RESUMO
BACKGROUND: It is beyond doubt that blood transfusion services have added to the decline in maternal mortality in high-resource countries. To quantify the clinical benefit of red blood cell (RBC) transfusion in obstetric care, we performed a hypothetical experimental study using data from a prospective nationwide cohort of women giving birth in the Netherlands. STUDY DESIGN AND METHODS: Data were abstracted from a nationwide cohort study on severe maternal morbidity, including obstetric haemorrhage requiring 4 or more units of RBC, to obtain an observed and a hypothetical control group consisting of the same women. In the hypothetical control group, we simulated a situation where RBC transfusion was unavailable and estimated how many of these women would have died in that situation. A questionnaire survey asked experts in major (obstetric) haemorrhage to choose a critical minimal number of RBC transfusions at which a woman with obstetric haemorrhage would have died if RBC transfusion was not available. Maternal mortality rate per 100,000 maternities [maternal mortality ratios (MMR)] and relative risk were calculated for the observed and hypothetical group. RESULTS: The observed MMR was 13 per 100,000 maternities. According to 47 responding experts, the median number of RBC units without which a woman would have most probably died was nine, resulting in a hypothetical MMR of 87 per 100,000 maternities (relative risk 6·5; 95% confidence interval 4·2-10·0). CONCLUSIONS: It can be expected that unavailability of RBC transfusion in obstetric care increases the risk of maternal death 6.5-fold. Blood transfusion thus largely contributes to the decline of MMR and would also be an important pillar of improving quality of care in resource-poor settings.
Assuntos
Transfusão de Eritrócitos/métodos , Transfusão de Eritrócitos/estatística & dados numéricos , Mortalidade Materna , Estudos de Coortes , Feminino , Hemorragia/mortalidade , Hemorragia/prevenção & controle , Humanos , Modelos Teóricos , Países Baixos , Obstetrícia/estatística & dados numéricos , Gravidez , Estudos Prospectivos , Qualidade da Assistência à Saúde , Inquéritos e Questionários , Resultado do TratamentoRESUMO
INTRODUCTION: The fraction of transfusion-related acute lung injury (TRALI) cases preventable by deferral of allo-exposed donors has previously been estimated, under the assumption this indirectly estimated the contribution of leucocyte antibodies to the occurrence of TRALI. Our aim was to estimate the fraction preventable by deferral of leucocyte antibody positive donors and to investigate the validity of allo-exposure as a marker for leucocyte antibodies. METHODS: All donors involved in a series of previously published TRALI patients were tested for leucocyte antibodies. The observed number of antibody positive donors was compared to the expected number. From this comparison we estimated the contribution of leucocyte antibodies to the occurrence of TRALI and compared this to the previously reported estimate for allo-exposed donors. RESULTS: Sixty-one TRALI patients were included. Of 288 involved donors 43 were expected and 67 were observed to be leucocyte antibody positive. The observed percentage of positive donors was 8.3% (95% confidence interval (CI): 5.1-11.5%) in excess of the expected. Overall 59% (95% CI: 34-85%) of TRALI cases was estimated to be preventable by the exclusion of all leucocyte antibody positive donors. For plasma-poor products this was 16% (95% CI: -5.0 to 36%). CONCLUSIONS: These estimates were similar to those previously published for allo-exposed donors. This suggests allo-exposure status can effectively be used in donor deferral strategies.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Doadores de Sangue , Seleção do Doador/métodos , Isoanticorpos/sangue , Isoanticorpos/imunologia , Leucócitos/imunologia , Reação Transfusional , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
