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[PMID]:28729433
[Au] Autor:Kamikubo Y; Mendolicchio GL; Zampolli A; Marchese P; Rothmeier AS; Orje JN; Gale AJ; Krishnaswamy S; Gruber A; Østergaard H; Petersen LC; Ruf W; Ruggeri ZM
[Ad] Endereço:Department of Molecular Medicine and.
[Ti] Título:Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex.
[So] Source:Blood;130(14):1661-1670, 2017 Oct 05.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have a lesser impact on hemostasis. We found that the extrinsic tissue factor (TF) coagulation initiation complex can selectively activate the antihemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the threshold for thrombus formation through contact phase-generated FIXa. In vitro, FXa stably associated with TF-FVIIa activates FVIII, but not FV. Moreover, nascent FXa product of TF-FVIIa can transiently escape the slow kinetics of Kunitz-type inhibition by TF pathway inhibitor and preferentially activates FVIII over FV. Thus, TF synergistically primes FIXa-dependent thrombin generation independently of cofactor activation by thrombin. Accordingly, FVIIa mutants deficient in direct TF-dependent thrombin generation, but preserving FVIIIa generation by nascent FXa, can support intrinsic pathway coagulation. In ex vivo flowing blood, a TF-FVIIa mutant complex with impaired free FXa generation but activating both FVIII and FIX supports efficient FVIII-dependent thrombus formation. Thus, a previously unrecognized TF-initiated pathway directly yielding FVIIIa-FIXa intrinsic tenase complex may be prohemostatic before further coagulation amplification by thrombin-dependent feedback loops enhances the risk of thrombosis.
[Mh] Termos MeSH primário: Coagulação Sanguínea
Fator VIII/metabolismo
Fator VIIa/metabolismo
Fator Xa/metabolismo
Tromboplastina/metabolismo
[Mh] Termos MeSH secundário: Fator VIIIa/metabolismo
Seres Humanos
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
72175-66-7 (Factor VIIIa); 9001-27-8 (Factor VIII); 9035-58-9 (Thromboplastin); EC 3.4.21.21 (Factor VIIa); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-02-767079


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[PMID]:28522609
[Au] Autor:Roy A; Ansari SA; Das K; Prasad R; Bhattacharya A; Mallik S; Mukherjee A; Sen P
[Ad] Endereço:From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and.
[Ti] Título:Coagulation factor VIIa-mediated protease-activated receptor 2 activation leads to ß-catenin accumulation via the AKT/GSK3ß pathway and contributes to breast cancer progression.
[So] Source:J Biol Chem;292(33):13688-13701, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell migration and invasion are very characteristic features of cancer cells that promote metastasis, which is one of the most common causes of mortality among cancer patients. Emerging evidence has shown that coagulation factors can directly mediate cancer-associated complications either by enhancing thrombus formation or by initiating various signaling events leading to metastatic cancer progression. It is well established that, apart from its distinct role in blood coagulation, coagulation factor FVIIa enhances aggressive behaviors of breast cancer cells, but the underlying signaling mechanisms still remain elusive. To this end, we investigated FVIIa's role in the migration and invasiveness of the breast cancer cell line MDA-MB-231. Consistent with previous observations, we observed that FVIIa increased the migratory and invasive potential of these cells. We also provide molecular evidence that protease-activated receptor 2 activation followed by PI3K-AKT activation and GSK3ß inactivation is involved in these processes and that ß-catenin, a well known tumor-regulatory protein, contributes to this signaling pathway. The pivotal role of ß-catenin was further indicated by the up-regulation of its downstream targets cyclin D1, c-Myc, COX-2, MMP-7, MMP-14, and Claudin-1. ß-Catenin knockdown almost completely attenuated the FVIIa-induced enhancement of breast cancer migration and invasion. These findings provide a new perspective to counteract the invasive behavior of breast cancer, indicating that blocking PI3K-AKT pathway-dependent ß-catenin accumulation may represent a potential therapeutic approach to control breast cancer.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Fator VIIIa/metabolismo
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/agonistas
Receptor PAR-2/agonistas
Transdução de Sinais
beta Catenina/agonistas
[Mh] Termos MeSH secundário: Mama/citologia
Mama/metabolismo
Mama/patologia
Neoplasias da Mama/enzimologia
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Fator VIIIa/genética
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Genes Reporter/efeitos dos fármacos
Glicogênio Sintase Quinase 3 beta/química
Glicogênio Sintase Quinase 3 beta/metabolismo
Seres Humanos
Invasividade Neoplásica/patologia
Proteínas de Neoplasias/agonistas
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Oligopeptídeos/farmacologia
Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Fosfatidilinositol 3-Quinase/química
Fosfatidilinositol 3-Quinase/metabolismo
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Interferência de RNA
Receptor PAR-2/antagonistas & inibidores
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Transdução de Sinais/efeitos dos fármacos
Tromboplastina/agonistas
Tromboplastina/genética
Tromboplastina/metabolismo
beta Catenina/antagonistas & inibidores
beta Catenina/genética
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTNNB1 protein, human); 0 (Enzyme Inhibitors); 0 (Neoplasm Proteins); 0 (Oligopeptides); 0 (Receptor, PAR-2); 0 (Recombinant Proteins); 0 (beta Catenin); 0 (seryl-leucyl-isoleucyl--glycyl-lysyl-valine); 72175-66-7 (Factor VIIIa); 9035-58-9 (Thromboplastin); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.764670


