Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
1.
J Proteome Res ; 23(8): 3726-3730, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39013105

RESUMO

Intact-mass spectrometry has huge potential for clinical application, as it enables both quantitative and qualitative analysis of intact proteins and possibly unlocks additional pathophysiological information via, e.g., detection of specific post-translational modifications (PTMs). Such valuable and clinically useful selectivity is typically lost during conventional bottom-up mass spectrometry. We demonstrate an innovative immunoprecipitation protein enrichment assay coupled to ultrahigh performance liquid chromatography quadrupole time-of-flight high resolution mass spectrometry (UPLC-QToF-HRMS) for the fast and simple identification of the protein tumor marker Neuron Specific Enolase Gamma (NSEγ) at low endogenous concentrations in human serum. Additionally, using the combination of immunoaffinity purification with intact mass spectrometry, the presence of NSEγ in an acetylated form in human serum was detected. This highlights the unique potential of immunoaffinity intact mass spectrometry in clinical diagnostics.


Assuntos
Biomarcadores Tumorais , Espectrometria de Massas , Fosfopiruvato Hidratase , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/isolamento & purificação , Humanos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Acetilação , Espectrometria de Massas/métodos , Processamento de Proteína Pós-Traducional , Imunoprecipitação/métodos , Cromatografia Líquida de Alta Pressão/métodos
2.
Br J Haematol ; 204(5): 2103-2111, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38494337

RESUMO

Red blood cell autoimmunity and alloimmunity are potentially linked. Quantification of this association can tailor extensively matched red blood cell transfusions in patients with autoimmunity. Using an incident new-user cohort comprising 47 285 previously non-transfused, non-alloimmunised patients, we compared transfusion-induced red blood cell alloimmunisation incidences in direct antiglobulin test (DAT)-positive and control patients. Additionally, we performed case-control analyses to handle potential confounding by clinical immunomodulators. Among (IgG and/or C3d) DAT-positive patients (N = 380), cumulative red blood cell alloimmunisation incidences after 10 units transfused reached 4.5% (95% confidence interval [CI] 2.5-8.2) versus 4.2% (CI 3.9-4.5, p = 0.88) in controls. In case-control analyses, alloimmunisation relative risks among DAT-positive patients increased to 1.7 (CI 1.1-2.8). Additional adjustments for pre-DAT transfusion exposure or the extent of Rh/K mismatching did not impact results. In conclusion, while patients with DAT positivity show an intrinsically increased alloimmune red blood cell response, their absolute risk is comparable to control patients due to counteracting co-existing immunosuppressive conditions. Consequently, isolated DAT positivity in patients lacking overt haemolysis or complicated alloantibody testing does not seem to warrant extended matching strategies.


Assuntos
Autoimunidade , Transfusão de Eritrócitos , Eritrócitos , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Eritrócitos/imunologia , Fatores de Risco , Adulto , Idoso , Transfusão de Eritrócitos/efeitos adversos , Teste de Coombs , Estudos de Casos e Controles , Isoanticorpos/sangue , Isoanticorpos/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Reação Transfusional/imunologia , Reação Transfusional/sangue , Reação Transfusional/etiologia
3.
Haematologica ; 109(8): 2478-2486, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38385259

RESUMO

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from ever-pregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR]=0.91, 95% confidence interval [CI]: 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR=1.81, 95% CI: 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.