INTRODUCTION: Donor leucocyte antibodies have been associated with transfusion-related acute lung injury (TRALI) and can be present in allo-exposed donors. Donor deferral policies aiming at excluding allo-exposed donors are increasingly implemented worldwide. We aimed at assessing the prevalence of leucocyte antibodies in different subgroups of allo-exposed donors in the Dutch donor population. METHODS: Consecutive donors were enrolled during routine whole blood donation. Donors filled out a questionnaire on allo-exposure history. Blood samples were tested for human leucocyte antigens (HLA) (LifeScreen Deluxe and the Lifecodes LSA I/II assays) and granulocyte-reactive (GIFT, GAT, and MAIGA) antibodies. RESULTS: Six thousand and thirty-four consecutive donors (60% men) were included. A total of 2.5% reported a history of blood transfusions, and 51% (of female donors) reported a history of pregnancy. In never allo-exposed donors, the prevalence of granulocyte-reactive antibodies was 2.0% (95% CI: 1.6-2.4), and for HLA antibodies, it was 7.0% (95% CI: 6.3-7.8). In previously pregnant donors, the prevalence of granulocyte-reactive antibodies was increased to 3.0% (95% CI: 2.0-4.0), and for HLA antibodies, it was increased to 33% (95% CI: 30-36). Prevalence of leucocyte antibodies of all types depended on transfusion history, number of pregnancies, time since last pregnancy, and pregnancy outcome. CONCLUSIONS: Fourteen percent of Dutch blood donors are allo-immunized against HLA or granulocyte antigens. Deferral of all self-reported allo-exposed donors will decrease this prevalence to 9%. Deferral of all female donors and transfused male donors will result in a similar prevalence among remaining donors but approximately twice as many deferrals.
Assuntos
Doadores de Sangue , Isoanticorpos/sangue , Leucócitos/imunologia , Lesão Pulmonar Aguda/etiologia , Granulócitos/imunologia , Antígenos HLA/sangue , Humanos , Masculino , Países Baixos , Prevalência , Inquéritos e Questionários , Reação TransfusionalRESUMO
INTRODUCTION: Blood products from female donors have been associated with worse outcome after blood transfusions. We aimed to quantify the association of overall mortality with transfusions from female blood donors. METHODS: We performed a cohort study of all transfusion recipients during a 5-year period at the Leiden University Medical Center. Analyses were performed in a sub-cohort of recipients with all transfusions from donors of the same sex. Effects in male and female recipients were analysed both separately and averaged, for an overall estimate. RESULTS: Overall, when averaged over both male and female recipients, transfusions from female donors were not associated with increased mortality. However, in male recipients transfusions from female donors were positively associated with mortality, while in female recipients the association was reversed. The hazard ratio for mortality after sex-mismatched transfusions was 1.2 (95% CI, 0.98-1.4). In recipients aged 1-55 it was 1.8 (95% CI, 1.2-2.7). In recipients over 55, with more other risk factors for mortality, it was 1.0 (95% CI, 0.83-1.2). CONCLUSIONS: Overall transfusions from female donors were not associated with increased mortality. However, male recipients of blood from female donors did have an increased risk of death. Female recipients of blood from male donors showed a weaker increase in mortality.
Assuntos
Doadores de Sangue , Transfusão de Sangue/mortalidade , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Hospitais Universitários , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores SexuaisRESUMO
Restriction fragment length polymorphisms (RFLPs), using the enzymes Bgl II and Xba I in conjunction with human von Willebrand factor (vWF) cDNA probes, have been described previously. In the present study we demonstrate the localization of both genetic markers within the vWF gene. The RFLPs were used to study the segregation of alleles associated with von Willebrand's disease (vWD) type IIA in a comprehensive, affected family. Individuals of this family were tested for their bleeding time and their plasma was analyzed for vWF antigen concentration and vWF ristocetin-cofactor activity. Based on these data, the affected members were diagnosed as vWD type-IIA patients; this conclusion was confirmed by the analysis of the multimeric vWF pattern of some of the patients. It was demonstrated that both RFLPs are completely linked with the vWD type-IIA trait. From this finding, we conclude that the defect that causes the vWD type IIA is most likely due to a mutation in the vWF gene and not to a mutation in a gene involved in posttranslational processing of the vWF protein.