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[PMID]:27789475
[Au] Autor:Leiderman K; Chang WC; Ovanesov M; Fogelson AL
[Ad] Endereço:From the Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden (K.L.); Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD (W.C.C., M.O.); and Departments of Mathematics and Bioengineering,
[Ti] Título:Synergy Between Tissue Factor and Exogenous Factor XIa in Initiating Coagulation.
[So] Source:Arterioscler Thromb Vasc Biol;36(12):2334-2345, 2016 Dec.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Recent evidence suggests involvement of coagulation factor XIa (FXIa) in thrombotic event development. This study was conducted to explore possible synergies between tissue factor (TF) and exogenous FXIa (E-FXIa) in thrombin generation. APPROACH AND RESULTS: In thrombin generation assays, for increasing concentrations of E-FXIa with low, but not with high TF concentrations, peak thrombin significantly increased whereas lag time and time to peak significantly decreased. Similar dependencies of lag times and rates of thrombin generation were found in mathematical model simulations. In both in vitro and in silico experiments that included E-FXIa, thrombin bursts were seen for TF levels much lower than those required without E-FXIa. For in silico thrombin bursts initiated by the synergistic action of TF and E-FXIa, the mechanisms leading to the burst differed substantially from those for bursts initiated by high TF alone. For the synergistic case, sustained activation of platelet-bound FIX by E-FXIa, along with the feedback-enhanced activation of platelet-bound FVIIIa and FXa, was needed to elicit a thrombin burst. Furthermore, the initiation of thrombin bursts by high TF levels relied on different platelet FIX/FIXa binding sites than those involved in bursts initiated by low TF levels with E-FXIa. CONCLUSIONS: Low concentrations of TF and exogenous FXIa, each too low to elicit a burst in thrombin production alone, act synergistically when in combination to cause substantial thrombin production. The observation about FIX/FIXa binding sites may have therapeutic implications.
[Mh] Termos MeSH primário: Coagulação Sanguínea
Plaquetas/metabolismo
Fator Xa/metabolismo
Ativação Plaquetária
Trombina/metabolismo
Tromboplastina/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Testes de Coagulação Sanguínea
Simulação por Computador
Cisteína Endopeptidases/metabolismo
Fator VIIIa/metabolismo
Seres Humanos
Modelos Biológicos
Proteínas de Neoplasias/metabolismo
Ligação Proteica
Transdução de Sinais
Trombose/sangue
Fatores de Tempo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 72175-66-7 (Factor VIIIa); 9035-58-9 (Thromboplastin); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa); EC 3.4.22.- (Cysteine Endopeptidases); EC 3.4.22.26 (cancer procoagulant)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170612
[Lr] Data última revisão:
170612
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE


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[PMID]:26116330
[Au] Autor:Berczi C; Razso K; Osvath P; Boda Z; Flasko T
[Ad] Endereço:Department of Urology, University of Debrecen, Debrecen, Hungary. Electronic address: berczi@med.unideb.hu.
[Ti] Título:Acquired Hemophilia Caused by Ureteral Tumor.
[So] Source:Clin Genitourin Cancer;13(6):e387-9, 2015 Dec.
[Is] ISSN:1938-0682
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Hemofilia A/diagnóstico
Neoplasias Ureterais/complicações
[Mh] Termos MeSH secundário: Fator VIIIa/uso terapêutico
Feminino
Hematúria/diagnóstico
Hematúria/tratamento farmacológico
Hemofilia A/tratamento farmacológico
Seres Humanos
Masculino
Meia-Idade
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
72175-66-7 (Factor VIIIa)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151107
[Lr] Data última revisão:
151107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150628
[St] Status:MEDLINE


