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  1 / 2051 MEDLINE  
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[PMID]:29350259
[Au] Autor:Zhu X; Zhang J; Wang Q; Fu H; Chang Y; Kong Y; Lv M; Xu L; Liu K; Huang X; Zhang X
[Ad] Endereço:Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China.
[Ti] Título:Diminished expression of ß2-GPI is associated with a reduced ability to mitigate complement activation in anti-GPIIb/IIIa-mediated immune thrombocytopenia.
[So] Source:Ann Hematol;97(4):641-654, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Anti-GPIIb/IIIa-mediated complement activation has been reported to be important in the pathogenesis of immune thrombocytopenia (ITP). However, the role of the complement system and the involved regulatory mechanism remain equivocal. Beta2-glycoprotein I (ß2-GPI), known as the main target for antiphospholipid autoantibodies, has been demonstrated as a complement regulator. Here, we investigated the complement-regulatory role of ß2-GPI in anti-GPIIb/IIIa-mediated ITP. Plasma complement activation and enhanced complement activation capacity (CAC) were found in ITP patients with anti-GPIIb/IIIa antibodies in vivo and in vitro. Diminished plasma levels of ß2-GPI were shown in patients of this group, which was inversely correlated with C5b-9 deposition. C5b-9 generation was inhibited by approximate physiological concentrations of ß2-GPI, in a dose-dependent manner. Inhibition of C3a generation by ß2-GPI and the existence of ß2-GPI/C3 complexes in plasma indicated a regulation on the level of the C3 convertase. Furthermore, ß2-GPI down-regulated the phosphorylation levels of c-Jun N-terminal kinase (JNK) and cleavage of BH3 interacting domain death agonist (Bid) and ultimately harbored platelet lysis. Our findings may provide a novel link between diminished plasma levels of ß2-GPI and enhanced complement activation, indicating ß2-GPI as a potential diagnostic biomarker and therapeutic target in the treatment of anti-GPIIb/IIIa-mediated ITP.
[Mh] Termos MeSH primário: Ativação do Complemento
Regulação para Baixo
Isoanticorpos/metabolismo
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores
Púrpura Trombocitopênica Idiopática/metabolismo
beta 2-Glicoproteína I/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Biomarcadores/sangue
Plaquetas/imunologia
Plaquetas/metabolismo
Plaquetas/patologia
China/epidemiologia
Convertases de Complemento C3-C5/metabolismo
Complemento C3a/metabolismo
Feminino
Seres Humanos
Masculino
Meia-Idade
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Púrpura Trombocitopênica Idiopática/imunologia
Púrpura Trombocitopênica Idiopática/patologia
Púrpura Trombocitopênica Idiopática/fisiopatologia
Risco
Trombocitopenia/sangue
Trombocitopenia/imunologia
Trombocitopenia/metabolismo
Trombose/epidemiologia
Trombose/etiologia
Adulto Jovem
beta 2-Glicoproteína I/sangue
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Isoantibodies); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (beta 2-Glycoprotein I); 0 (glycoprotein receptor GPIb-IX); 80295-42-7 (Complement C3a); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3215-3


  2 / 2051 MEDLINE  
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[PMID]:28455282
[Au] Autor:Sim X; Jarocha D; Hayes V; Hanby HA; Marks MS; Camire RM; French DL; Poncz M; Gadue P
[Ad] Endereço:Department of Cell and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia, PA.
[Ti] Título:Identifying and enriching platelet-producing human stem cell-derived megakaryocytes using factor V uptake.
