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)

Aminoglycoside antibiotics exhibit their bactericidal effect by interfering with normal ribosomal activity. In this pilot study, we have evaluated the effect of the aminoglycoside antibiotic gentamicin on the factor VIII (FVIII) and IX levels of severe hemophiliacs with known nonsense mutations. Five patients were enrolled and each patient was given 3 consecutive days of gentamicin at a dose of 7 mg/kg intravenously every 24 hours. Two patients (patient no. 1: hemophilia A, Ser1395Stop; and patient no. 5: hemophilia B, Arg333Stop) showed a decrease in their activated partial thromboplastin time (aPTT), an increase in their FVIII (0.016 IU/mL, 1.6%) or FIX (0.02 IU/mL, 2%) levels, and an increase in thrombin generation. The remaining 3 patients (patient no. 2: hemophilia B, Arg252Stop; patient no. 3: hemophilia A, Arg2116Stop; and patient no. 4: hemophilia A, Arg427Stop) showed no response in the aPTTs or factor levels, but one (patient no. 2: hemophilia B, Arg252Stop) showed an increase in the factor IX antigen level (2%-5.5%) that persisted throughout the period of the study and was concordant with an increase in thrombin generation. Gentamicin is unlikely to be an effective treatment for severe hemophilia due to its potential toxicities and the minimal response documented in this report. This study, however, does provide a proof of principle, suggesting that ribosomal interference with a less toxic agent may be a potential therapeutic mechanism for severe hemophilia patients with nonsense mutations.
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PMID:Aminoglycoside suppression of nonsense mutations in severe hemophilia. 1605 41

Autoimmune thrombocytopenic purpura (ITP) is a disease that presents with skin and mucous membrane bleeding due to thrombocytopenia. In the literature, there are a few studies about the effect of high-dose steroid therapy on coagulation tests in different diseases, but their results are still controversial. In this study, coagulation parameters were investigated that might have a role in hemostatic compensation in childhood acute ITP before and after high-dose methylprednisolone (HDMP) treatment. The study includes 21 children age 1.5 to 14 years with acute ITP and 21 healthy age-matched control subjects. All patients with acute ITP received HDMP for 7 days. Before and after HDMP treatment (0 and 8 days) prothrombin time, partial thromboplastin time, fibrinogen, Protein C, Protein S, antithrombin III, and the levels of factor II (FII), FV, FVII, FVIII, FIX, FX, FXI, and FXII were studied in all subjects. The results were compared with those of the control group. Pre-treatment Protein C and Protein S levels in the patient group were significantly lower than those in the control groups (p<0.05). Protein S and Protein C levels were significantly improved after HDMP treatment in patient group. There were lower FV, FVII, FX values in the patient group compared to the control groups on admission. There was no difference in AT III and fibrinogen levels before and after treatment. As a result, some changes in the coagulation system associated with thrombocytopenia were observed in patients with acute ITP. These changes may be accepted as compensatory mechanisms to maintain hemostasis.
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PMID:Effects of high-dose methylprednisolone therapy on coagulation factors in patients with acute immune thrombocytopenic purpura. 1624 77

Tissue factor (TF) exposure is a potent pro-thrombotic trigger that initiates activation of the coagulation cascade, while thrombomodulin (TM) is a potent anticoagulant protein that limits the extent of activation. Both TF neutralizing antibodies and soluble TM (sTM) are effective anticoagulants. We have developed a novel anticoagulant fusion protein, Ab(TF)-TM, by fusing a TFneutralizing single-chain antibody, Ab(TF), to an active fragment of TM. Ab(TF)-TM is a novel anticoagulant targeting to sites of TF exposure with a dual mechanism of action. The Ab(TF) portion of the molecule inhibitsTF/factorVIIa mediated activation of FIX and FX, and the TM portion of the molecule acts as a cofactor for activation of protein C. In-vitro coagulation assays show that Ab(TF)-TM more potently inhibits TF-initiated coagulation (prothrombin time) than can its individual components, Ab(TF) (20-fold) and sTM (80-fold) alone, or in combination (10-fold). In contrast, the potency of Ab(TF)-TM in the activated partial thromboplastin and thrombin clotting time assays was similar to sTM alone. In a rat model of disseminated intravascular coagulation (DIC), intravenous injection of a human TF-containing thromboplastin reagent (0.5 ml/kg) resulted in an immediate death in approximately 60% of the animals and a clinical score of approximately 2.5. Pre-injection of Ab(TF)-TM or Ab(TF) and sTM, given alone or in combination, showed dose-dependent efficacy. At a dose of 0.7 nmol/kg, Ab(TF)-TM completely prevented death and reduced clinical scores by 79%, while neitherAb(TF) nor sTM, given alone or in combination, showed significant therapeutic effects. Calculated effective doses that reduced mortality by 50% relative to that in the control group (ED(50), nmol/kg) were 0.21 for Ab(TF)-TM, 3.2 for an equimolar mixture of Ab(TF) and sTM, 4.3 for sTM and 20 for Ab(TF). Thus, Ab(TF)-TM presented 10- to 100-fold enhancement of the anticoagulant potency, relative to the ED(50) in Ab(TF) and sTM given either alone or in combination, in a rat DIC model.
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PMID:Amplified anticoagulant activity of tissue factor-targeted thrombomodulin: in-vivo validation of a tissue factor-neutralizing antibody fused to soluble thrombomodulin. 1695 73

