagnosed acute promyelocytic leukemia (APL) and 15 patients with relapsed APL. Activated partial thromboplastin time and prothrombin time were prolonged at initial onset of APL. Plasma level of fibrinogen was significantly decreased in patients with initial disease of APL, but it was not decreased significantly during the relapse of APL. Plasma fibrin and fibrinogen degradation products levels were significantly increased and platelet counts significantly decreased in both groups. Plasma levels of antiplasmin significantly decreased at initial onset but not during relapse. Plasma levels of antithrombin were within normal range in patients with initial disease but significantly decreased in those with relapse. Plasma levels of D-dimer, soluble fibrin monomer (sFM), plasmin-plasmin inhibitor complex (PPIC), and thrombin antithrombin complex (TAT) levels were significantly high in both groups. Plasma levels of PPIC, sFM, and D-dimer were significantly higher at initial onset of APL than during relapse. However, there was no significant difference in DIC score between patients with initial onset and those with relapse; plasma levels of tissue factor (TF) significantly increased in both groups, but they were significantly higher at initial onset of APL than during relapse. TF and tissue type plasminogen activator (t-PA) antigen levels in leukemic cell lysate were significantly increased in both groups, and they were significantly lower during relapse than at initial onset. Hemostatic abnormalities occurring in patients with relapsed APL might be the result of the decrease of TF and t-PA in leukemic cells. These findings suggest that DIC in APL patients with relapse might not be caused only by TF and t-PA and thus should be treated with different therapy from patients with initial onset of APL.
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PMID:Decreased tissue factor and tissue-plasminogen activator antigen in relapsed acute promyelocytic leukemia. 1086 7

In 1967 we reported for the first time five cases of an acquired bleeding disorder in humans which developed after contact with saturnidae caterpillars. Since that time, other cases have been reported in Brazil, French Guyana, Peru, Paraguay and Argentina. The caterpillars have been identified as Lonomia achelous (LA) in Venezuela and northern Brazil and as Lonomia obliqua (LO) in southern Brazil. All patients present pain and a burning sensation at the site of contact. Within a few hours hematomas and hematuria are seen in combination with intracerebral and intraperitoneal hemorrhage (in some cases also renal failure). Hematological tests show: mild anemia with leucocytosis; prolonged PT, PTT and ThT; decreased fibrinogen, factor V, factor XIII, plasminogen and alpha2-antiplasmin levels; increased factor VIII:c, von Willebrand factor, and FDPs/D-dimers levels with normal ATIII and platelets. Factor VII, factor II and PC levels varied. Several activities similar to or directed against blood clotting factors have been identified in LA: fibrinolytic enzymes, which degrade fibrinogen producing abnormal FDPs; prothrombin activators: one direct and one factor Xa-like; a thermostable factor V activator; a thermolabile factor V inhibitor; a factor XIII proteolytic/urokinase-like activity; and a kallikrein-like activitiy. In LO three activities have been described: a prothrombin activator called 'Lonomia obliqua prothrombin activator protease' (LOPAP); a factor X activator; and a phospholipase A(2)-like activity called Lonomiatoxin. No fibrinolytic activity has been described in LO. Subcutaneous injection of crude hemolymph and some chromatographic fractions of LA induce a decrease in fibrinogen, plasminogen and factor XIII. Intravenous injection of factor XIII proteolytic/urokinase-like activity induce a dose-dependent thrombolysis with a decrease in plasmatic factor XIII without hemorrhagic manifestations. Intradermal injection of LO bristle extracts in rats and rabbits produce incoagulability whereas intravenous injection of LOPAP induced DIC in mice.
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PMID:Lonomia genus caterpillar toxins: biochemical aspects. 1108 23

The rejection of xenografts is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation. Natural regulators of coagulation in porcine xenografts have abnormal physiological interaction with human effectors. We have demonstrated the enhanced potential of porcine von Willebrand factor to associate with human platelet GPlb to be dependent upon the isolated AI domain of von Willebrand factor. The inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C may all be pathogenetic in the DIC following xenograft rejection. In this brief review, molecular incompatibilities of contributors in the physiologically fine tuned system of hemostasis are summarized and brought in context with the disordered thromboregulation, that seems to be invariably associated with delayed xenograft rejection. Possible therapeutic interventions are discussed.
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PMID:Molecular incompatibilities in hemostasis between swine and men--impact on xenografting. 1189 92