[So] Source:Blood;130(2):192-204, 2017 07 13.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Stem cell-derived platelets have the potential to replace donor platelets for transfusion. Defining the platelet-producing megakaryocytes (MKs) within the heterogeneous MK culture may help to optimize the in vitro generation of platelets. Using 2 human stem cell models of megakaryopoiesis, we identified novel MK populations corresponding to distinct maturation stages. An immature, low granular (LG) MK pool (defined by side scatter on flow cytometry) gives rise to a mature high granular (HG) pool, which then becomes damaged by apoptosis and glycoprotein Ib α chain (CD42b) shedding. We define an undamaged HG/CD42b MK subpopulation, which endocytoses fluorescently labeled coagulation factor V (FV) from the media into α-granules and releases functional FV CD42b human platelet-like particles in vitro and when infused into immunodeficient mice. Importantly, these FV particles have the same size distribution as infused human donor platelets and are preferentially incorporated into clots after laser injury. Using drugs to protect HG MKs from apoptosis and CD42b shedding, we also demonstrate that apoptosis precedes CD42b shedding and that apoptosis inhibition enriches the FV HG/CD42b MKs, leading to increased platelet yield in vivo, but not in vitro. These studies identify a transition between distinct MK populations in vitro, including one that is primed for platelet release. Technologies to optimize and select these platelet-ready MKs may be important to efficiently generate functional platelets from in vitro-grown MKs.
[Mh] Termos MeSH primário: Plaquetas/citologia
Células da Medula Óssea/imunologia
Fator V/genética
Células Progenitoras de Megacariócitos/citologia
Megacariócitos/citologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Arteríolas/efeitos dos fármacos
Arteríolas/imunologia
Arteríolas/lesões
Biomarcadores/sangue
Plaquetas/imunologia
Células da Medula Óssea/citologia
Células da Medula Óssea/efeitos dos fármacos
Diferenciação Celular
Linhagem da Célula/imunologia
Endocitose
Fator V/imunologia
Fator V/farmacologia
Citometria de Fluxo
Expressão Gênica
Seres Humanos
Imunofenotipagem
Lasers
Células Progenitoras de Megacariócitos/imunologia
Megacariócitos/imunologia
Camundongos
Camundongos SCID
Complexo Glicoproteico GPIb-IX de Plaquetas/genética
Complexo Glicoproteico GPIb-IX de Plaquetas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Biomarkers); 0 (Platelet Glycoprotein GPIb-IX Complex); 9001-24-5 (Factor V)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-01-761049


  3 / 2051 MEDLINE  
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[PMID]:29187375
[Au] Autor:Sharma R; Flood VH
[Ad] Endereço:Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI.
[Ti] Título:Advances in the diagnosis and treatment of Von Willebrand disease.
[So] Source:Blood;130(22):2386-2391, 2017 11 30.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
[Mh] Termos MeSH primário: Doenças de von Willebrand/diagnóstico
Doenças de von Willebrand/terapia
[Mh] Termos MeSH secundário: Animais
Colágeno/análise
Variação Genética
Hemorragia/diagnóstico
Hemorragia/genética
Hemorragia/terapia
Seres Humanos
Complexo Glicoproteico GPIb-IX de Plaquetas/análise
Doenças de von Willebrand/genética
Fator de von Willebrand/análise
Fator de von Willebrand/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Platelet Glycoprotein GPIb-IX Complex); 0 (adhesion receptor); 0 (von Willebrand Factor); 9007-34-5 (Collagen)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-05-782029


  4 / 2051 MEDLINE  
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[PMID]:28256724
[Au] Autor:Löf A; Müller JP; Brehm MA
[Ad] Endereço:Department of Physics and Center for NanoScience, LMU Munich, Munich, Germany.
[Ti] Título:A biophysical view on von Willebrand factor activation.
