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1.
Eur J Neurol ; 21(4): 643-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24495004

RESUMO

BACKGROUND AND PURPOSE: The endothelium is crucial in maintaining the haemostatic balance between pro- and anti-thrombotic factors. In this pilot study, the association of endothelial biomarkers with arterial recanalization and clinical outcome in the setting of acute ischaemic stroke (AIS) was evaluated amongst patients treated with recombinant tissue plasminogen activator (rt-PA). METHODS: Sixty-four AIS patients treated with rt-PA were prospectively recruited. Blood was collected before thrombolysis and analysed for von Willebrand factor (vWF), soluble thrombomodulin (sTM) and soluble endothelial protein C receptor (sEPCR). Complete recanalization was defined by a Thrombolysis in Myocardial Infarction Score of 3. Favourable clinical outcome was defined by a modified Rankin Score of 0-2 at 90 days. RESULTS: Amongst the 64 patients, 31 had no documented occlusion, 19 had persistent occlusion and 14 had complete recanalization. After adjustment for confounding factors, these patients presented lower sTM and sEPCR levels than patients with persistent occlusion (median sTM, 21 vs. 48 ng/ml, P = 0.008; median sEPCR, 78 vs. 114 ng/ml, P = 0.018), but similar levels compared with patients without occlusion. vWF levels did not differ between groups. None of these biomarkers was significantly associated with favourable outcome. CONCLUSIONS: Recanalization after thrombolytic therapy is associated with low sTM and sEPCR levels but not with vWF levels. If corroborated in further larger studies, these findings could be helpful in the identification of patients resistant to rt-PA thrombolysis who could benefit from a modified recanalization therapy.


Assuntos
Antígenos CD/sangue , Fibrinolíticos/uso terapêutico , Receptores de Superfície Celular/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Trombomodulina/sangue , Ativador de Plasminogênio Tecidual/uso terapêutico , Fator de von Willebrand/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cateteres de Demora , Angiografia Cerebral , Receptor de Proteína C Endotelial , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
2.
Clin Pharmacol Ther ; 91(5): 777-86, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22472992

RESUMO

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.


Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/farmacocinética , Fenindiona/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Fenindiona/farmacocinética , Fenindiona/farmacologia
3.
J Pathol ; 212(3): 249-59, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17534843

RESUMO

Apoptosis participates in every step of atherogenesis, but the process of clearance of apoptotic cells by phagocytosis has been underestimated. Rapid removal of apoptotic cells is critical for tissue homeostasis, in order to avoid accumulation of necrotic material and subsequent inflammation in the pathological vascular wall. We have demonstrated by RT-PCR, western blot and immunocytofluorescence that vascular smooth muscle cells (VSMCs) express the phosphatidylserine receptor (PSR). We then tested the involvement of PSR in the ability of VSMCs to bind and engulf apoptotic cells. We used a model of senescent erythrocytes, which expose PS after 4 days of culture (85% of cells relative to 8% in freshly isolated erythrocytes). The pseudo-peroxidase activity of haemoglobin contained within erythrocytes allowed us to quantify per se both binding and phagocytosis by VSMCs. We have also shown by light and confocal microscopy that VSMCs were able to ingest aged erythrocytes. Addition of a blocking antibody or transfection of VSMCs by a siRNA directed against PSR reduced the binding and engulfment of aged erythrocytes by more than 90%. These results suggest that PSR is involved in phagocytosis of PS-presenting cells. Incubation of aged erythrocytes with VSMCs also significantly increased the expression of PSR, suggesting that the tethering/ingestion of apoptotic cells triggers this process. Immunostaining for PSR in complicated atherosclerotic plaques shows positivity in the media and macrophage-rich areas. The mechanisms underlying phagocytosis and involving PSR in vivo, within the pathological arterial wall, deserve further investigation.


