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Pesquisa : D12.776.124.125.300.300 [Categoria DeCS]
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[PMID]:27421960
[Au] Autor:Deguchi H; Sinha RK; Marchese P; Ruggeri ZM; Zilberman-Rudenko J; McCarty OJT; Cohen MJ; Griffin JH
[Ad] Endereço:Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
[Ti] Título:Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va.
[So] Source:Blood;128(14):1870-1878, 2016 Oct 06.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To test the hypothesis that skeletal muscle myosins can directly influence blood coagulation and thrombosis, ex vivo studies of the effects of myosin on thrombogenesis in fresh human blood were conducted. Addition of myosin to blood augmented the thrombotic responses of human blood flowing over collagen-coated surfaces (300 s shear rate). Perfusion of human blood over myosin-coated surfaces also caused fibrin and platelet deposition, evidencing myosin's thrombogenicity. Myosin markedly enhanced thrombin generation in both platelet-rich plasma and platelet-poor plasma, indicating that myosin promoted thrombin generation in plasma primarily independent of platelets. In purified reaction mixtures composed only of factor Xa, factor Va, prothrombin, and calcium ions, myosin greatly enhanced prothrombinase activity. The Gla domain of factor Xa was not required for myosin's prothrombinase enhancement. When binding of purified clotting factors to immobilized myosin was monitored using biolayer interferometry, factors Xa and Va each showed favorable binding interactions. Factor Va reduced by 100-fold the apparent of myosin for factor Xa ( ∼0.48 nM), primarily by reducing k , indicating formation of a stable ternary complex of myosin:Xa:Va. In studies to assess possible clinical relevance for this discovery, we found that antimyosin antibodies inhibited thrombin generation in acute trauma patient plasmas more than in control plasmas ( = .0004), implying myosin might contribute to acute trauma coagulopathy. We posit that myosin enhancement of thrombin generation could contribute either to promote hemostasis or to augment thrombosis risk with consequent implications for myosin's possible contributions to pathophysiology in the setting of acute injuries.
[Mh] Termos MeSH primário: Fator Va/metabolismo
Fator Xa/metabolismo
Protrombina/metabolismo
Miosinas de Músculo Esquelético/farmacologia
Trombose/patologia
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Circulação Sanguínea/efeitos dos fármacos
Estudos de Casos e Controles
Seres Humanos
Proteínas Imobilizadas/farmacologia
Interferometria
Modelos Biológicos
Plasma Rico em Plaquetas/metabolismo
Ligação Proteica/efeitos dos fármacos
Coelhos
Trombose/metabolismo
Ferimentos e Lesões/sangue
Ferimentos e Lesões/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immobilized Proteins); 65522-14-7 (Factor Va); 9001-26-7 (Prothrombin); EC 3.4.21.6 (Factor Xa); EC 3.6.1.- (Skeletal Muscle Myosins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160717
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-03-707679


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[PMID]:26974491
[Au] Autor:Kamisato C; Furugohri T; Morishima Y
[Ad] Endereço:Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
[Ti] Título:A direct thrombin inhibitor suppresses protein C activation and factor Va degradation in human plasma: Possible mechanisms of paradoxical enhancement of thrombin generation.
[So] Source:Thromb Res;141:77-83, 2016 May.
[Is] ISSN:1879-2472
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have demonstrated that antithrombin (AT)-independent thrombin inhibitors paradoxically increase thrombin generation (TG) in human plasma in a thrombomodulin (TM)- and protein C (PC)-dependent manner. We determined the effects of AT-independent thrombin inhibitors on the negative-feedback system, activation of PC and production and degradation of factor Va (FVa), as possible mechanisms underlying the paradoxical enhancement of TG. TG in human plasma containing 10nM TM was assayed by means of the calibrated automated thrombography. As an index of PC activation, plasma concentration of activated PC-PC inhibitor complex (aPC-PCI) was measured. The amounts of FVa heavy chain and its degradation product (FVa(307-506)) were examined by western blotting. AT-independent thrombin inhibitors, melagatran and dabigatran (both at 25-600nM) and 3-30µg/ml active site-blocked thrombin (IIai), increased peak levels of TG. Melagatran, dabigatran and IIai significantly decreased plasma concentration of aPC-PCI complex at 25nM or more, 75nM or more, and 10 and 30µg/ml, respectively. Melagatran (300nM) significantly increased FVa and decreased FVa(307-506). In contrast, a direct factor Xa inhibitor edoxaban preferentially inhibited thrombin generation (≥25nM), and higher concentrations were required to inhibit PC activation (≥150nM) and FVa degradation (300nM). The present study suggests that the inhibitions of protein C activation and subsequent degradation of FVa and increase in FVa by antithrombin-independent thrombin inhibitors may contribute to the paradoxical TG enhancement, and edoxaban may inhibit PC activation and FVa degradation as a result of TG suppression.