[So] Source:J Cell Physiol;233(2):799-810, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The process of hemostatic plug formation at sites of vascular injury crucially relies on the large multimeric plasma glycoprotein von Willebrand factor (VWF) and its ability to recruit platelets to the damaged vessel wall via interaction of its A1 domain with platelet GPIbα. Under normal blood flow conditions, VWF multimers exhibit a very low binding affinity for platelets. Only when subjected to increased hydrodynamic forces, which primarily occur in connection with vascular injury, VWF can efficiently bind to platelets. This force-regulation of VWF's hemostatic activity is not only highly intriguing from a biophysical perspective, but also of eminent physiological importance. On the one hand, it prevents undesired activity of VWF in intact vessels that could lead to thromboembolic complications and on the other hand, it enables efficient VWF-mediated platelet aggregation exactly where needed. Here, we review recent studies that mainly employed biophysical approaches in order to elucidate the molecular mechanisms underlying the complex mechano-regulation of the VWF-GPIbα interaction. Their results led to two main hypotheses: first, intramolecular shielding of the A1 domain is lifted upon force-induced elongation of VWF; second, force-induced conformational changes of A1 convert it from a low-affinity to a high-affinity state. We critically discuss these hypotheses and aim at bridging the gap between the large-scale behavior of VWF as a linear polymer in hydrodynamic flow and the detailed properties of the A1-GPIbα bond at the single-molecule level.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Hemostasia
Mecanotransdução Celular
Ativação Plaquetária
Fator de von Willebrand/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Hidrodinâmica
Agregação Plaquetária
Complexo Glicoproteico GPIb-IX de Plaquetas/química
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Relação Estrutura-Atividade
Fator de von Willebrand/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Platelet Glycoprotein GPIb-IX Complex); 0 (adhesion receptor); 0 (von Willebrand Factor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25887


  5 / 2051 MEDLINE  
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[PMID]:28817667
[Au] Autor:Corona de la Peña N; Gutiérrez-Aguilar M; Hernández-Reséndiz I; Marín-Hernández Á; Rodríguez-Enríquez S
[Ad] Endereço:Unidad de Investigación en Trombosis, Hemostasia y Aterogénesis, Hospital Carlos McGregor, México City, México.
[Ti] Título:Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets.
[So] Source:PLoS One;12(8):e0182374, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway i.e., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3-38 times vs. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Glicólise
Fosforilação Oxidativa
Ativação Plaquetária
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Trombina/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Cálcio/metabolismo
Seres Humanos
Mitocôndrias/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Platelet Glycoprotein GPIb-IX Complex); 8L70Q75FXE (Adenosine Triphosphate); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.21.5 (Thrombin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182374


  6 / 2051 MEDLINE  
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[PMID]:28642239
[Au] Autor:Aymé G; Adam F; Legendre P; Bazaa A; Proulle V; Denis CV; Christophe OD; Lenting PJ
[Ad] Endereço:From the Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (G.A., F.A., P.L., A.B., V.P., C.V.D., O.D.C., P.J.L.); and Department of Biological Hematology, CHU Bicetre, Hôpitaux Universitaires Paris-Sud, A
[Ti] Título:A Novel Single-Domain Antibody Against von Willebrand Factor A1 Domain Resolves Leukocyte Recruitment and Vascular Leakage During Inflammation-Brief Report.
[So] Source:Arterioscler Thromb Vasc Biol;37(9):1736-1740, 2017 Sep.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: von Willebrand factor (VWF) is crucial to hemostasis, but also plays a role in inflammatory processes. Unfortunately, no proper monoclonal antibodies to study VWF function in mice are currently available. We therefore aimed to generate single-domain antibodies (sdAbs) recognizing murine VWF and blocking its function in vivo. APPROACH AND RESULTS: Llama-derived sdAbs recognizing both human and murine VWF were isolated via phage display technology. One of them (designated KB-VWF-006) recognized the VWF A1 domain with picomolar affinity. This sdAb avidity was strongly enhanced via dimerization using a triple Ala linker (KB-VWF-006bi). When administered in vivo to wild-type mice, KB-VWF-006bi dose dependently induced bleeding in a tail clip model. In 2 distinct models of inflammation, KB-VWF-006bi efficiently interfered with leukocyte recruitment and vascular leakage. CONCLUSIONS: KB-VWF-006bi is an sdAb recognizing the A1 domain of human VWF and murine VWF that interferes with VWF-platelet interactions in vivo. By using this sdAb, we now also show that the A1 domain is pertinent to the participation of VWF in the inflammatory response.