Assuntos
Artérias Carótidas/patologia , Estenose das Carótidas/patologia , Miócitos de Músculo Liso/fisiologia , Fagocitose/fisiologia , Receptores de Superfície Celular/metabolismo , Anticorpos Monoclonais/imunologia , Apoptose , Western Blotting , Artérias Carótidas/metabolismo , Estenose das Carótidas/metabolismo , Células Cultivadas , Senescência Celular , Envelhecimento Eritrocítico , Imunofluorescência , Humanos , Microscopia Confocal , Interferência de RNA , RNA Mensageiro/análise , RNA Interferente Pequeno/farmacologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
4.
Ann Dermatol Venereol ; 134(4 Pt 1): 374-7, 2007 Apr.
Artigo em Francês | MEDLINE | ID: mdl-17483759

RESUMO

BACKGROUND: Interferon-beta-1b is a valuable first-line therapy for patients with relapsing-remitting multiple sclerosis. Many non-severe cutaneous reactions to recombinant interferon beta are described at injection sites. Panniculitis after subcutaneous injection of beta interferon is a rare adverse event; we describe two such cases at beta interferon injection sites. CASE-REPORTS: Two women aged 22 years and 45 years with severe multiple sclerosis receiving immunotherapy with beta interferon were admitted to an emergency department following the appearance of extremely painful induration at injection sites rendering walking impossible after several months of interferon injections. One of the patients had fever. Histology tests showed vasculitis and capillary thrombosis in one-woman and dermal oedema in the other. MRI scanners showed extensive avascular necrosis of soft tissue without fasciitis in both patients. Interferon withdrawal and surgical debridement was carried out in one case and beta interferon was successfully reintroduced in both cases. DISCUSSION: Only two cases have been reported of panniculitis induced by subcutaneous beta interferon injection. Clinically, such cases may mimic infectious processes. The present cases show that MRI may be useful in diagnosis and that the vascular toxicity of interferon beta probably plays a role in panniculitis. Temporary withdrawal of treatment, rotation of several injection sites and alternative routes of administration may all be proposed.


Assuntos
Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Paniculite/induzido quimicamente , Adjuvantes Imunológicos/toxicidade , Adulto , Feminino , Humanos , Injeções Intramusculares , Interferon beta-1a , Interferon beta/administração & dosagem , Interferon beta/toxicidade , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Paniculite/patologia
5.
J Thromb Haemost ; 5(2): 266-73, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17087729

RESUMO

BACKGROUND: Postpartum hemorrhage (PPH) is a major source of maternal morbidity. OBJECTIVES: This study's objective was to determine whether changes in hemostasis markers during the course of PPH are predictive of its severity. PATIENTS AND METHODS: We enrolled 128 women with PPH requiring uterotonic prostaglandin E2 (sulprostone) infusion. Two groups were defined (severe and non-severe PPH) according to the outcome during the first 24 hours. According to our criteria, 50 of the 128 women had severe PPH. Serial coagulation tests were performed at enrollment (H0), and 1, 2, 4 and 24 hours thereafter. RESULTS: At H0, and through H4, women with severe PPH had significantly lower fibrinogen, factor V, antithrombin activity, protein C antigen, prolonged prothrombin time, and higher D-dimer and TAT complexes than women with non-severe PPH. In multivariate analysis, from H0 to H4, fibrinogen was the only marker associated with the occurrence of severe PPH. At H0, the risk for severe PPH was 2.63-fold higher for each 1 gL(-1) decrease of fibrinogen. The negative predictive value of a fibrinogen concentration >4 gL(-1) was 79% and the positive predictive value of a concentration

Assuntos
Fibrinogênio/análise , Hemorragia Pós-Parto/diagnóstico , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Adulto , Biomarcadores/análise , Testes de Coagulação Sanguínea , Dinoprostona/administração & dosagem , Dinoprostona/análogos & derivados , Feminino , Humanos , Gravidez , Fatores de Tempo , Resultado do Tratamento
6.
Cancer ; 74(5): 1533-41, 1994 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-7520347