Assuntos
Doenças de von Willebrand/genética , Fator de von Willebrand/genética , Mapeamento Cromossômico , Genes , Ligação Genética , Humanos , Mutação , Linhagem , Fenótipo , Polimorfismo de Fragmento de RestriçãoRESUMO
Two structurally different forms of activated human Factor IX (Factor IXa alpha and IXa beta) have been previously reported to have essentially identical clotting activity in vitro. Although it has been shown that activated Factor IX Chapel Hill, an abnormal Factor IX isolated from the plasma of a patient with mild hemophilia B, and normal Factor IXa alpha are structurally very similar, the clotting activity of activated Factor IX Chapel Hill is much lower (approximately fivefold) than that of normal Factor IXa beta. In the present study we have prepared activated Factor IX by incubating human Factor IX with calcium and Russell's viper venom covalently bound to agarose. Fractionation of the activated Factor IX by high-performance liquid chromatography demonstrated the presence of both Factors IXa alpha and IXa beta. On the basis of active site concentration, determined by titration with antithrombin III, the clotting activities of activated Factor IX Chapel Hill and IXa alpha were similar, but both activities were less than 20% of the clotting activity of Factor IXa beta. Activated Factor IX activity was also measured in the absence of calcium, phospholipid, and Factor VIII, by determination of the rate of Factor X activation in the presence of polylysine. In the presence of polylysine, the rates of Factor X activation by activated Factor IX Chapel Hill, Factor IXa alpha, and Factor IXa beta were essentially identical. We conclude that the clotting activity of activated Factor IX Chapel Hill is reduced when compared with that of Factor IXa beta but essentially normal when compared with that of Factor IXa alpha.
Assuntos
Coagulação Sanguínea , Enzimas/fisiologia , Fator IX/fisiologia , Cálcio/farmacologia , Fator IXa , Fator X/metabolismo , Humanos , Polilisina/farmacologia , Sefarose/farmacologia , Venenos de Víboras/farmacologiaRESUMO
Expression of the human blood-clotting factor VIII (FVIII) cDNA is hampered by the presence of sequences located in the coding region that repress transcription. We have previously identified a 305-bp fragment within the FVIII cDNA that is involved in the repression (R.C. Hoeben, F.J. Fallaux, S.J. Cramer, D.J.M. van den Wollenberg, H. van Ormondt, E. Briet, and A.J. van der Eb, Blood 85:2447-2454, 1995). Here, we show that this 305-bp region of FVIII cDNA contains sequences that resemble the yeast (Saccharomyces cerevisiae) autonomously replicating sequence consensus. Two of these DNA elements coincide with AT-rich sequences that are often found in matrix attachment regions or scaffold-attached regions. One of these elements, consisting of nucleotides 1569 to 1600 of the FVIII cDNA (nucleotide numbering is according to the system of Wood et al. (W.I. Wood, D.J. Capon, C.C. Simonsen, D.L. Eaton, J. Gitschier, D. Keyt, P.H. Seeburg, D.H. Smith, P. Hollingshead, K.L. Wion, et al., Nature [London] 312:330-337,1984), binds a nuclear factor in vitro but loses this capacity after four of its base pairs have been changed. A synthetic heptamer of this segment can repress the expression of a chloramphenicol acetyltransferase (CAT) reporter gene and also loses this capacity upon mutation. Furthermore, we demonstrate that repression by FVIII sequences can be relieved by sodium butyrate. We demonstrate that the synthetic heptamer (FVIII nucleotides 1569 to 1600), when placed upstream of the Moloney murine leukemia virus long terminal repeat promoter that drives the CAT reporter, can render the CAT reporter inducible by butyrate. This effect was absent when the same element was mutated. The stimulatory effect of butyrate could not be attributed to butyrate-responsive elements in the studied long terminal repeat promoters. Our data provide a functional characterization of the sequences that repress expression of the FVIII cDNA. These data also suggest a link between transcriptional repression by FVIII cDNA elements and the stimulatory effect of butyrate on FVIII cDNA expression.