[Mh] Termos MeSH primário: Antitrombinas/farmacologia
Azetidinas/farmacologia
Benzilaminas/farmacologia
Ativação Enzimática/efeitos dos fármacos
Fator Va/metabolismo
Proteína C/antagonistas & inibidores
Proteólise/efeitos dos fármacos
Trombina/metabolismo
[Mh] Termos MeSH secundário: Coagulação Sanguínea/efeitos dos fármacos
Testes de Coagulação Sanguínea
Seres Humanos
Proteína C/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antithrombins); 0 (Azetidines); 0 (Benzylamines); 0 (Protein C); 2A9QP32MD4 (melagatran); 65522-14-7 (Factor Va); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160315
[St] Status:MEDLINE


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[PMID]:26960296
[Au] Autor:Gale AJ; Bhat V; Pellequer JL; Griffin JH; Mosnier LO; Von Drygalski A
[Ad] Endereço:Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, California, USA. gale.andy@gmail.com.
[Ti] Título:Safety, Stability and Pharmacokinetic Properties of (super)Factor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding.
[So] Source:Pharm Res;33(6):1517-26, 2016 06.
[Is] ISSN:1573-904X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Activated (super)Factor V ((super)FVa) is a novel engineered FV with excellent prohemostatic efficacy. (Super)FVa has three APC cleavage site mutations and an interdomain disulfide bond. Stability, pharmacokinetics, and immunogenic and thrombogenic potential are reported here. METHODS: Stability and circulating half-life were determined after incubation in buffer and human plasma, and after injection into FVIII-deficient mice. Immunogenicity potential was assessed by B- and T-cell specific epitope prediction and structural analysis using surface area and atomic depth computation. Thrombogenic potential was determined by quantification of lung fibrin deposition in wild-type mice after intravenous injection of (super)FVa (200 U/kg), recombinant human (rh) Tissue Factor (0.4-16 pmol/kg), rhFVIIa (3 mg/kg) or saline. RESULTS: FVa retained full activity over 30 h in buffer, the functional half-life in human plasma was 4.9 h, and circulating half-life in FVIII-deficient mice was ~30 min. Predicted immunogenicity was not increased compared to human FV. While rh Tissue Factor, the positive control, resulted in pronounced lung fibrin depositions (mean 121 µg/mL), (super)FVa did not (6.7 µg/mL), and results were comparable to fibrin depositions with rhFVIIa (7.6 µg/mL) or saline (5.6 µg/mL). CONCLUSION: FVa has an appropriate safety and stability profile for further preclinical development as a prohemostatic against severe bleeding.
[Mh] Termos MeSH primário: Fator Va/farmacocinética
Hemofilia A/tratamento farmacológico
Hemostáticos/farmacocinética
Engenharia de Proteínas/métodos
Proteínas Recombinantes/farmacocinética
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Estabilidade de Medicamentos
Fator VIII/genética
Fator VIII/metabolismo
Fator Va/administração & dosagem
Fator Va/genética
Fator Va/toxicidade
Feminino
Fibrina/metabolismo
Meia-Vida
Hemofilia A/sangue
Hemofilia A/genética
Hemostáticos/administração & dosagem
Hemostáticos/toxicidade
Seres Humanos
Injeções Intravenosas
Pulmão/efeitos dos fármacos
Pulmão/metabolismo
Masculino
Camundongos Endogâmicos BALB C
Camundongos Knockout
Mutagênese Sítio-Dirigida
Mutação
Estabilidade Proteica
Proteínas Recombinantes/administração & dosagem
Proteínas Recombinantes/genética
Proteínas Recombinantes/toxicidade
Índice de Gravidade de Doença
Trombina/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Hemostatics); 0 (Recombinant Proteins); 65522-14-7 (Factor Va); 9001-27-8 (Factor VIII); 9001-31-4 (Fibrin); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160311
[St] Status:MEDLINE
[do] DOI:10.1007/s11095-016-1895-3


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[PMID]:26721892
[Au] Autor:Mattheij NJ; Swieringa F; Mastenbroek TG; Berny-Lang MA; May F; Baaten CC; van der Meijden PE; Henskens YM; Beckers EA; Suylen DP; Nolte MW; Hackeng TM; McCarty OJ; Heemskerk JW; Cosemans JM
[Ad] Endereço:Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
[Ti] Título:Coated platelets function in platelet-dependent fibrin formation via integrin αIIbß3 and transglutaminase factor XIII.