RESUMO

BACKGROUND: An important marker for hepatocellular carcinoma is the presence of des-gamma-carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown. METHODS: Two groups of patients were defined according to the absence (Group I, n = 7) or presence (Group II, n = 8) of des-gamma-carboxy prothrombin. The enzymatic activity of gamma-carboxylase and the total microsomal prothrombin concentration were determined in all tumors. The kinetic parameters for the synthetic peptide Phe-Leu-Glu-Glu-Leu (FLEEL) were measured in eight tumors. The gamma-carboxylase mRNA expression was evaluated by Northern blot analysis in 12 of 15 tumors. In addition, the total vitamin K content (K1, K1 epoxide, and menaquinones 4-10) in 10 tumors was investigated by high performance liquid chromatography. RESULTS: Concentrations of menaquinones 4-10 were normal in the nontumorous part of the liver but significantly decreased (P = 0.02) in all the tumors (Groups I and II). This decrease was more severe in Group II (P = 0.02). The tumors in Group I had normal or increased gamma-carboxylase activity and increased mRNA expression (P < 0.02) as compared with their nontumorous counterparts. The tumors in Group II were heterogeneous. Five tumors displayed low gamma-carboxylase activity, associated with low mRNA expression in two, whereas two others had high gamma-carboxylase activity and mRNA expression. The concentration of FLEEL at half-maximal velocity was normal in all the tumors examined (Groups I and II), and a relation was found between the level of expression of gamma-carboxylase and the maximal velocity for FLEEL carboxylation in the tumors in Group II (r = 0.98; P < 0.01). The microsomal content of normal prothrombin was within normal limits in all tumors (Groups I and II). CONCLUSIONS: Tumor vitamin K content has a critical role in the synthesis of des-gamma-carboxy prothrombin. Furthermore, the gamma-carboxylase defect, which is observed in some secreting tumors, is the result of the defective gene expression of a normal enzyme and not the consequence of the presence of a competitive inhibitor. It is possible that a 75% reduction in gamma-carboxylase gene expression could take a part in the secretion of des-gamma-carboxy prothrombin, but this mechanism is not predominant.


Assuntos
Biomarcadores , Carbono-Carbono Ligases , Carcinoma Hepatocelular/metabolismo , Ligases/metabolismo , Neoplasias Hepáticas/metabolismo , Precursores de Proteínas/metabolismo , Protrombina/metabolismo , Vitamina K/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Fator V/análise , Regulação Neoplásica da Expressão Gênica , Humanos , Ligases/análise , Ligases/genética , Fígado/enzimologia , Fígado/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Microssomos Hepáticos/enzimologia , Precursores de Proteínas/análise , Precursores de Proteínas/genética , Protrombina/análise , Protrombina/genética , RNA/análise , RNA/genética , RNA Neoplásico/análise , RNA Neoplásico/genética , Vitamina K/análogos & derivados , Vitamina K/análise , Vitamina K 1/análogos & derivados , Vitamina K 1/análise , Vitamina K 2/análogos & derivados , alfa-Fetoproteínas/análise
7.
Blood ; 80(11): 2781-6, 1992 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-1450405

RESUMO

We describe here the alteration of thrombin specificity induced by its interaction with glycocalicin. Glycocalicin is the external part of platelet glycoprotein Ib alpha (GPIb alpha) and contains binding sites for von Willebrand factor and thrombin. Taking advantage of its solubility, we have used glycocalicin in competition assays on various thrombin activities. Glycocalicin did not inhibit chromogenic substrate hydrolysis nor diisopropylfluorophosphate iPr2 (PF) incorporation, indicating that thrombin binding to GPIb does not alter access to or the conformation of the thrombin catalytic site. Glycocalicin competitively inhibited thrombin binding to fibrin (Ki = 0.1 mumol/L) and blocked fibrinogen clotting activity of thrombin. Glycocalicin also inhibited thrombin binding to thrombomodulin in a competitive manner (Ki = 3 to 5 mumol/L), but failed to prevent thrombin interaction with protein C in the absence of thrombomodulin. Previous results have indicated that GPIb binds to thrombin within the anion binding exosite masked by the carboxy-terminal hirudin peptide 54-65. The present results confirm the implication of the anion binding exosite in GPIb recognition, and further indicate that the thrombin binding site for GPIb overlaps with the thrombin binding sites for fibrin and thrombomodulin, whereas it is distinct from the thrombin binding site for protein C. Some of the structural requirements for thrombin binding to GPIb appear to be very similar to those reported for binding to its platelet receptor. However, thrombin-GPIb interaction does not appear to compete with receptor hydrolysis but rather increases the sensitivity and the rate of platelet responses elicited by the receptor.