[Mh] Termos MeSH primário: Permeabilidade Capilar/efeitos dos fármacos
Quimiotaxia de Leucócito/efeitos dos fármacos
Inflamação/tratamento farmacológico
Leucócitos/efeitos dos fármacos
Anticorpos de Cadeia Única/farmacologia
Fator de von Willebrand/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Especificidade de Anticorpos
Plaquetas/efeitos dos fármacos
Plaquetas/metabolismo
Reações Cruzadas
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Hemorragia/induzido quimicamente
Seres Humanos
Inflamação/genética
Inflamação/imunologia
Inflamação/metabolismo
Leucócitos/imunologia
Leucócitos/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Knockout
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Domínios Proteicos
Anticorpos de Cadeia Única/imunologia
Anticorpos de Cadeia Única/toxicidade
Fator de von Willebrand/genética
Fator de von Willebrand/imunologia
Fator de von Willebrand/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Platelet Glycoprotein GPIb-IX Complex); 0 (Single-Chain Antibodies); 0 (adhesion receptor); 0 (von Willebrand Factor)
[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:170624
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309319


  7 / 2051 MEDLINE  
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[PMID]:28533135
[Au] Autor:Tischer A; Machha VR; Frontroth JP; Brehm MA; Obser T; Schneppenheim R; Mayne L; Walter Englander S; Auton M
[Ad] Endereço:Division of Hematology, Departments of Internal Medicine and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
[Ti] Título:Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping.
[So] Source:J Mol Biol;429(14):2161-2177, 2017 Jul 07.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor (VWF) causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, which quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα-mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway. Constrained by the disulfide, conformational selection between weak and tight binding states of A1 takes precedence and drives normal platelet adhesion to VWF. Less restrained through mutation, loss of the disulfide preferentially diverts binding through an induced-fit disease pathway enabling high-affinity GPIbα binding and firm platelet adhesion to a partially disordered A1 domain. HXMS reveals a dynamic asymmetry of flexible and ordered regions common to both variants, indicating that the partially disordered A1 lacking the disulfide retains native-like structural dynamics. Both binding mechanisms share common structural and thermodynamic properties, but the enhanced local disorder in the disease state perpetuates high-affinity platelet agglutination, characteristic of type 2B VWD, upon DDAVP-stimulated secretion of VWF leading to transient thrombocytopenia and a subsequent deficiency of plasma VWF, characteristic of type 2A VWD.
[Mh] Termos MeSH primário: Desamino Arginina Vasopressina/efeitos adversos
Proteínas Mutantes/metabolismo
Agregação Plaquetária
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Trombocitopenia/induzido quimicamente
Trombocitopenia/genética
Fator de von Willebrand/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Criança
Cisteína/genética
Cisteína/metabolismo
Desamino Arginina Vasopressina/administração & dosagem
Dissulfetos
Feminino
Seres Humanos
Espectrometria de Massas
Proteínas Mutantes/genética
Mutação de Sentido Incorreto
Pletismografia de Impedância
Ressonância de Plasmônio de Superfície
Trombocitopenia/patologia
Fator de von Willebrand/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disulfides); 0 (Mutant Proteins); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (adhesion receptor); 0 (von Willebrand Factor); ENR1LLB0FP (Deamino Arginine Vasopressin); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170720
[Lr] Data última revisão:
170720
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE


  8 / 2051 MEDLINE  
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[PMID]:28444742
[Au] Autor:Arnold DM; Vrbensky JR; Karim N; Smith JW; Liu Y; Ivetic N; Kelton JG; Nazy I
[Ad] Endereço:Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
[Ti] Título:The effect of rituximab on anti-platelet autoantibody levels in patients with immune thrombocytopenia.