[So] Source:Haematologica;101(4):427-36, 2016 Apr.
[Is] ISSN:1592-8721
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:Coated platelets, formed by collagen and thrombin activation, have been characterized in different ways: i) by the formation of a protein coat of α-granular proteins; ii) by exposure of procoagulant phosphatidylserine; or iii) by high fibrinogen binding. Yet, their functional role has remained unclear. Here we used a novel transglutaminase probe, Rhod-A14, to identify a subpopulation of platelets with a cross-linked protein coat, and compared this with other platelet subpopulations using a panel of functional assays. Platelet stimulation with convulxin/thrombin resulted in initial integrin α(IIb)ß3 activation, the appearance of a platelet population with high fibrinogen binding, (independently of active integrins, but dependent on the presence of thrombin) followed by phosphatidylserine exposure and binding of coagulation factors Va and Xa. A subpopulation of phosphatidylserine-exposing platelets bound Rhod-A14 both in suspension and in thrombi generated on a collagen surface. In suspension, high fibrinogen and Rhod-A14 binding were antagonized by combined inhibition of transglutaminase activity and integrin α(IIb)ß3 Markedly, in thrombi from mice deficient in transglutaminase factor XIII, platelet-driven fibrin formation and Rhod-A14 binding were abolished by blockage of integrin α(IIb)ß3. Vice versa, star-like fibrin formation from platelets of a patient with deficiency in α(IIb)ß3(Glanzmann thrombasthenia) was abolished upon blockage of transglutaminase activity. We conclude that coated platelets, with initial α(IIb)ß3 activation and high fibrinogen binding, form a subpopulation of phosphatidylserine-exposing platelets, and function in platelet-dependent star-like fibrin fiber formation via transglutaminase factor XIII and integrin α(IIb)ß3.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Fator XIII/metabolismo
Fibrina/metabolismo
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Trombastenia/sangue
[Mh] Termos MeSH secundário: Animais
Coagulação Sanguínea
Plaquetas/efeitos dos fármacos
Plaquetas/patologia
Venenos de Crotalídeos/farmacologia
Fator Va/química
Fator Va/metabolismo
Fator XIII/química
Fator Xa/química
Fator Xa/metabolismo
Fibrina/química
Fibrinogênio/química
Fibrinogênio/metabolismo
Seres Humanos
Lectinas Tipo C
Camundongos
Camundongos Knockout
Sondas Moleculares/química
Fosfatidilserinas/química
Fosfatidilserinas/metabolismo
Ativação Plaquetária/efeitos dos fármacos
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química
Cultura Primária de Células
Ligação Proteica
Trombastenia/patologia
Trombina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Crotalid Venoms); 0 (Lectins, C-Type); 0 (Molecular Probes); 0 (Phosphatidylserines); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 37206-04-5 (convulxin); 65522-14-7 (Factor Va); 9001-31-4 (Fibrin); 9001-32-5 (Fibrinogen); 9013-56-3 (Factor XIII); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160102
[St] Status:MEDLINE
[do] DOI:10.3324/haematol.2015.131441


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[PMID]:26660948
[Au] Autor:He Z; Si Y; Jiang T; Ma R; Zhang Y; Cao M; Li T; Yao Z; Zhao L; Fang S; Yu B; Dong Z; Thatte HS; Bi Y; Kou J; Yang S; Piao D; Hao L; Zhou J; Shi J
[Ti] Título:Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease.
[So] Source:Thromb Haemost;115(4):738-51, 2016 Apr.
