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)

We investigated whether Hepcheck heparin removal filters could remove residual platelets from platelet-poor plasma (PPP) without compromising samples for lupus anticoagulant (LA) testing. Furthermore we assessed what effect, if any, plasma filtration has on various clotting tests that form the foundation for LA testing. Citrated blood was obtained from 35 normal donors. Two sets of citrated tubes were processed in order to obtain PPP. Citrated blood was also obtained from a single donor to check the actual amounts of platelets removed by the Hepcheck filtration device. One set of PPP samples was filtered using the Hepchek filter device and the other was not processed, i.e. unfiltered. Prothrombin time (PT), activated partial thromboplastin time (APTT), and kaolin clotting time (KCT) were performed on both unfiltered and filtered samples that were tested immediately and after freezing at -70 degrees C for 24 h. Platelet counts on the single donor's citrated plasma were dramatically reduced after filtration. PT and APTT values showed small but statistically significant differences between unfiltered and filtered plasmas whether these were fresh or frozen samples. However, these differences were not clinically significant. KCT data showed statistical and clinical differences between unfiltered and filtered plasmas whether fresh or frozen plasmas were used. In contrast, KCT values were similar if unfiltered, fresh plasmas or filtered, frozen plasmas were used. Coagulation factor assays for factors VIII, IX and X were performed on both sets of PPP samples after freezing to determine if the filtration device affected these levels and would as a result, compromise APTT based lupus testing. Factor IX levels demonstrated a loss of activity following use of the device but no change was observed in factor VIII or factor X. Von Willebrand factor antigen and function as well as multimer structure were not affected by the filtration device in 10 normal donors. Filtering plasmas of two donors with a history of an LA dramatically prolonged clotting times for APTT, Dilute Viper Venom Time, mixing studies, and STACLOT LA tests in comparison with unfiltered plasmas. The data indicate that plasma filtration using the Hepchek device does not adversely affect coagulation testing. Furthermore samples requiring testing for the lupus anticoagulant can be filtered and subsequently frozen and compare favorably with freshly processed samples.
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PMID:Rapid removal of platelets from plasma utilizing the Hepcheck heparin removal filter. 910 33

Previous studies of hemoglobin-based oxygen carriers and their effects on coagulation have shown conflicting results. This study re-examined the effect of hemoglobin solution on blood coagulation in whole blood using highly purified human hemoglobin Ao (HbAo). Citrated human whole blood samples were diluted 1:1 with HbAo (7gHb/dl) or human serum albumin (HSA; 5g/dl) as a protein control, and both activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured using a mechanically based whole blood coagulometer. Multiple runs were performed with the same volunteer donor sample. The mean aPTT time of HbAo-diluted samples (105.9 +/- 19.9 sec., n = 41) was significantly longer than the undiluted controls (46.4 +/- 5.6 sec., n = 54) or HSA-diluted blood (77.1 +/- 12.7 sec., n = 41) indicating an abnormal intrinsic coagulation pathway. There was no significant difference between the PT times of the HbAo and HSA-diluted samples. To examine the cause of the prolonged aPTT times with HbAo dilution, we performed activity assays of intrinsic factors XII, XI, IX, and VIII in a citrated human whole blood system diluted 1/5 and 1/10 with normal saline solution (NSS), and then 1:1 with either HbAo, HSA, or NSS. Only the Factor IX activity was significantly depressed by hemodilution (1/5 HbAo 50.20 +/- 8.11; HSA 61.05 +/- 6.72; NSS 74.75 +/- 9.83. 1/10 HbAo 46.50 +/- 5.57; HSA 64.97 +/- 11.01; NSS 67.92 +/- 16.03). These results suggest that in-vitro hemodilution with HbAo causes a hypocoagulatory response through interference with Factor IX function.
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PMID:Decreased whole blood factor IX activity following hemodilution with hemoglobin A-zero in-vitro. 916 43