[So] Source:Br J Haematol;178(2):302-307, 2017 Jul.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Rituximab is an effective therapy resulting in a platelet count improvement in 60% of patients with immune thrombocytopenia (ITP). Rituximab depletes B cells; thus, a reduction in platelet autoantibody levels would be anticipated in patients who achieve a clinical response to this treatment. The objectives of this study were to determine whether rituximab was associated with a reduction in platelet autoantibody levels, and to correlate the loss of autoantibodies with the achievement of a treatment response. We performed a case-control study nested within a previous randomized controlled trial of standard therapy plus adjuvant rituximab or placebo. We measured platelet-bound anti-glycoprotein (GP) IIbIIIa and anti-GPIbIX using the antigen capture test. Of 55 evaluable patients, 25 (45%) had a detectable platelet autoantibody at baseline. Rituximab was associated with a significant reduction in anti-GPIIbIIIa levels (P = 0·02) but not anti-GPIbIX levels (P = 0·51) compared with placebo. Neither the presence of an autoantibody at baseline nor the loss of the autoantibody after treatment was associated with a response to rituximab. The subset of patients with persistent autoantibodies after treatment failed to achieve a platelet count response, suggesting that persistence of platelet autoantibodies can be a marker of disease severity.
[Mh] Termos MeSH primário: Autoanticorpos/metabolismo
Plaquetas/imunologia
Fatores Imunológicos/uso terapêutico
Púrpura Trombocitopênica Idiopática/tratamento farmacológico
Rituximab/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Autoanticorpos/efeitos dos fármacos
Estudos de Casos e Controles
Feminino
Seres Humanos
Masculino
Meia-Idade
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia
Complexo Glicoproteico GPIb-IX de Plaquetas/imunologia
Púrpura Trombocitopênica Idiopática/imunologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Immunologic Factors); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (glycoprotein receptor GPIb-IX); 4F4X42SYQ6 (Rituximab)
[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:170427
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14664


  9 / 2051 MEDLINE  
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[PMID]:28441050
[Au] Autor:Dudley A; Byron JK; Burkhard MJ; Warry E; Guillaumin J
[Ti] Título:Comparison of platelet function and viscoelastic test results between healthy dogs and dogs with naturally occurring chronic kidney disease.
[So] Source:Am J Vet Res;78(5):589-600, 2017 May.
[Is] ISSN:1943-5681
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE To compare platelet function and viscoelastic test results between healthy dogs and dogs with chronic kidney disease (CKD) to assess whether dogs with CKD have platelet dysfunction and altered blood coagulation. ANIMALS 10 healthy control dogs and 11 dogs with naturally occurring CKD. PROCEDURES Blood and urine were collected once from each dog for a CBC, serum biochemical analysis, urinalysis, and determination of the urine protein-to-creatinine ratio, prothrombin time, activated partial thromboplastin time, plasma fibrinogen concentration, and antithrombin activity. Closure time was determined by use of a platelet function analyzer and a collagen-ADP platelet agonist. Thromboelastography (TEG) variables (reaction time, clotting time, α angle, maximum amplitude, and global clot strength [G value]) were determined by use of recalcified nonactivated TEG. Platelet expression of glycoprotein Ib (GPIb; receptor for von Willebrand factor), integrin αIIbß3 (αIIbß3; receptor for fibrinogen), and P-selectin (marker for platelet activation) was assessed by flow cytometry. RESULTS Compared with healthy control dogs, the median closure time was prolonged, the median maximum amplitude and G value were increased, and the median clotting time was decreased for dogs with CKD. Platelet expression of both αIIbß3 and P-selectin was also significantly increased for dogs with CKD, compared with that for control dogs. Platelet expression of GPIb, αIIbß3, and P-selectin was not correlated with closure time or any TEG variable. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that dogs with CKD frequently had evidence of platelet dysfunction and hypercoagulability that were not totally attributable to alterations in platelet surface expression of GPIb, αIIbß3, and P-selectin.