[Is] ISSN:0340-6245
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Inflammatory bowel disease (IBD)-associated thromboembolic event often lacks precise aetiology. The aim of this study was to investigate the contribution of phosphatidylserine (PS) exposure and neutrophil extracellular traps (NETs) towards the hypercoagulable state in IBD. We demonstrated that the levels of PS exposed MPs and the sources of MP-origin, platelets, erythrocytes, leukocytes and cultured endothelial cells (ECs) were higher in IBD groups than in healthy controls using flow cytometry and confocal microscopy. Wright-Giemsa and immunofluorescence staining demonstrated that the elevated NETs were released by activated IBD neutrophils or by control neutrophils treated with IBD sera obtained from patients with the active disease. MPs and MP-origin cells in IBD groups, especially in active stage, markedly shortened coagulation time and had increased levels of fibrin, thrombin and FXa production as assessed by coagulation function assays. Importantly, we found that on stimulated ECs, PS rich membranes provided binding sites for FXa and FVa, promoting fibrin formation while TNF blockage or IgG depletion attenuated this effect. Treatment of control neutrophils with TNF and isolated IgG from PR3-ANCA-positive active IBD patients also resulted in the release of NETs. Blockade of PS with lactadherin prolonged coagulation time, decreased fibrin formation to control levels, and inhibited the procoagulant enzymes production in the MPs and MP-origin cells. NET cleavage by DNase I partly decreased PCA in IBD or stimulated neutrophils. Our study reveals a previously unrecognised link between hypercoagulable state and PS exposure or NETs, and may further explain the epidemiological association of thrombosis within IBD patients.
[Mh] Termos MeSH primário: Coagulação Sanguínea/efeitos dos fármacos
Micropartículas Derivadas de Células/efeitos dos fármacos
Desoxirribonuclease I/farmacologia
Armadilhas Extracelulares/efeitos dos fármacos
Armadilhas Extracelulares/metabolismo
Doenças Inflamatórias Intestinais/sangue
Fosfatidilserinas/farmacologia
Trombofilia/sangue
[Mh] Termos MeSH secundário: Adulto
Idoso
Antígenos de Superfície/farmacologia
Micropartículas Derivadas de Células/fisiologia
Células Cultivadas
Fator Va/metabolismo
Fator Xa/metabolismo
Feminino
Fibrina/metabolismo
Seres Humanos
Masculino
Meia-Idade
Proteínas do Leite/farmacologia
Ligação Proteica/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Surface); 0 (MFGE8 protein, human); 0 (Milk Proteins); 0 (Phosphatidylserines); 65522-14-7 (Factor Va); 9001-31-4 (Fibrin); EC 3.1.21.1 (Deoxyribonuclease I); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161231
[Lr] Data última revisão:
161231
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.1160/TH15-09-0710


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[PMID]:26607136
[Au] Autor:Peraramelli S; Thomassen S; Heinzmann A; Hackeng TM; Hartmann R; Scheiflinger F; Dockal M; Rosing J
[Ti] Título:Role of exosite binding modulators in the inhibition of Fxa by TFPI.
[So] Source:Thromb Haemost;115(3):580-90, 2016 Mar.
[Is] ISSN:0340-6245
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Tissue factor pathway inhibitor (TFPI) down-regulates the extrinsic coagulation pathway by inhibiting FXa and FVIIa. Both TFPI and FXa interact with several plasma proteins (e. g. prothrombin, FV/FVa, protein S) and non-proteinaceous compounds (e. g. phospholipids, heparin). It was our aim to investigate effects of ligands that bind to FXa and TFPI on FXa inhibition by full-length TFPI (designated TFPI) and truncated TFPI (TFPI1-150). Inhibition of FXa by TFPI and TFPI1-150 and effects of phospholipids, heparin, prothrombin, FV, FVa, and protein S thereon was quantified from progress curves of conversion of the FXa-specific chromogenic substrate CS11-(65). Low concentrations negatively charged phospholipids (~10 µM) already maximally stimulated (up to 5- to 6-fold) FXa inhibition by TFPI. Unfractionated heparin at concentrations (0.2-1 U/ml) enhanced FXa inhibition by TFPI ~8-fold, but impaired inhibition at concentrations > 1 U/ml. Physiological protein S and FV concentrations both enhanced FXa inhibition by TFPI 2- to 3-fold. In contrast, thrombin-activated FV (FVa) impaired the ability of TFPI to inhibit FXa. FXa inhibition by TFPI1-150 was not affected by FV, FVa, protein S, phospholipids and heparin. TFPI potently inhibited FXa-catalysed prothrombin activation in the absence of FVa, but hardly inhibited prothrombin activation in the presence of thrombin-activated FVa. In conclusion, physiological concentrations TFPI (0.25-0.5 nM TFPI) inhibit FXa with a t1/2 between 3-15 minutes. Direct FXa inhibition by TFPI is modulated by physiological concentrations prothrombin, FV, FVa, protein S, phospholipids and heparin indicating the importance of these modulators for the in vivo anticoagulant activity of TFPI.