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[PMID]:26028322
[Au] Autor:Silvain J
[Ad] Endereço:ACTION Study Group, Institute of Cardiology, Pitié-Salpêtrière Hospital (APHP), University Pierre et Marie Curie 6 (UPMC).
[Ti] Título:Assessment of the Anticoagulation Activity of Apixaban--Reply.
[So] Source:Circ J;79(7):1642, 2015.
[Is] ISSN:1347-4820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Mh] Termos MeSH primário: Fatores de Coagulação Sanguínea/farmacologia
Fator VIII/farmacologia
Fator VIIIa/farmacologia
Hemostasia/efeitos dos fármacos
Rivaroxabana/farmacologia
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:COMMENT; LETTER
[Nm] Nome de substância:
0 (Blood Coagulation Factors); 72175-66-7 (Factor VIIIa); 9001-27-8 (Factor VIII); 9NDF7JZ4M3 (Rivaroxaban)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150629
[Lr] Data última revisão:
150629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150602
[St] Status:MEDLINE
[do] DOI:10.1253/circj.CJ-15-0487


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[PMID]:26028321
[Au] Autor:Gonçalves LR; Araújo F
[Ad] Endereço:Department of Transfusion Medicine, Centre of Thrombosis and Hemostasis, São João University Hospital, Faculty of Medicine, Porto University.
[Ti] Título:Assessment of the Anticoagulation Activity of Apixaban.
[So] Source:Circ J;79(7):1641, 2015.
[Is] ISSN:1347-4820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Mh] Termos MeSH primário: Fatores de Coagulação Sanguínea/farmacologia
Fator VIII/farmacologia
Fator VIIIa/farmacologia
Hemostasia/efeitos dos fármacos
Rivaroxabana/farmacologia
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:COMMENT; LETTER
[Nm] Nome de substância:
0 (Blood Coagulation Factors); 72175-66-7 (Factor VIIIa); 9001-27-8 (Factor VIII); 9NDF7JZ4M3 (Rivaroxaban)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150629
[Lr] Data última revisão:
150629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150602
[St] Status:MEDLINE
[do] DOI:10.1253/circj.CJ-15-0399


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[PMID]:26023895
[Au] Autor:Lu Q; Yang L; Manithody C; Wang X; Rezaie AR
[Ad] Endereço:†Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
[Ti] Título:Expression and Characterization of Gly-317 Variants of Factor IX Causing Variable Bleeding in Hemophilia B Patients.
[So] Source:Biochemistry;54(24):3814-21, 2015 Jun 23.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We recently identified two hemophilia B patients who carried Gly-317 to Arg (FIX-G317R) or Gly-317 to Glu (FIX-G317E) substitutions in their FIX gene. The former mutation caused severe and the latter moderate bleeding in afflicted patients. To understand the molecular basis for the variable clinical manifestation of Gly-317 mutations, we prepared recombinant G317R and G317E derivatives of FIX and compared their kinetic properties to those of recombinant wild-type FIX in appropriate assay systems. Both physiological activators, factor XIa and extrinsic Tenase (factor VIIa-tissue factor), activated both zymogen variants with an ∼1.5-fold elevated K(m); however, extrinsic Tenase activated FIX-G317E with an ∼2-fold improved k(cat). By contrast to zymogen activation, the catalytic activities of both FIXa-G317R and FIXa-G317E enzymes toward the natural substrate, factor X, were dramatically (>4 orders of magnitude) impaired, but their apparent affinity for interaction with factor VIIIa was only slightly (<2-fold) decreased. Further studies revealed that the reactivity of FIXa-G317R and FIXa-G317E with antithrombin has been impaired 10- and 13-fold, respectively, in the absence and 166- and 500-fold, respectively, in the presence of pentasaccharide. As expected, the clotting activities of FIX variants could not be measured by the aPTT assay. These results implicate a critical role for Gly-317 in maintaining normal catalytic function for FIX/FIXa in the clotting cascade. The results further suggest that improved k(cat) of FIX-G317E activation in the extrinsic pathway together with dramatically impaired reactivity of FIXa-G317E with antithrombin may account for the less severe bleeding phenotype of a hemophilia B patient carrying the FIX-G317E mutation.
[Mh] Termos MeSH primário: Precursores Enzimáticos/metabolismo
Fator IX/metabolismo
Glicina/química
Hemofilia B/genética
Hemorragia/etiologia
Proteínas Mutantes/metabolismo
Mutação
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Cisteína Endopeptidases/metabolismo
Ativação Enzimática
Precursores Enzimáticos/genética
Fator IX/genética
Fator VIIIa/metabolismo
Fator X/metabolismo
Fator XIa/metabolismo
Células HEK293
Hemofilia B/metabolismo
Hemofilia B/fisiopatologia
Seres Humanos
Cinética
Masculino
Mutagênese Sítio-Dirigida
Proteínas de Neoplasias/metabolismo
Proteínas Recombinantes/metabolismo
Índice de Gravidade de Doença
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Enzyme Precursors); 0 (Mutant Proteins); 0 (Neoplasm Proteins); 0 (Recombinant Proteins); 72175-66-7 (Factor VIIIa); 9001-28-9 (Factor IX); 9001-29-0 (Factor X); EC 3.4.21.27 (Factor XIa); EC 3.4.22.- (Cysteine Endopeptidases); EC 3.4.22.26 (cancer procoagulant); TE7660XO1C (Glycine)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150530
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.5b00270