Assuntos
Butiratos/farmacologia , Fator VIII/genética , Regulação da Expressão Gênica , RNA Mensageiro/genética , Proteínas de Saccharomyces cerevisiae , Proteínas de Schizosaccharomyces pombe , Fatores de Transcrição , Sequência de Bases , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Matriz Nuclear/metabolismo , Proteínas Nucleares/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sequências Reguladoras de Ácido Nucleico , Transcrição Gênica/efeitos dos fármacosRESUMO
We determined whether the membrane defect in hereditary pyropoikilocytosis (HPP) is associated with thermally induced changes in the lipid bilayer, the stability of which was probed by the rate of translocation of phosphatidylcholine (PC) over the two leaflets. [14C]PC was incorporated into the outer leaflet of the lipid bilayer of the intact erythrocytes using a PC-specific phospholipid exchange protein. The transbilayer equilibration of this PC was determined by measuring the time-dependent changes in its accessibility to exogenous phospholipase A2. The rate of transbilayer equilibration of PC was increased in HPP cells at 37 degrees C when compared to normal erythrocytes (rate constants, 0.07 +/- 0.02 and 0.03 +/- 0.01 h-1, respectively). A further dramatic increase in PC transbilayer equilibration was noted in HPP cells incubated at 44 degrees C (rate constant, 0.15 +/- 0.02 h-1). A similar marked acceleration in transbilayer movement of PC was also seen in normal erythrocytes when incubated at 46 degrees C (rate constant, 0.13 +/- 0.03 h-1). Despite the enhanced transbilayer mobility of PC in HPP cells when compared to normal erythrocytes, no major alteration in the asymmetric distribution could be observed when probed with phospholipase A2. Since changes in transbilayer mobility of PC and cell morphology occur in HPP cells at lower temperature than in normal red cells, it may be concluded that the enhanced thermal sensitivity of spectrin is the major factor responsible for these changes. Our results therefore support the view that the structural integrity of the skeletal network is essential for stabilization of the lipid bilayer of the red cell membrane.
Assuntos
Anemia Hemolítica Congênita/sangue , Membrana Eritrocítica/fisiologia , Fosfatidilcolinas/sangue , Espectrina/fisiologia , Anemia Hemolítica Congênita/fisiopatologia , Eritrócitos Anormais/fisiologia , Eritrócitos Anormais/ultraestrutura , Temperatura Alta , Humanos , Bicamadas Lipídicas , Fluidez de MembranaRESUMO
OBJECTIVES: This study attempted to determine the optimal intensity of anticoagulant therapy in patients after myocardial infarction. BACKGROUND: Treatment with oral anticoagulant therapy entails a delicate balance between over- (risk of bleeding) and under-anticoagulation (risk of thromboemboli). The optimal intensity required to prevent the occurrence of either event (bleeding or thromboembolic) is not known. METHODS: A method was used to determine the optimal intensity of anticoagulant therapy by calculating incidence rates for either event associated with a specific international normalized ratio. The numerator included events occurring at given international normalized ratios, and the denominator comprised the total observation time. RESULTS: The study population included 3,404 myocardial infarction patients enrolled in the ASPECT (Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) trial. Total treatment was 6,918 patient-years. Major bleeding occurred in 57 patients (0.8/100 patient-years), and thromboembolic complications in 397 (5.7/100 patient-years). The incidence of the combined outcome (bleeding or thromboembolic complications) with international normalized ratio <2 was 8.0/100 patient-years (283 events in 3,559 patient-years), with international normalized ratios between 2 and 3, 3.9/100 patient-years (33 events in 838 patient-years); 3.2/100 patient-years (57 events in 1,775 patient-years) for international normalized ratios between 3 and 4; 6.6/100 patient-years (37 events in 564 patient-years) for international normalized ratios between 4 and 5; and 7.7/100 patient-years (14 events in 182 patient-years) for international normalized ratios >5. After adjustment for achieved international normalized ratio levels, significant predictors were higher levels of systolic blood pressure and age. CONCLUSIONS: If equal weight is given to hemorrhagic and thromboembolic complications, these results suggest that the optimal intensity of long-term anticoagulant therapy for myocardial infarction patients lies between 2.0 and 4.0 international normalized ratio, with a trend to suggest an optimal intensity of 3.0 to 4.0.