Factor VII deficiency is the least rare among uncommon congenital coagulation disorders. The majority of cases are isolated deficiencies. In some cases, FVII deficiency has been found to be associated with the deficiency in another coagulation factor or with non-coagulation-related abnormalities or defects. The evaluation of all published studies on the subject has shown that the FVII defect has been reported in association with FV, FVIII, FIX, FX, FXI and protein C defects. Furthermore, FVII deficiency has been described in association with bilirubin metabolism disorders, mental retardation, microcephaly, epicanthus, cleft palate and persistence of ductus arteriosus. The most interesting association appears to be that with FX. This has been shown to be due to a deletion in part of the long arm of chromosome 13. This arm contains genes coding for both FVII and FX. Interestingly, this combined coagulation defect has been found to be associated with carotid body tumors and several other malformations. Combined defects in blood coagulation often create diagnostic difficulties since results cannot be explained if a single factor deficiency is assumed. For example the combined FVII and FX defect yields a rather peculiar laboratory picture (prolonged prothrombin time and partial thromboplastin time, but normal thrombin time) that could suggest FII or FV or FX single deficiency and not FVII deficiency, indicating the need for specific factor assays whenever data are confusing. Finally, the elevated incidence of mental and skeletal malformations present in these combined defects indicates the need for a careful evaluation of all these patients lest some aspects of the defect are missed.
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PMID:Congenital combined defects of factor VII: a critical review. 1709 60

External quality assurance (EQA) is an important component of the total quality assurance program of a clinical hemostasis laboratory. The College of American Pathologists (CAP) helps meet this requirement by providing a proficiency testing program that evaluates a broad range of hemostasis methods and analytes. This article reviews the published experience of the CAP proficiency testing program in hemostasis. The purpose is to formulate general conclusions about the benefits of EQA. Between 1963 and 2006, the performance characteristics of a variety of tests have been evaluated, including the prothrombin time, activated partial thromboplastin time, coagulation factor activity assays (e.g., fibrinogen, factor [F] VIII, FIX, FXI), von Willebrand factor assays, unfractionated heparin monitoring, lupus anticoagulant testing, and platelet function. Based on the results of these evaluations, the major benefits of EQA are to (1) enhance patient care and safety through improved laboratory testing; (2) characterize test accuracy and precision across multiple methods; (3) correlate specific method variables with accuracy and precision; (4) identify interfering substances and quantify their effects across multiple methods; (5) identify clinical laboratories that are at risk for poor performance so that their performance can improve; and (6) satisfy accreditation and regulatory requirements.
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PMID:Quality assurance in hemostasis: the perspective from the College of American Pathologists proficiency testing program. 1742 59

In order to analyze the clinical features and laboratory findings in patients with acquired hemophilia A, one case of acquired hemophilia A was studied, the medical history, clinical features, ultrasonography and laboratory examination including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and FVIII:C, FIX:C, FXI:C, FXII:C ratio, as well as medical treatment were analyzed. The results showed 99.3 sec of APTT, 13 sec of PT, and 13.5 sec of TT, 2% of FVIII:C, 7% of FIX:C, 9% of FXI:C and 21% of FXII:C. The prolongation of APTT could not be completely corrected by mixing the patient plasma with an equal volume of normal fresh plasma; the APTT increased with prolongation of incubation time, when patient plasma was mixed with an equal volume of normal fresh plasma and incubated at 37 degrees C. The plasma FVIII:C, FIX:C, FXI:C and FXII:C levels in patient were 6%, 75%, 95% and 123% respectively, when patient's plasma was diluted by tenfold and mixed with an equal volume of non-diluted normal plasma. FVIII inhibitor in the patient's serum was at a level >32.0 Bethesda units/ml after acquired hemophilia was diagnosed, the patient was admitted to hospital and given orally prednisone and azathioprine therapy. One month later, clinical status of the patient were improved with 33.3 seconds of APTT, 128% of FVIII level and elimination of FVIII inhibitor. In conclusion, inquiring case history, analyzing imaging results, detecting level of APTT, performing dilution test and assaying titer of FVIII inhibitor can reduce misdiagnosis and wrong therapy for patients with acquired hemophilia A. The FVIII inhibitor can be eliminated and function of clotting can be recovered by using immunosuppressive therapy.
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PMID:[Clinical analysis and laboratory findings in a patient with acquired hemophilia A]. 1923 80