The wide availability of fibrinogen estimations based on the prothrombin time (PT-Fg) has caused concern about the variability and clinical utility of fibrinogen assays. In a multi-centre study, we investigated fibrinogen assays using various reagents and analysers. Clauss assays generally gave good agreement, although one reagent gave 15-30% higher values in DIC and thrombolysis. Two commercial reference preparations had much lower potencies than the manufacturers declared, and plasma turbidity influenced parallelism in some Clauss assays. PT-Fg assays gave higher values than Clauss and showed calibrant dependent effects, the degree of disparity correlating with calibrant and test sample turbidity. Analyser and thromboplastin dependent differences were noted. The relationship between Clauss and PT-Fg assays was sigmoid, and the plateau of maximal PT-Fg differed by about 2 g/l between reagents. ELISA and immunonephelometric assays correlated well, but with a high degree of scatter. Antigen levels were higher than Clauss, but slightly lower than PT-Fg assays, which appeared to be influenced by degraded fibrinogen. Clauss assays are generally reproducible between centres, analysers and reagents, but PT-Fg assays are not reliable in clinical settings.
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PMID:A performance evaluation of commercial fibrinogen reference preparations and assays for Clauss and PT-derived fibrinogen. 1208 8

A series of benzimidazole derivatives with the side chain on the nitrogen atom oriented to the prime site of factor Xa (FXa) were designed and synthesized. Compounds with substituted aminocarbonylmethyl groups as the side chain showed potent FXa inhibitory activity. Compounds 1 and 2 exhibited most potent inhibitory activity and were effective as anticoagulants in a DIC model.
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PMID:Structure-activity relationships of potent and selective factor Xa inhibitors: benzimidazole derivatives with the side chain oriented to the prime site of factor Xa. 1526 Dec 87

The aim of this study was to test the efficacy of different dosages of low molecular weight heparin (LMWH) in acute DIC which was induced in anaesthetised dogs by 4 h infusions of a canine lung thromboplastin extract. In all animals during the first 2 h, development of acute DIC was characterised by decreasing fibrinogen concentrations, platelet numbers, factor V- and antithrombin activities. Two hours after starting the thromboplastin infusion, intravenous LMWH treatment in different dosages started in groups 2 and 3 to achieve plasma levels between 0.27+/-0.01 and 0.36+/-0.02 anti-FXaUml(-1) or 0.62+/-0.08 and 0.90+/-0.07 antiFXaUml(-1) (mean+/-SD), respectively, during the time period of parallel administration of thromboplastin and LMWH (group 1=control; 4 dogs/group). In this time period, changes in factor V activity and fibrinogen concentration did not differ between group 2 and the control group. This was in contrast to group 3. The results of this study indicate that an efficacious interruption of the consumption reaction in cases of severe canine DIC requires high plasma heparin levels.
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PMID:Efficacy of low molecular weight heparin in a canine model of thromboplastin-induced acute disseminated intravascular coagulation. 1589 27

During the last decades in Georgia was observed significant increase of cases of visceral leishmaniasis and fight against this disease became important problem as far as the management of this disease is rather problematic. According to references and our clinical experience patients with visceral leishmaniasis are predisposed to bleeding. The objective of our study was the assessment of functional status of hemostasis related to the degree of clinical severity. We have studied platelet count, activated partial thromboplastin time (APTT), prothrombin time, thrombin time, plasma concentration of fibrinogen, the soluble fibrin-monomeric complexes (SFMC), fibrinogen/fibrin degradation products (D-dimer) and anticoagulant protein C. Haemostatic functional tests were studied in 45 patients with visceral leishmaniasis before and after treatment (with 20-25 day intervals). Before treatment the reduction of platelet count was observed in 95%. Prolonged APTT and prothrombin time was found in severe forms of the disease. Thrombin time prolonged in 45.7%, SFMC level was increased in 80% (p=0.003) and D-dimer level in 95.6% (p=0.023). Protein C was in normal value in 73%. The results indicate that leishmania infection affects primary haemostasis, coagulation and fibrinolysis and these alterations are related to the severity of clinical symptoms. Investigation of SFMC and D-dimer showed that in case of visceral leishmaniasis activation of intravascular coagulation takes place, particularly during the severe forms of the disease, study of these markers is of the diagnostic and prognostic importance and the treatment at an early stage of infection may potentially avoid the possibility of developing an uncompensated DIC.
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PMID:[Functional status of haemostasis system in patients with visceral leishmaniasis]. 1636 67


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