Assuntos
Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIb-IX de Plaquetas , Glicoproteínas da Membrana de Plaquetas/metabolismo , Trombina/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Eletroforese em Gel de Poliacrilamida , Fibrinogênio/metabolismo , Humanos , Cinética , Dados de Sequência Molecular , Peso Molecular , Oligopeptídeos/metabolismo , Glicoproteínas da Membrana de Plaquetas/isolamento & purificação , Proteína C/metabolismo , Especificidade por Substrato
9.
Thromb Haemost ; 66(3): 300-5, 1991 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-1746000

RESUMO

The carboxy-terminal region of hirudin (residues 54-65) has previously been shown to inhibit thrombin clotting activity without binding to the catalytic site of the enzyme. In the present study, the effect of hirudin 54-65 on thrombin interaction with specified platelet proteins has been investigated. Hirudin 54-65 was found to inhibit thrombin-induced platelet aggregation and secretion in a dose-dependent manner. Substitution of either Phe56, Glu57, Ile59, Pro60 or Leu64 showed that these residues were critical for inhibition of thrombin-induced platelet activation whereas sulfation of Tyr63 increased the inhibitory potency of the peptide. Hydrolysis of glycoprotein V, a platelet membrane substrate for thrombin, was only partially inhibited by hirudin 54-65. Although hirudin 54-65 did not decrease the amount of thrombin bound to platelets during cross-linking experiments, it was found to inhibit the specific binding of thrombin to platelet glycoprotein Ib. Since the carboxy-terminal region of hirudin has previously been reported to bind near the trypsin-catalyzed beta cleavage site, we have analyzed the consequences of alpha to beta-thrombin conversion on both thrombin-hirudin 54-65 interaction and thrombin activity toward platelets. The beta cleavage induced a decrease in the affinity of thrombin for both glycoprotein Ib and hirudin 54-65. Altogether, our results indicate that thrombin recognition sites for hirudin 54-65 and platelet membrane glycoprotein Ib share common structures located near the beta cleavage site at Arg 73 on the thrombin B chain.


Assuntos
Plaquetas/efeitos dos fármacos , Hirudinas/farmacologia , Fragmentos de Peptídeos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Trombina/metabolismo , Sequência de Aminoácidos , Plaquetas/metabolismo , Quimotripsina , Hirudinas/análogos & derivados , Hirudinas/química , Humanos , Hidrólise , Dados de Sequência Molecular , Ativação Plaquetária/fisiologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Ligação Proteica/efeitos dos fármacos
10.
Blood Coagul Fibrinolysis ; 2(4): 521-8, 1991 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1768765

RESUMO

The purpose of this study was to determine the effect of chemical modification of lysyl residues on thrombin interaction with platelet membrane proteins. Modification of lysyl residues by pyridoxal-5'-phosphate affected two different sites on thrombin and resulted in a greatly decreased binding to platelets. Using a crosslinking bifunctional reagent [bis(sulphosuccinimidyl) suberate (BS3)], we show that modified thrombin retained the ability to form high molecular mass (greater than or equal to 400 kDa) complexes with yet unidentified platelet proteins and to bind to platelet protease nexin I, but had lost the ability to bind to platelet glycoprotein Ib (GPIb). As previously reported by others, heparin protected one of the two sites from phosphopyridoxylation. In contrast modified thrombin, heparin-protected modified thrombin retained the ability to bind to GPIb, indicating that the lysyl residue(s) protected by heparin from the modification are essential for GPIb binding. While unprotected modified thrombin failed to bind hirudin, heparin-protected modified thrombin retained its ability to bind the carboxy-terminal hirudin peptide H54-65. Tritium-labelling of the modified lysyl residues and degradation of modified thrombins by CNBr or trypsin confirmed that the lysyl residue(s) protected by heparin and essential for GPIb binding are located in the thrombin binding domain for the carboxyl-terminal tail of hirudin, within the sequence 18-73 of the thrombin B chain.