Assuntos
Doadores de Sangue , Transfusão de Eritrócitos , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Gravidez , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/mortalidade , Adolescente , Adulto Jovem , Países Baixos/epidemiologia , Fatores Sexuais , Idoso
4.
Vox Sang ; 119(1): 43-52, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37920882

RESUMO

BACKGROUND AND OBJECTIVES: Donor characteristics have been implicated in transfusion-related adverse events. Uncertainty remains about whether sex, and specifically pregnancy history of the blood donor, could affect patient outcomes. Whether storage duration of the blood product could be important for patient outcomes has also been investigated, and a small detrimental effect of fresh products remains a possibility. Here, we hypothesize that fresh red blood cell products donated by ever-pregnant donors are associated with mortality in male patients. MATERIALS AND METHODS: We used data from a cohort study of adult patients receiving a first transfusion between 2005 and 2015 in the Netherlands. The risk of death after receiving a transfusion from one of five exposure categories (female never-pregnant stored ≤10 days, female never-pregnant stored >10 days, female ever-pregnant stored ≤10 days, female ever-pregnant stored >10 days and male stored for ≤10 days), compared to receiving a unit donated by a male donor, which was stored for >10 days (reference), was calculated using a Cox proportional hazards model. RESULTS: The study included 42,456 patients who contributed 88,538 person-years in total, of whom 13,948 died during the follow-up of the study (33%). Fresh units (stored for ≤10 days) from ever-pregnant donors were associated with mortality in male patients, but the association was not statistically significant (hazard ratio 1.39, 95% confidence interval 0.97-1.99). Sensitivity analyses did not corroborate this finding. CONCLUSION: These findings do not consistently support the notion that the observed association between ever-pregnant donor units and mortality is mediated by blood product storage.


Assuntos
Transfusão de Eritrócitos , Eritrócitos , Adulto , Gravidez , Humanos , Masculino , Feminino , Estudos de Coortes , Transfusão de Eritrócitos/efeitos adversos , Modelos de Riscos Proporcionais , Doadores de Sangue , Preservação de Sangue/efeitos adversos
5.
Clin Chem Lab Med ; 62(6): 1118-1125, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38253354

RESUMO

OBJECTIVES: Urea and creatinine concentrations in plasma are used to guide hemodialysis (HD) in patients with end-stage renal disease (ESRD). To support individualized HD treatment in a home situation, there is a clinical need for a non-invasive and continuous alternative to plasma for biomarker monitoring during and between cycles of HD. In this observational study, we therefore established the correlation of urea and creatinine concentrations between sweat, saliva and plasma in a cohort of ESRD patients on HD. METHODS: Forty HD patients were recruited at the Dialysis Department of the Catharina Hospital Eindhoven. Sweat and salivary urea and creatinine concentrations were analyzed at the start and at the end of one HD cycle and compared to the corresponding plasma concentrations. RESULTS: A decrease of urea concentrations during HD was observed in sweat, from 27.86 mmol/L to 12.60 mmol/L, and saliva, from 24.70 mmol/L to 5.64 mmol/L. Urea concentrations in sweat and saliva strongly correlated with the concentrations in plasma (ρ 0.92 [p<0.001] and 0.94 [p<0.001], respectively). Creatinine concentrations also decreased in sweat from 43.39 µmol/L to 19.69 µmol/L, and saliva, from 59.00 µmol/L to 13.70 µmol/L. However, for creatinine, correlation coefficients were lower than for urea for both sweat and saliva compared to plasma (ρ: 0.58 [p<0.001] and 0.77 [p<0.001], respectively). CONCLUSIONS: The results illustrate a proof of principle of urea measurements in sweat and saliva to monitor HD adequacy in a non-invasive and continuous manner. Biosensors enabling urea monitoring in sweat or saliva could fill in a clinical need to enable at-home HD for more patients and thereby decrease patient burden.


Assuntos
Creatinina , Diálise Renal , Saliva , Suor , Ureia , Humanos , Ureia/análise , Ureia/sangue , Saliva/química , Creatinina/sangue , Creatinina/análise , Suor/química , Feminino , Masculino , Estudos de Coortes , Pessoa de Meia-Idade , Idoso , Falência Renal Crônica/terapia , Falência Renal Crônica/sangue , Adulto , Biomarcadores/análise , Biomarcadores/sangue
6.
Clin Chem Lab Med ; 62(4): 720-728, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-37886827