In order to investigate the patterns of FIX gene mutation in 3 unrelated hemophilia B (HB) patients, the activated partial thromboplastin time (APTT) and FIX activity (FIX: C) tests were adopted for phenotype diagnosis. All of the eight exons and their flank of FIX gene were amplified by polymerase chain reaction (PCR), the nucleic acid sequences were detected by dideoxymediated chain-termination method. The results indicated that as compared with normal control, the APTT value significantly increased, FIX: C value obviously decreased, PT value was normal. Sequencing results showed that all of 3 HB patients had the changes of gene sequences, among 3 patients the G22119A point mutation of exon 6 existed in case No.1, the G7932C point mutation of exon 2 was detected in case No.2 and the T32685C point mutation of exon 8 was found in case No.3. In conclusion, the relevant changes of gene sequences in all of 3 HB patients were detected, which provides some evidences for molecular mechanism of gene deficiency in HB patients.
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PMID:[Detection of factor IX gene mutation in patients with hemophilia B by DNA sequencing]. 1937 92

Factor X (FX) deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1,000,000 people. Its clinical presentation places FX deficiency among the most severe of the rare coagulation defects, typically including hemarthroses, hematomas, and umbilical cord, gastrointestinal, and central nervous system bleeding. Phenotype diagnosis is based on the concomitant prolongation of the prothrombin time and activated partial thromboplastin time. Through the measurement of plasma level of FX antigen and its coagulant activity, two main types of deficiency can be distinguished: type I (concomitantly low levels of activity and antigen) and type II (low coagulant activity, but normal or borderline antigen levels). FX protein is mainly synthesized by the liver and is encoded by a gene ( F10) of 27 kb located on chromosome 13, containing 8 exons. One hundred five mutations on F10 have been identified to date, 78% being missense mutations, with no hot-spot regions. There is no specific FX concentrate available, and current treatment includes the administration of fresh-frozen plasma or prothrombin complex concentrates (PCCs) containing FX in addition to other vitamin K-dependent factors. Administration of PCCs is associated with the risk of thromboembolic complication due to the unknown concentrations of other coagulant factors; however, to overcome this problem, a concentrate containing well-defined amounts of FX (and FIX) has recently been developed.
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PMID:Factor X deficiency. 1959 69

Although short activated partial thromboplastin times (APTTs) are generally considered to be laboratory artefacts of problematic blood collections, there is mounting evidence that in some cases a short APTT may reflect a hypercoagulable state, potentially associated with increased thrombotic risk and adverse cardiovascular events. We prospectively evaluated the phenomenon of short APTTs in 113 consecutive samples compared with an equal number of age and sex-matched normal APTT samples. We found a significant difference in various test parameters including prothrombin time (PT), Factor (F) V, FVIII, FXI, FXII, von Willebrand factor (VWF) antigen and collagen-binding activity, and in the level of procoagulant phospholipids, as assessed using a novel assay procedure (XACT). Interestingly, there was a significant negative association for fibrinogen, and although elevated, there was no significant association for FIX. On the basis of identified consecutive samples having multiple low APTTs on several sequential days, a proportion of laboratory-defined short APTTs appear to represent in-vivo hypercoagulability. In conclusion, plasma from patients presenting with short APTTs is reflective of a complex hypercoagulant milieu that could feasibly contribute to thrombotic risk, and 20% or more of laboratory definable short APTTs appear to reflect in-vivo phenomenon.
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PMID:A laboratory evaluation into the short activated partial thromboplastin time. 2005 42

Platelet membranes provide procoagulant surfaces for the assembly and expression of a variety of coagulation protease complexes. These assembled complexes promote the proteolytic activation of various coagulation proteins resulting in normal hemostasis. Recent studies from our laboratory and others indicate that platelets possess specific, high-affinity, saturable receptors for factor (F) XI, FXIa, FIX, FIXa, FX, FXa, FV, FVa, prothrombin, and thrombin. The molecular mechanisms involved in the assembly of the intrinsic tenase and prothrombinase enzyme-cofactor complexes on platelet membranes are the subject of intense investigation. Whether the procoagulant surface of platelets is defined exclusively by procoagulant phospholipids, or whether specific protein receptors exist for the coagulant cofactors and proteases, is currently unresolved. In this article, we review some of these platelet receptor-mediated coagulation protein interactions and discuss platelet receptor-mediated F-X activation as a point of attack for the development of antithrombotic agents.
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PMID:Platelet membrane-mediated coagulation protease complex assembly. 2124 78


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