[Mh] Termos MeSH primário: Inibidores do Fator Xa/química
Fator Xa/química
Lipoproteínas/química
[Mh] Termos MeSH secundário: Coagulação Sanguínea
Catálise
Fator V/química
Fator Va/química
Heparina/química
Heparina de Baixo Peso Molecular/química
Seres Humanos
Ligantes
Fosfolipídeos/química
Polissacarídeos/química
Ligação Proteica
Proteína S/química
Protrombina/química
Proteínas Recombinantes/química
Trombina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Factor Xa Inhibitors); 0 (Heparin, Low-Molecular-Weight); 0 (Ligands); 0 (Lipoproteins); 0 (Phospholipids); 0 (Polysaccharides); 0 (Protein S); 0 (Recombinant Proteins); 0 (lipoprotein-associated coagulation inhibitor); 65522-14-7 (Factor Va); 9001-24-5 (Factor V); 9001-26-7 (Prothrombin); 9005-49-6 (Heparin); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170210
[Lr] Data última revisão:
170210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151127
[St] Status:MEDLINE
[do] DOI:10.1160/TH15-04-0354


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[PMID]:26601957
[Au] Autor:Wiencek JR; Hirbawi J; Yee VC; Kalafatis M
[Ad] Endereço:From the Department of Chemistry and Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio 44115.
[Ti] Título:The Dual Regulatory Role of Amino Acids Leu480 and Gln481 of Prothrombin.
[So] Source:J Biol Chem;291(4):1565-81, 2016 Jan 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prothrombin (FII) is activated to α-thrombin (IIa) by prothrombinase. Prothrombinase is composed of a catalytic subunit, factor Xa (fXa), and a regulatory subunit, factor Va (fVa), assembled on a membrane surface in the presence of divalent metal ions. We constructed, expressed, and purified several mutated recombinant FII (rFII) molecules within the previously determined fVa-dependent binding site for fXa (amino acid region 473-487 of FII). rFII molecules bearing overlapping deletions within this significant region first established the minimal stretch of amino acids required for the fVa-dependent recognition exosite for fXa in prothrombinase within the amino acid sequence Ser(478)-Val(479)-Leu(480)-Gln(481)-Val(482). Single, double, and triple point mutations within this stretch of rFII allowed for the identification of Leu(480) and Gln(481) as the two essential amino acids responsible for the enhanced activation of FII by prothrombinase. Unanticipated results demonstrated that although recombinant wild type α-thrombin and rIIa(S478A) were able to induce clotting and activate factor V and factor VIII with rates similar to the plasma-derived molecule, rIIa(SLQ→AAA) with mutations S478A/L480A/Q481A was deficient in clotting activity and unable to efficiently activate the pro-cofactors. This molecule was also impaired in protein C activation. Similar results were obtained with rIIa(ΔSLQ) (where rIIa(ΔSLQ) is recombinant human α-thrombin with amino acids Ser(478)/Leu(480)/Gln(481) deleted). These data provide new evidence demonstrating that amino acid sequence Leu(480)-Gln(481): 1) is crucial for proper recognition of the fVa-dependent site(s) for fXa within prothrombinase on FII, required for efficient initial cleavage of FII at Arg(320); and 2) is compulsory for appropriate tethering of fV, fVIII, and protein C required for their timely activation by IIa.