Assuntos
Anticoagulantes/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Administração Oral , Fatores Etários , Anticoagulantes/efeitos adversos , Pressão Sanguínea , Overdose de Drogas , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Padrões de Referência , Tromboembolia/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Insufficient data are available about the safety of oral anticoagulant therapy. The specialized organization of thrombosis services in the Netherlands can provide important information on the bleeding risk and various risk factors for bleeding in patients receiving oral anticoagulant therapy. METHODS: In a follow-up study over a 12-month period beginning in January 1988 on all patients treated by the Leiden Thrombosis Service, the frequency of bleeding complications was assessed. A Poisson regression model was used to assess the relative contribution to the bleeding risk of age, sex, target zone (intensity of anticoagulant effect aimed at), achieved intensity of anticoagulant therapy (International Normalized Ratio), and the type of coumarin derivative used. RESULTS: Six thousand eight hundred fourteen patients experienced 1003 bleeding complications (16.5 per 100 treatment-years), 162 of which were major bleeds (2.7 per 100 treatment-years). Bleeding increased significantly with age (32% increase for all bleeding, 46% for major bleeding for every 10-year increase in age in comparison with age < 40 years). Women had more minor bleeding complications than men, whereas both sexes experienced major bleeding in an equal frequency. There was no influence of target zone, while every one-point increase in International Normalized Ratio gave 42% more major bleeding (54% more regarding all bleeding). Use of acenocoumarol resulted in fewer bleeds (26% less regarding all bleeding and 46% less regarding major bleeding) than use of phenprocoumon. CONCLUSIONS: The risk of anticoagulant therapy in a routine, real-life situation is similar as in the setting of several well-organized clinical trials. The risk of bleeding complications rises significantly with age and with the achieved intensity of anticoagulation, and is dependent on the type of coumarin derivative that is used.
Assuntos
Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Anticoagulantes/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Hemorragia/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Análise de Regressão , Fatores de Risco , Caracteres SexuaisRESUMO
BACKGROUND: It is not known which questions in a medical interview are most informative for diagnosing mild bleeding disorders, and what the value is of the entire interview in screening for hemostatic disorders. METHODS: A questionnaire was sent to 222 patients with a proven bleeding disorder, to 134 patients suspected of a bleeding disorder but whose hemostasis proved normal, and to 341 healthy volunteers. A first comparison, between patients with a bleeding disorder and patients with bleeding complaints whose hemostasis proved normal, mimics the situation in a department of hematology where patients are referred because of complaints. The second comparison, between patients with a proven bleeding disorder and healthy volunteers, may serve as a model for the situation where the interview is used as a screening tool to detect patients with a bleeding disorder in a population where there is no prior suspicion, eg, before surgical intervention. For each question we calculated a univariate odds ratio, multivariate odds ratios, and a positive and negative likelihood ratio. With a receiver operating characteristic curve analysis we evaluated the value of a simple vs an elaborate interview. RESULTS: Ninety-two percent of the questionnaires were returned. For both comparisons the most informative questions were questions about bleeding disorders in the family and traumatic events, with the exception of delivery. Noninformative questions were frequent gumbleeds and blood in the urine. A receiver operating characteristic curve analysis revealed that a simple interview has a high discriminating power in a screening situation, whereas in a referred situation even an elaborate interview has a low performance. CONCLUSIONS: A simple interview is useful as a screening tool for the dentist or surgeon. In a specialized hematology center with referred patients, however, the interview is of little value in identifying patients with a bleeding disorder.