Assuntos
Glicoproteínas da Membrana de Plaquetas/metabolismo , Fosfato de Piridoxal/metabolismo , Trombina/metabolismo , Sítios de Ligação , Reagentes de Ligações Cruzadas , Brometo de Cianogênio , Heparina/farmacologia , Hirudinas/metabolismo , Humanos , Lisina/metabolismo , Peso Molecular , Agregação Plaquetária/efeitos dos fármacos , Ligação Proteica , Trombina/farmacologia , Trítio , Tripsina
11.
Gastroenterology ; 94(4): 1063-9, 1988 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-3345875

RESUMO

In a prospective study of 33 adults with portal vein thrombosis unrelated to a liver tumor, we have assessed the prevalence of primary myeloproliferative disorders using conventional criteria and cultures of bone marrow progenitor cells. A primary myeloproliferative disorder was documented in 14 patients investigated at the time of recognition of portal vein thrombosis. Among these 14 patients, the main clue to the presence of the myeloproliferative disorder was (a) the observation of suggestive abnormalities of peripheral blood cell counts in 4 patients; (b) characteristic findings at bone marrow biopsy or determination of total red cell volume in 3 patients; and (c) formation of "spontaneous" erythroid colonies in cultures of bone marrow progenitor cells in erythropoietin-poor medium in 7 patients. In 2 other patients, agnogenic myeloid metaplasia with myelosclerosis of apparently recent onset developed 5 yr after recognition of portal vein thrombosis. In conclusion, primary myeloproliferative disorders--in a full-blown or latent form, or at an early stage--are a major cause of portal vein thrombosis.


Assuntos
Transtornos Mieloproliferativos/complicações , Veia Porta , Trombose/etiologia , Contagem de Células Sanguíneas , Medula Óssea/patologia , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Transtornos Mieloproliferativos/patologia , Estudos Prospectivos
13.
Thromb Res ; 44(1): 11-21, 1986 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-3787558

RESUMO

An abnormal prothrombin has been detected in a 23 yr-old healthy female and her mother. Both patients appeared to be heterozygous for the abnormality, plasma prothrombin being 50% of normal using the usual one stage assay, but normal when measured either by using Echis carinatus venom or by immunoassay. No abnormality in the immunoelectrophoretic pattern was observed. Prothrombin isolation on DEAE Sephadex failed to separate the abnormal population (prothrombin Clamart) from the normal one. The rates of prothrombin activation by factor Xa, in the presence or absence of phospholipids and/or factor Va, were determined by measuring the production of both clotting and amidolytic activities. The thrombin generation rate from prothrombin isolated from the propositus plasma was 50% slower than normal whatever the method of measurement and the composition of the activation mixture. Analysis of the final activation products by SDS polyacrylamide gel electrophoresis revealed that equal amounts of prethrombin 2 and thrombin had been formed. Prethrombin 2 Clamart was shown to be resistant to proteolysis upon further incubation with factor Xa, whereas it was readily converted to thrombin by Echis carinatus venom. Prothrombin Clamart appears to be characterized by an impairment of Arg 320-IIe cleavage by factor Xa.


Assuntos
Fator X/fisiologia , Protrombina/genética , Adulto , Arginina/metabolismo , Transtornos da Coagulação Sanguínea/genética , Fator Xa , Feminino , Variação Genética , Heterozigoto , Humanos , Imunoeletroforese Bidimensional , Protrombina/isolamento & purificação , Protrombina/metabolismo , Tempo de Protrombina , Relação Estrutura-Atividade , Trombina/análise , Trombina/metabolismo
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