[Mh] Termos MeSH primário: Glutamina/metabolismo
Leucina/metabolismo
Protrombina/química
Protrombina/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sequência de Aminoácidos
Fator Va/genética
Fator Va/metabolismo
Fator Xa/genética
Fator Xa/metabolismo
Glutamina/genética
Seres Humanos
Leucina/genética
Dados de Sequência Molecular
Proteína C/genética
Proteína C/metabolismo
Processamento de Proteína Pós-Traducional
Protrombina/genética
Tromboplastina/genética
Tromboplastina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein C); 0RH81L854J (Glutamine); 65522-14-7 (Factor Va); 9001-26-7 (Prothrombin); 9035-58-9 (Thromboplastin); EC 3.4.21.6 (Factor Xa); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170125
[Lr] Data última revisão:
170125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151126
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.691956


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[PMID]:26466980
[Au] Autor:Bhat V; von Drygalski A; Gale AJ; Griffin JH; Mosnier LO
[Ti] Título:Improved coagulation and haemostasis in haemophilia with inhibitors by combinations of superFactor Va and Factor VIIa.
[So] Source:Thromb Haemost;115(3):551-61, 2016 Mar.
[Is] ISSN:0340-6245
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Bypassing inhibitors in haemophilia patients is limited to activated (a) Factor(F)VII products. We introduced "FVa activity augmentation" as another bypassing strategy and studied effects of an engineered FVa variant designated superFVa. Procoagulant and clot stabilising properties of superFVa and recombinant human (rh)FVIIa, either alone or in combination, were studied in thrombin generation and clot lysis assays in normal human plasma (NHP) with or without anti-FVIII inhibitors, in haemophilia plasma, and in FVIII-deficient mice or in wild-type mice with anti-FVIII inhibitors. SuperFVa was as effective as rhFVIIa to improve thrombin generation or clot lysis. Furthermore, procoagulant effects were significantly enhanced when these compounds were combined. RhFVIIa at 40 nM (a therapeutic concentration) improved thrombin generation mildly, but markedly improved thrombin generation when combined with a low concentration (e. g. 3 nM) of superFVa. In clot lysis studies, the concentration of rhFVIIa to normalise clot lysis times could be reduced by 100-fold (e. g. from 40 nM to 0.4 nM) when combined with a low concentration (0.37 nM) of superFVa. In haemostasis studies of FVIII-deficient mice, blood loss was dose-dependently reduced by either superFVa or rhFVIIa. SuperFVa (200 U/kg) corrected mean blood loss indistinguishably from rhFVIII. Blood loss correction by rhFVIIa was greatly improved when combined with superFVa. Similar blood loss correction results were observed for therapies in wild-type mice after infusion with anti-FVIII inhibitors. Thus, superFVa may be an effective procoagulant agent in the setting of haemophilia with inhibitors and it merits further evaluation for new bypassing strategies.
[Mh] Termos MeSH primário: Coagulação Sanguínea/efeitos dos fármacos
Coagulantes/administração & dosagem
Fator VIIa/administração & dosagem
Fator Va/administração & dosagem
Hemofilia A/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos/química
Relação Dose-Resposta a Droga
Fator VIII/antagonistas & inibidores
Feminino
Hemofilia A/sangue
Hemostasia
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Proteínas Recombinantes/administração & dosagem
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Coagulants); 0 (Recombinant Proteins); 65522-14-7 (Factor Va); 9001-27-8 (Factor VIII); AC71R787OV (recombinant FVIIa); EC 3.4.21.21 (Factor VIIa); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170303
[Lr] Data última revisão:
170303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151016
[St] Status:MEDLINE
[do] DOI:10.1160/TH15-07-0525


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[PMID]:26263376
[Au] Autor:Yegneswaran S; Banerjee Y; Fernández JA; Deguchi H; Griffin JH
[Ad] Endereço:Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
[Ti] Título:Lyso-Sulfatide Binds Factor Xa and Inhibits Thrombin Generation by the Prothrombinase Complex.