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Hemorragia/etiologia , Anamnese/métodos , Transtornos da Coagulação Sanguínea/complicações , Humanos , Razão de Chances , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Endurance exercise has been advocated in diabetes mellitus to improve both metabolic control and prevent atherosclerotic complications. The response of the fibrinolytic system during prolonged exercise has not been studied in diabetes. RESEARCH DESIGN AND METHODS: In seven male marathon runners with IDDM and eight healthy nondiabetic male control subjects, matched for age and degree of training, we studied fibrinolytic and coagulation parameters during a 3-h 32-km outdoor running session. Measurements included t-PA, u-PA, PAI-1, PAP (as a measure of in vivo activation of fibrinolysis), FbDPs, FGN, vWF, and VIII:C. RESULTS: In both IDDM and control subjects, levels of t-PA, u-PA, PAP, vWF, and VIII:C continued to rise throughout the exercise, whereas PAI-1 showed a similar decline in both groups. FbDP rose slightly in both groups, and FGN remained unchanged. t-PA levels during exercise correlated closely with exercise intensity. These findings indicate that continued stimulation by exercise does not deplete endothelial PA stores. Differences between IDDM and control subjects were seen only for t-PA, vWF, and u-PA. The AUC during exercise (AUC0.5-3.0) of t-PA in IDDM was insignificantly lower than in control subjects (53 +/- 19 vs. 67 +/- 31 ng.ml-1.h), but the ratio of t-PA to exercise intensity was lower in IDDM (0.24 +/- 0.11 vs. 0.31 +/- 0.13, P less than 0.05). The AUC0.5-3.0 of vWF was lower in IDDM than in control subjects (569 +/- 268 vs. 880 +/- 265%.h, P less than 0.05). The AUC0.5-3.0 of u-PA was higher in IDDM than in control subjects (15.1 +/- 3.5 vs. 11.2 +/- 1.8 ng.ml-1.h, P less than 0.05). CONCLUSIONS: Despite a defect in the exercise-induced endothelial release of vWF and t-PA, the overall potential to activate fibrinolysis is intact in IDDM, possibly by enhancement of u-PA after exercise. Our data suggest that in IDDM, as in nondiabetic subjects, long-distance running may slow the progression of atherosclerosis by stimulating fibrinolysis.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Exercício Físico , Fibrinólise , Corrida , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 1/fisiopatologia , Fator VIII/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hemoglobinas Glicadas/análise , Frequência Cardíaca , Humanos , Inativadores de Plasminogênio/análise , Valores de Referência , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tipo Uroquinase/sangue , Fator de von Willebrand/análiseRESUMO
Hemophilia A is caused by the lack of functional blood-clotting factor VIII. We have used retrovirus-mediated gene transfer to generate various cell lines, rodent as well as human, that secrete the human factor VIII protein. To study whether transplantation of genetically modified fibroblasts is a feasible approach for gene therapy of hemophilia A, we implanted the factor VIII-secreting cells into immune-deficient mice. Implantation of factor VIII-secreting primary human skin fibroblasts resulted in long-term persistence of the transplanted cells; cells recovered from the implants up to 2 months post-implantation still had the capacity to secrete factor VIII when regrown in tissue culture. However, we were unable to detect any human factor VIII in plasma samples of the recipient mice. The absence of human factor VIII in the recipients' plasma is shown to be due neither to (epigenetic) inactivation of the retroviral vector in vivo, nor to inability of the stationary cells to secrete factor VIII protein. However, we did note a rapid clearing of the human factor VIII: CAg from plasma upon intravenous injection of plasma-derived human factor VIII in mice (t1/2 < 60 min vs. 10 hr in humans). This phenomenon can fully explain the apparent absence of human factor VIII in the recipients' plasma.