Two patients who presented with active bleeding and were diagnosed with acquired hemophilia A (AHA) are reported herein. One was a 27-year-old woman who experienced spontaneous oozing from an episiotomy wound six days after her second normal delivery. Bleeding became progressively worse, despite treatment with primary sutures and curettage of the uterus at a local hospital. She underwent emergency exploratory laparotomy because of intra-abdominal bleeding, during which perforations of the uterus were discovered. Unremitting bleeding from the surgical wound occurred after surgery. The patient was finally diagnosed with AHA when Factor VIII (FVIII) inhibitor (titer, 19 Bethesda units (BU)/ml) was detected in her plasma. She died of refractory hemorrhaging, despite intensive treatment with Factor IX concentrate infusion and cyclophosphamide therapy. The second patient was a 22-year-old man who sustained spontaneous and recurrent intramuscular hemorrhage in the right thigh for one month. Laboratory studies including complete blood count, biochemical evaluation, coagulation screening and immunologic assays were all within normal limits, except for a prolonged activated partial thromboplastin time. Idiopathic AHA was diagnosed after the detection of plasma FVIII inhibitor with a concentration of 5.9 BU/ml. The patient's coagulopathy was successfully managed with plasma exchange and subsequent treatment with oral prednisolone and cyclophosphamide.
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PMID:Acquired hemophilia A: report of two cases. 979 3

The pharmacokinetics and pharmacodynamics (PK/PD) of a humanized anti-Factor IX IgG1 monoclonal antibody (SB 249417, FIX mAb) were studied in Cynomolgus monkeys. Single i.v. bolus doses of 1, 3, or 10 mg/kg of FIX mAb were administered. The total FIX mAb concentration, activated partial thromboplastin time (aPTT), and Factor IX activity were monitored for up to 4 weeks after dosing. In the monkey, FIX mAb had a plasma clearance of 0.6 ml/h/kg and a steady-state volume of distribution of approximately 70 ml/kg. The elimination phase half-life (3.8 days) was considerably less than other humanized IgG1 mAbs in the monkey, for which there is no binding to endogenous antigen. The suppression of Factor IX activity and the prolongation of aPTT were rapid and dose dependent. The time for aPTT values to return to basal levels (25-170 h) increased with increasing dose. A mechanism-based PK/PD model consistent with the stoichiometry of binding (2:1) was developed to describe the Factor IX activity and aPTT response time course. The model incorporated Factor IX synthesis and degradation rates that were interrupted by the sequestration of Factor IX by the antibody. aPTT values were related to free Factor IX activity. This model was able to describe the PD profiles from the three dose levels simultaneously. The estimated Factor IX half-life was 11 h and the third-order association rate constant was 3.96 x 10(3) microM(-2) h(-1). The PK/PD modeling was useful in summarizing the major determinants (endogenous and antibody-ligand binding) controlling FIX mAb-related effects.
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PMID:Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys. 1064 Mar 22

A new series of peptide inhibitors of human Factor VIIa (FVIIa) has been identified and affinity matured from naive and partially randomized peptide phage libraries selected against the immobilized tissue factor x Factor VIIa (TF x FVIIa) complex. These "A-series" peptides contain a single disulfide bond and a 13-residue minimal core required for maximal affinity. They are exemplified by peptide A-183 (EEWEVLCWTWETCER), which binds at a newly identified exosite on the FVIIa protease domain, described in the accompanying report [Roberge, M., Santell, L., Dennis, M. S., Eigenbrot, C., Dwyer, M. A., and Lazarus, R. A. (2001) Biochemistry 40, 9522-9531]. A-183 was obtained from a trypsin digest of A-100-Z, a recombinant protein comprising A-183 and the Z domain of protein A. Surprisingly, A-183 was a very potent inhibitor of TF x FVIIa, inhibiting activation of Factor X (FX) and Factor IX and amidolytic activity of Chromozym t-PA with IC50 values of 1.6 +/- 1.2, 3.5 +/- 0.3, and 8.5 +/- 3.5 nM, respectively. Kinetic analysis revealed that A-183 was a partial (hyperbolic) mixed-type inhibitor of FX activation having a Ki of 200 pM as well as a partial competitive inhibitor of amidolytic activity. The A-series peptides were also specific and potent inhibitors of TF-dependent clotting as measured in a prothrombin time (PT) clotting assay and had no effect on the TF-independent activated partial thromboplastin time. At saturating concentrations of peptide, the maximal extent by which A-183 and A-100-Z inhibited the rate of FX activation was 78 +/- 3 and 89 +/- 6%, respectively. The degree of inhibition of the rate of FX activation correlated with a maximum fold prolongation in the PT assay of 1.8-fold for A- 183 and 3.3-fold for A-100-Z. The A-series peptides represent a new class of peptide exosite inhibitors that are capable of attenuating, rather than completely inhibiting, the activity of TF x FVIIa, potentially leading to anticoagulants with an increased therapeutic window.
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PMID:Selection and characterization of a new class of peptide exosite inhibitors of coagulation factor VIIa. 1158 50