[Mh] Termos MeSH primário: Plaquetas
Doenças do Cão/sangue
Insuficiência Renal Crônica/veterinária
[Mh] Termos MeSH secundário: Animais
Doenças do Cão/fisiopatologia
Cães
Fibrinogênio/metabolismo
Citometria de Fluxo/veterinária
Selectina-P/biossíntese
Tempo de Tromboplastina Parcial
Ativação Plaquetária
Testes de Função Plaquetária/veterinária
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/biossíntese
Complexo Glicoproteico GPIb-IX de Plaquetas/biossíntese
Tempo de Protrombina/veterinária
Insuficiência Renal Crônica/sangue
Insuficiência Renal Crônica/fisiopatologia
Tromboelastografia/veterinária
Trombofilia/veterinária
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (P-Selectin); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Platelet Glycoprotein GPIb-IX Complex); 9001-32-5 (Fibrinogen)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170426
[St] Status:MEDLINE
[do] DOI:10.2460/ajvr.78.5.589


  10 / 2051 MEDLINE  
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[PMID]:28142075
[Au] Autor:Panes O; González C; Hidalgo P; Valderas JP; Acevedo M; Contreras S; Sánchez X; Pereira J; Rigotti A; Mezzano D
[Ad] Endereço:Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
[Ti] Título:Platelet tissue factor activity and membrane cholesterol are increased in hypercholesterolemia and normalized by rosuvastatin, but not by atorvastatin.
[So] Source:Atherosclerosis;257:164-171, 2017 Feb.
[Is] ISSN:1879-1484
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIMS: High plasma LDL-cholesterol (LDL-C) and platelet responses have major pathogenic roles in atherothrombosis. Thus, statins and anti-platelet drugs constitute mainstays in cardiovascular prevention/treatment. However, the role of platelet tissue factor-dependent procoagulant activity (TF-PCA) has remained unexplored in hypercholesterolemia. We aimed to study platelet TF-PCA and its relationship with membrane cholesterol in vitro and in 45 hypercholesterolemic patients (HC-patients) (LDL-C >3.37 mmol/L, 130 mg/dL) and 37 control subjects (LDL-C <3.37 mmol/L). The effect of 1-month administration of 80 mg/day atorvastatin (n = 21) and 20 mg/day rosuvastatin (n = 24) was compared. METHODS: Platelet TF-PCA was induced by GPIbα activation with VWF-ristocetin. RESULTS: Cholesterol-enriched platelets in vitro had augmented aggregation/secretion and platelet FXa generation (1.65-fold increase, p = 0.01). HC-patients had 1.5-, 2.3- and 2.5-fold increases in platelet cholesterol, TF protein and activity, respectively; their platelets had neither hyper-aggregation nor endogenous thrombin generation (ETP). Rosuvastatin, but not atorvastatin, normalized platelet cholesterol, TF protein and FXa generation. It also increased slightly the plasma HDL-C levels, which correlated negatively with TF-PCA. CONCLUSIONS: Platelets from HC-patients were not hyper-responsive to low concentrations of classical agonists and had normal PRP-ETP, before and after statin administration. However, washed platelets from HC-patients had increased membrane cholesterol, TF protein and TF-PCA. The platelet TF-dependent PCA was specifically expressed after VWF-induced GPIbα activation. Rosuvastatin, but not atorvastatin treatment, normalized the membrane cholesterol, TF protein and TF-PCA in HC-patients, possibly unveiling a new pleiotropic effect of rosuvastatin. Modulation of platelet TF-PCA may become a novel target to prevent/treat atherothrombosis without increasing bleeding risks.
[Mh] Termos MeSH primário: Atorvastatina Cálcica/uso terapêutico
Plaquetas/efeitos dos fármacos
Membrana Celular/efeitos dos fármacos
Colesterol/sangue
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Hipercolesterolemia/tratamento farmacológico
Rosuvastatina Cálcica/uso terapêutico
Tromboplastina/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Biomarcadores/sangue
Coagulação Sanguínea/efeitos dos fármacos
Plaquetas/metabolismo
Membrana Celular/genética
Chile
HDL-Colesterol/sangue
Fator Xa/metabolismo
Feminino
Seres Humanos
Hipercolesterolemia/sangue
Hipercolesterolemia/diagnóstico
Masculino
Meia-Idade
Agregação Plaquetária/efeitos dos fármacos
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Biomarkers); 0 (Cholesterol, HDL); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (adhesion receptor); 48A5M73Z4Q (Atorvastatin Calcium); 83MVU38M7Q (Rosuvastatin Calcium); 9035-58-9 (Thromboplastin); 97C5T2UQ7J (Cholesterol); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE



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