Assuntos
Fator VIII/metabolismo , Fibroblastos/transplante , Terapia Genética , Hemofilia A/terapia , Hospedeiro Imunocomprometido , Animais , Células Cultivadas , Fator VIII/genética , Fibroblastos/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , RatosRESUMO
The objective of the present study was to assess the prevalence of moderate and severe stenosis of the right carotid artery in the elderly and its associations with smoking, blood pressure, serum lipid levels, and hemostatic factors. The Rotterdam Elderly Study is a recently started single-center prospective follow-up study of a cohort of 11,854 elderly people aged 55 years or more. In 1990, 954 participants of the Rotterdam Elderly Study underwent ultrasonic duplex examination of the right internal carotid artery. A reduction of the lumen diameter of 16-49% was found in 29 people (3.0%). Severe stenosis (50% or more) was observed in 13 people (1.4%). With differences in age, sex, and body mass index taken into account, subjects with moderate-to-severe carotid artery disease had, compared with participants without stenosis, lower mean high density lipoprotein cholesterol levels (mean difference, 0.10 mmol/l; 95% confidence interval, 0, 0.20) and higher mean fibrinogen levels (difference, 0.24 g/l; 0.04, 0.45). Among them were more people with hypertension (mean difference, 16%) and more current smokers (mean difference, 13%). Factor VIIc and factor VIIIc activity was higher in subjects with carotid artery disease, without, however, reaching statistical significance (mean difference, 0.06 IU/ml [-0.01, 0.12] and 0.21 IU/ml [-0.05, 0.47], respectively). Our data suggest that hypertension, smoking, and reduced serum high density lipoprotein cholesterol levels, combined with unfavorable increases in hemostatic factors, may be related to carotid artery disease in the elderly.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Doenças das Artérias Carótidas/etiologia , Idoso , Estenose das Carótidas/diagnóstico por imagem , Estudos de Coortes , Feminino , Seguimentos , Hemostasia , Humanos , Hipertensão/complicações , Arteriosclerose Intracraniana/complicações , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fumar , UltrassonografiaRESUMO
After finding prolonged bleeding times in 2 patients treated with mitotane, we prospectively studied 7 patients with adrenocortical cancer on mitotane therapy. Before and 1 and 2 or more weeks after starting mitotane we determined the platelet counts, bleeding times and global coagulation parameters. All patients had a normal bleeding time before treatment. In 6 cases the bleeding time became prolonged (245-555 s). 4 patients exhibited platelet aggregation responses compatible with an aspirin-like defect. It is concluded that mitotane may cause a clinically relevant defect of platelet function.
Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Tempo de Sangramento , Carcinoma/tratamento farmacológico , Mitotano/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Contagem de Plaquetas/efeitos dos fármacos , Fator de von Willebrand/químicaRESUMO
In this paper, a five generation Greek family is described with haemophilia B. The disease is characterized by a normal ox-brain prothrombin time, normal levels of the vitamin-K dependent clotting factors VII and X and a proportional reduction of factor IX activity and antigen levels all of which is consistent with the cross-reacting material negative form of haemophilia B. However, in this family the factor IX levels in the three patients of generation V are around 1 U/dl while the three older patients in generation III have factor IX levels ranging from 28 to 44 U/dl. In the oldest patient of generation V we observed a rise of the factor IX level from 1 U/dl up to the age of 13 to 10 U/dl at age 14. In addition, the older patients have very mild bleeding symptoms or none at all, while the young ones have occasional spontaneous haemorrhages in muscles and joints, compatible with severe or moderately severe haemophilia. The disease appears to be similar to haemophilia B Leyden which has been described in a Dutch family.