A method of investigating the coagulation mechanism is described.Results obtained by this procedure are compared with those of tests carried out on venous blood obtained simultaneously from normal subjects and patients with a variety of clotting defects. Good correlation was found between the results of P and P tests on venous and capillary blood, and also between thromboplastin screening tests on capillary blood and antihaemophilic and Christmas factor levels. The methods described have proved reliable as a pre-operative screening procedure in routine use over a period of nearly two years.
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PMID:Coagulation tests on capillary blood. A screening procedure for use in small children. 1388 83

The amount of factor IX (Christmas factor) for different genotypic classes was determined by means of a variant of the thromboplastin generation test. The mean value for females heterozygous for the Christmas gene was about half the mean values for normal males and for normal homozygous females; means for the latter two groups were about equal. This dosage compensation is interpreted as evidence in support of Lyon's hypothesis, according to which one X chromosome is inactive in mammalian females.
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PMID:Christmas factor: dosage compensation and the production of blood coagulation factor IX. 1394 45

Stored serum reduces the anticoagulant effect of heparin on the clotting times of normal plasma. This is also well marked with sera from patients with Christmas (factor IX) deficiency, with factor VII-deficient sera, and in sera derived from patients treated with phenindione with a gross defect in thromboplastin generation. The possible relationship between antiheparin activity of serum and heparin resistance in recent thrombosis is discussed. The antiheparin agent resembles factor VII and Christmas factor in being present in excess in serum, adsorbed and subsequently eluted from alumina. Unlike these, however, it does not appear to be appreciably reduced by phenindione treatment. It appears to have some properties in common with those described for the thrombotic agent of serum described by Wessler and his colleagues. It may play a part in the increased coagulability associated with thrombosis from the release of serum products into the circulation, although its relationship to the production of thrombosis in man remains to be established.
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PMID:The possible relationship between the antiheparin activity of serum and thrombosis. 1443 69

Factor IX is a vitamin K-dependent serine protease, which exists as a zymogen in the blood. On activation to factor IXa, by factor XIa or tissue factor-factor VIIa complex, it forms tenase complex with factor VIIIa, in the presence of Ca2+. This tenase complex enzymatically converts factor X to factor Xa, thereby bringing about the coagulation cascade. Mutations in factor IX gene have been shown to cause haemophilia B, which is inherited as an X-linked recessive disorder. Herein we report a novel missense mutation at the nucleotide position 30829-T > A in the exon 8 of factor IX gene. This transversion leads to the substitution of histidine 236 to glutamine. This resulting abnormal protein has been named factor IXDelhi. Molecular modelling was performed to predict the molecular pathology of this mutation. We predict that this change in the catalytic domain may affect the surface loop that accommodates Ca2+, thereby leading to severe bleeding disorder.
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PMID:Novel missense mutation in the coagulation factor IX catalytic domain associated with severe haemophilia B--Factor IXDelhi. 1535 82

Factor IX-binding protein (AHP IX-bp), a Ca2+- and Zn2+-binding protein from the venom of Agkistrodon Halys Pallas was reported to bind specifically with factor IX in a Zn2+-dependent manner. Here we have purified AHP IX-bp by a simple two-step of chromatography procedure and found that AHP IX-bp also binds factor Xa (FXa) with high binding-affinity in a Mg2+-dependent manner. Although Mg2+ ions have a significantly low binding-affinity for apo-AHP IX-bp as determined by isothermal titration calorimetry, they can induce the binding of apo-AHP IX-bp with FXa even in the absence of Ca2+ as determined by native PAGE and surface plasmon resonance. Mg2+ ions are required to maintain in vivo function of FX Gla domain for its recognition of AHP IX-bp. Both Ca2+ and Zn2+ ions fail to induce the binding between apo-AHP IX-bp and FXa. The abundant Mg2+ ions in blood play an important role in the anticoagulation of AHP IX-bp.
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PMID:Mg(II)-induced binding of factor IX-binding protein from the venom of Agkistrodon Halys Pallas with factor Xa. 2015 70


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