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[PMID]:26012870
[Au] Autor:Baroni M; Pavani G; Pinotti M; Branchini A; Bernardi F; Camire RM
[Ad] Endereço:Department of Life Sciences and Biotechnology, University of Ferrara, Italy. Electronic address: marcello.baroni@unife.it.
[Ti] Título:Asymmetric processing of mutant factor X Arg386Cys reveals differences between intrinsic and extrinsic pathway activation.
[So] Source:Biochim Biophys Acta;1854(10 Pt A):1351-6, 2015 Oct.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Alterations in coagulation factor X (FX) activation, mediated by the extrinsic VIIa/tissue factor (FVIIa/TF) or the intrinsic factor IXa/factor VIIIa (FIXa/FVIIIa) complexes, can result in hemorrhagic/prothrombotic tendencies. However, the molecular determinants involved in substrate recognition by these enzymes are poorly defined. Here, we investigated the role of arginine 386 (chymotrypsin numbering c202), a surface-exposed residue on the FX catalytic domain. The naturally occurring FX386Cys mutant and FX386Ala variant were characterized. Despite the unpaired cysteine, recombinant (r)FX386Cys was efficiently secreted (88.6±21.3% of rFXwt) and possessed normal clearance in mice. rFX386Cys was also normally activated by FVIIa/TF and displayed intact amidolytic activity. In contrast, rFX386Cys activation by the FIXa/FVIIIa complex was 4.5-fold reduced, which was driven by a decrease in the kcat (1.6∗10(-4) s(-1) vs 5.8∗10(-4) s(-1), rFXwt). The virtually unaltered Km (70.6 nM vs 55.6nM, rFXwt) suggested no major alterations in the FX substrate exosite. Functional assays in plasma supplemented with rFX386Cys indicated a remarkable reduction in the thrombin generation rate and thus in coagulation efficiency. Consistently, the rFX386Ala variant displayed similar biochemical features suggesting that global changes at position 386 impact the intrinsic pathway activation. These data indicate that the FXArg386 is involved in FIXa/FVIIIa-mediated FX activation and help in elucidating the bleeding tendency associated with the FX386Cys in a rare FX deficiency case. Taking advantage of the unpaired cysteine, the rFX386Cys mutant may be efficiently targeted by thiol-specific ligands and represent a valuable tool to study FX structure-function relationships both in vitro and in vivo.
[Mh] Termos MeSH primário: Coagulação Sanguínea/genética
Fator X/metabolismo
Fator Xa/metabolismo
Mutação
[Mh] Termos MeSH secundário: Animais
Testes de Coagulação Sanguínea
Domínio Catalítico
Fator IXa/genética
Fator IXa/metabolismo
Fator VIIIa/genética
Fator VIIIa/metabolismo
Fator X/química
Fator X/genética
Fator Xa/química
Fator Xa/genética
Células HEK293
Seres Humanos
Cinética
Metaloendopeptidases/genética
Metaloendopeptidases/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Ligação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Trombina/genética
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Recombinant Proteins); 72175-66-7 (Factor VIIIa); 9001-29-0 (Factor X); EC 3.4.21.22 (Factor IXa); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa); EC 3.4.24.- (Metalloendopeptidases); EC 3.4.24.58 (russellysin)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150528
[St] Status:MEDLINE