Assuntos
Hemofilia B/genética , Envelhecimento/sangue , Fator IX/análise , Grécia , Hemofilia B/classificação , Humanos , LinhagemRESUMO
Hemophilia A is a hereditary, X-linked, bleeding disorder that is caused by a defect in the factor VIII gene. Here, we report two novel point mutations in the factor VIII gene that result in an aberrant electrophoretic mobility of double strand PCR fragments (double strand conformation polymorphism, DSCP). In exon 9 a TAC-->AAC mutation at codon 431, replacing Tyr by Asn, was observed in a family (A211) with moderately severe hemophilia A. A family with mild hemophilia A revealed an A-->T mutation in codon 280 (exon 7) that results in the replacement of Asn by Ile. One of these two mutations was not detected in an analysis based on single strand conformation polymorphisms (SSCP). At present we have no explanation for the effect of the nucleotide changes on the electrophoretic mobility of double strand DNA. Although DSCP is not able to detect all mutations the combination of DSCP analysis with SSCP analysis increases the sensitivity in a screening for factor VIII mutations.
Assuntos
Análise Mutacional de DNA , DNA/genética , Fator VIII/genética , Genes , Hemofilia A/genética , Conformação de Ácido Nucleico , Reação em Cadeia da Polimerase , Polimorfismo Genético , Sequência de Bases , Códon , Éxons , Humanos , Dados de Sequência MolecularRESUMO
Thirty-one non-hemophilic patients with acquired antibodies to factor VIII were entered into a prospective, randomized, multi-institutional trial to determine the safety and efficacy of prednisone (P), cyclophosphamide (C), or the combination in the treatment of this disorder. Patients were eligible if they had antibody demonstrated by the Bethesda assay, had not received these agents previously, and gave informed consent. All patients were treated initially with P, 1 mg/kg, for 3 weeks. If the antibody persisted and there was no rise in factor VIII activity, patients were randomized to either continue P for an additional 6 weeks; taper P and begin C, 2 mg per kg; or continue P and add C. Antibody disappeared in 10 during the initial P therapy, and in three of four others randomized to continue on P; one patient was discontinued because of an herpetic infection. Antibody disappeared in three of six patients treated with C alone, and five of ten given C and P. The titer of antibody was significantly lower in responders than in non-responders (p = 0.003), but seven patients with titers of more than five Bethesda units had complete remissions. There was no difference in antibody titers between those responding to P and those responding to C. We conclude that all patients with acquired antibodies to factor VIII should receive initial management with P, and that C is effective as second-line therapy for many of those who are steroid-resistant.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Fator VIII/imunologia , Transtornos Hemorrágicos/tratamento farmacológico , Prednisona/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Feminino , Transtornos Hemorrágicos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
The role of factor VIIa in haemostasis has been studied using a canine model of factor VIII deficiency. Highly purified human factor VIIa was administered to dogs at a dosage of 0.5 microgram/kg. At selected times pre- and post-infusion, haemostasis was evaluated by the cuticle bleeding time. Plasma was collected for the assay of various parameters, including fibrinopeptide A (FPA) as a marker for thrombin generation in vivo. Factor VIIa infusion resulted in a 6-fold increase of factor VII clotting activity with a t1/2 of 2 h. FPA levels, which were 1.4 ng/ml before infusion, did not increase significantly in haemophilic dogs. In normal dogs, however, FPA levels rose to a mean value of 190 ng/ml 30 min post-infusion. It appeared that thrombin generation by factor VIIa infusion had occurred mainly via the intrinsic, factor VIII-dependent pathway. In factor VIII-deficient dogs, factor VIIa infusion did not correct cuticle bleeding, but an inconsistent haemostatic effect was observed 15-30 min post-infusion. Similar results were obtained in haemophilic dogs with circulating antibodies against factor VIII. The haemostatic effectivity could not be improved by increasing the factor VIIa dosage up to 40-fold. Although these data suggest that the extrinsic, factor VII-dependent factor X activation provides only a minor pathway of thrombin generation in vivo, it is possible that the suboptimal haemostatic effect noted may be promoted in bleeding situations where tissue factor availability is less limited. As such, factor VIIa may prove useful in the treatment of haemophilia A patients with acquired inhibitors to factor VIII.