[So] Source:PLoS One;10(8):e0135025, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Blood coagulation reactions are strongly influenced by phospholipids, but little is known about the influence of sphingolipids on coagulation mechanisms. Lysosulfatide (lyso-SF) (sulfogalactosyl sphingosine) prolonged factor Xa (fXa) 1-stage plasma clotting assays, showing it had robust anticoagulant activity. In studies using purified clotting factors, lyso-SF inhibited >90% of prothrombin (II) activation for reaction mixtures containing fXa/factor Va (fVa)/II, and also inhibited II activation generation by fXa/ phospholipids and by Gla-domainless-fXa/fVa/phospholipids. When lyso-SF analogs were tested, results showed that N-acetyl-sulfatide was not anticoagulant, implying that the free amine group was essential for the anticoagulant effects of lyso-SF. Lyso-SF did not inhibit fXa enzymatic hydrolysis of small peptide substrates, showing it did not directly inhibit the fXa activity. In surface plasmon resonance studies, lyso-SF bound to immobilized inactivated fXa as well as inactivated Gla-domainless-fXa. Confirming this lyso-SF:fXa interaction, fluorescence studies showed that fluorescently-labeled-fXa in solution bound to lyso-SF. Thus, lyso-SF is an anticoagulant lipid that inhibits fXa when this enzyme is bound to either phospholipids or to fVa. Mechanisms for inhibition of procoagulant activity are likely to involve lyso-SF binding to fXa domain(s) that are distinct from the fXa Gla domain. This suggests that certain sphingolipids, including lyso-SF and some of its analogs, may down-regulate fXa activity without inhibiting the enzyme's active site or binding to the fXa Gla domain.
[Mh] Termos MeSH primário: Fator V/metabolismo
Fator Xa/metabolismo
Psicosina/análogos & derivados
Trombina/biossíntese
[Mh] Termos MeSH secundário: Coagulação Sanguínea/efeitos dos fármacos
Fator Va/metabolismo
Fator Xa/química
Fator Xa/farmacologia
Seres Humanos
Complexos Multiproteicos/metabolismo
Fosfolipídeos/metabolismo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Protrombina/antagonistas & inibidores
Psicosina/química
Psicosina/metabolismo
Psicosina/farmacologia
Trombina/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Multiprotein Complexes); 0 (Phospholipids); 0 (prothrombinase complex); 2238-90-6 (Psychosine); 65522-14-7 (Factor Va); 70005-46-8 (psychosine-3'-sulfate ester); 9001-24-5 (Factor V); 9001-26-7 (Prothrombin); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150812
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0135025


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[PMID]:25896652
[Au] Autor:Bouchard BA; Chapin J; Brummel-Ziedins KE; Durda P; Key NS; Tracy PB
[Ad] Endereço:Department of Biochemistry, and.
[Ti] Título:Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency.
[So] Source:Blood;125(23):3647-50, 2015 Jun 04.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Whole genome sequencing of an individual completely devoid of plasma- and platelet-derived factor V (FV) identified 167 variants in his F5 gene including previously identified and damaging missense mutations at rs6027 and Leu90Ser. Because the administration of fresh frozen plasma (FFP) prevents gastrointestinal bleeding in this individual, its effects on his plasma- and platelet-derived FV concentrations were assessed. The patient's plasma FV levels peaked by 2 hours following FFP administration and were undetectable 96 hours later. In contrast, increased platelet-derived FV/Va concentrations were observed within 6 hours, peaked at 24 hours, decreased slowly over 7 days, and originated from megakaryocyte endocytosis and intracellular processing of plasma FV. Ten days after transfusion, no thrombin was generated in a tissue factor-initiated whole blood clotting assay unless exogenous FV was added, consistent with the complete absence of plasma FV. In marked contrast, release of the patient's platelet-derived FV/Va (7% of normal) following platelet activation resulted in robust thrombin generation, similar to that in an individual with normal plasma- and platelet-derived FV concentrations. Thus, total FV deficiency can be corrected by plasma administration, which partially repletes and sustains the platelet cofactor pool, thereby highlighting the critical role of platelet-derived FV/Va in ensuring hemostatic competence.
[Mh] Termos MeSH primário: Transfusão de Componentes Sanguíneos
Plaquetas
Deficiência do Fator V/sangue
Deficiência do Fator V/terapia
Fator Va/administração & dosagem
Plasma
[Mh] Termos MeSH secundário: Idoso
Substituição de Aminoácidos
Deficiência do Fator V/complicações
Deficiência do Fator V/genética
Fator Va/genética
Fator Va/metabolismo
Hemorragia Gastrointestinal/sangue
Hemorragia Gastrointestinal/etiologia
Hemorragia Gastrointestinal/genética
Hemorragia Gastrointestinal/terapia
Seres Humanos
Masculino
Megacariócitos/metabolismo
Megacariócitos/patologia
Mutação de Sentido Incorreto
Tempo de Trombina
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
65522-14-7 (Factor Va)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150422
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2014-07-589580



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