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[PMID]:25927594
[Au] Autor:Gomperts E
[Ad] Endereço:Division of Hematology-Oncology, Children's Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
[Ti] Título:Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A.
[So] Source:Expert Rev Hematol;8(4):427-32, 2015 Aug.
[Is] ISSN:1747-4094
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hemophilia A is an inherited deficiency of clotting factor VIII (FVIII) often complicated by inhibitor development (CHAWI) in which neutralizing antibodies block the therapeutic benefit of replacement therapy. Inhibitors to FVIII can also be seen in an auto-immune disease known as acquired hemophilia A (AHA). 'Bypassing' therapies have been shown to provide hemostasis but dosing must be done empirically because current assays cannot measure objective markers of treatment efficacy and safety. A recombinant porcine sequence factor VIII (r-pFVIII) has been developed for the management of AHA. Preclinical, Phase I and Phase II clinical research studies in CHAWI subjects showed therapeutic potential and safety of this agent. A Phase II/III study in AHA with serious bleeding episodes shows a positive response in all subjects after administration. Based on current preclinical and clinical trial data, r-pFVIII should become the first line of treatment in the management of hemorrhage in patients with AHA.
[Mh] Termos MeSH primário: Fator VIIIa/uso terapêutico
Hemofilia A/tratamento farmacológico
Proteínas Recombinantes/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Animais
Ensaios Clínicos Fase I como Assunto
Ensaios Clínicos Fase II como Assunto
Ensaios Clínicos Fase III como Assunto
Fator VIIIa/farmacologia
Hemofilia A/diagnóstico
Seres Humanos
Proteínas Recombinantes/farmacologia
Índice de Gravidade de Doença
Suínos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Recombinant Proteins); 72175-66-7 (Factor VIIIa)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150707
[Lr] Data última revisão:
150707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150501
[St] Status:MEDLINE
[do] DOI:10.1586/17474086.2015.1040758


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[PMID]:25795563
[Au] Autor:Perot E; Enjolras N; Le Quellec S; Indalecio A; Girard J; Negrier C; Dargaud Y
[Ad] Endereço:EA 4174, Hemostase, Inflammation & Sepsis, Universite Lyon1, Faculte de Medecine Laennec, 69372 Lyon cedex 08, France.
[Ti] Título:Expression and characterization of a novel human recombinant factor IX molecule with enhanced in vitro and in vivo clotting activity.
[So] Source:Thromb Res;135(5):1017-24, 2015 May.
[Is] ISSN:1879-2472
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Hemophilia B is an inherited X-linked recessive bleeding disorder, due to a defect in human factor IX (FIX). The main treatment for hemophilia B is replacement therapy using FIX concentrates. Prophylactic treatment in severe hemophilia B is very effective but is limited by cost issues. Production of a recombinant FIX (rFIX) with enhanced clotting activity, offering the possibility of fewer infusions and fewer costs with similar efficacy, is one of the current challenges for hemophilia B treatment. The present study focused on an important amino acid sequence known to be involved in the interaction of activated FIX (FIXa) with its cofactor, activated factor VIII (FVIIIa). MATERIALS AND METHODS: Using site-directed mutagenesis of glutamate E410 (c240, chymotrypsin numbering), four recombinant FIX-E410 (E410H, A, L and N) mutants were developed and produced by the human hepatoma cell line Huh-7. RESULTS: The in-vitro clotting activity of mutant FIX molecules was 3 to 5-fold higher than wild-type recombinant FIX (FIX-WT). FIX-E410H compound showed the highest in-vitro procoagulant activity. Enhanced specific activity was confirmed using thrombin generation assay. FIX-E410H induced 5.2-fold higher thrombin generation than FIX-WT. In hemophilia B mice, we observed significantly higher in-vivo clotting activity and thrombin generating capacity with FIX-E410H compared to FIX-WT. We demonstrated that increased procoagulant activity of FIX-E410H was mainly explained by 2.5- fold enhanced affinity of the mutant for human FVIIIa. CONCLUSION: We have engineered and characterized four improved FIX proteins with enhanced in-vitro and in-vivo activity. Future studies are required to evaluate the immunogenicity of FIX-E410.
[Mh] Termos MeSH primário: Fator IX/genética
Fator IX/uso terapêutico
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Coagulação Sanguínea/efeitos dos fármacos
Testes de Coagulação Sanguínea
Plaquetas/metabolismo
Linhagem Celular
Modelos Animais de Doenças
Fator IX/metabolismo
Fator VIIIa/metabolismo
Fator VIIa/metabolismo
Fator XIa/metabolismo
Expressão Gênica
Hemofilia B/sangue
Hemofilia B/tratamento farmacológico
Hemofilia B/genética
Seres Humanos
Técnicas In Vitro
Masculino
Camundongos
Camundongos Mutantes
Mutagênese Sítio-Dirigida
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Proteínas Recombinantes/uso terapêutico
Tromboplastina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Recombinant Proteins); 72175-66-7 (Factor VIIIa); 9001-28-9 (Factor IX); 9035-58-9 (Thromboplastin); EC 3.4.21.21 (Factor VIIa); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150429
[Lr] Data última revisão:
150429
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150322
[St] Status:MEDLINE



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