RESUMO

OBJECTIVES: Numerous studies have proven the potential of cytokeratin 19 fragment 21-1 (CYFRA 21-1) detection in the (early) diagnosis and treatment monitoring of non-small cell lung cancer (NSCLC). Conventional immunoassays for CYFRA 21-1 quantification are however prone to interferences and lack diagnostic sensitivity and standardization. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an emerging approach based on a different, often superior, detection principle, which may improve the clinical applicability of CYFRA 21-1 in cancer diagnostics. Therefore, we developed and validated a protein precipitation, immunoaffinity (IA) LC-MS/MS assay for quantitative analysis of serum CYFRA 21-1. METHODS: Selective sample preparation was performed using ammonium sulfate (AS) precipitation, IA purification, tryptic digestion and LC-MS/MS quantification using a signature peptide and isotopically labeled internal standard. The workflow was optimized and validated according to EMA guidelines and results were compared to a conventional immunoassay. RESULTS: Significant interference effects were seen during IA purification, which were sufficiently solved by performing AS precipitation prior to IA purification. A linear calibration curve was obtained in the range of 1.0-100 ng/mL (R2=0.98). Accuracy and precision were well within acceptance criteria. In sera of patients suspected of lung cancer, the method showed good correlation with the immunoassay. CONCLUSIONS: A robust AS precipitation-IA LC-MS/MS assay for the quantification of serum CYFRA 21-1 was developed. With this assay, the clinically added value of LC-MS/MS-based detection over immunoassays can be further explored.


Assuntos
Antígenos de Neoplasias , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Cromatografia Líquida/métodos , Queratina-19 , Espectrometria de Massas em Tandem/métodos , Neoplasias Pulmonares/diagnóstico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Espectrometria de Massa com Cromatografia Líquida
7.
Br J Haematol ; 195(4): 604-611, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34346067

RESUMO

Maternal alloantibodies directed against fetal red blood cell (RBC) antigens may cause potentially life-threatening haemolytic disease of the fetus and newborn (HDFN). Dutch transfusion guidelines therefore prescribe preventive cEK matching for all (pre-)fertile females. To quantify the impact of cEK matching, we compared overall and antigen-specific cumulative RBC alloimmunisation incidences in females and males aged <45 years. Among a multicentre cohort comprised of patients who received their first and subsequent RBC unit between 2005 and 2019, first-formed RBC alloantibodies were detected in 47 of 2998 (1·6%) females and 49 of 2507 (2·0%) males. Comparing females and males, overall alloimmunisation incidences were comparable (3·1% [95% confidence interval (CI) 2·1-4·4] versus 3·5% (95% CI 2·4-4·9, P = 0·853) after 10 units transfused). However, cEK alloimmunisation incidences were significantly lower among females (0·6% (95% CI 0·3-1.5) versus 2·2% (95% CI 1·5-3·4, P = 0·001) after 10 units transfused). Yet, despite cEK-matching guidelines being in effect, 6·5%, 3·6% and 0·2% of all RBC units remained mismatched for c, E or K antigens respectively. Most of these mismatches were almost always due to emergency settings. Even though cEK alloimmunisation was not prevented completely, implementation of cEK matching resulted in an alloantigen-exposure risk reduction of up to 98%.


Assuntos
Incompatibilidade de Grupos Sanguíneos/genética , Tipagem e Reações Cruzadas Sanguíneas , Eritroblastose Fetal/etiologia , Eritrócitos/imunologia , Isoanticorpos/biossíntese , Sistema do Grupo Sanguíneo de Kell/imunologia , Sistema do Grupo Sanguíneo Rh-Hr/imunologia , Reação Transfusional/epidemiologia , Adulto , Eritroblastose Fetal/genética , Eritroblastose Fetal/imunologia , Feminino , Humanos , Incidência , Isoanticorpos/imunologia , Sistema do Grupo Sanguíneo de Kell/genética , Masculino , Sistema do Grupo Sanguíneo Rh-Hr/genética , Adulto Jovem
8.
Transfusion ; 61(1): 35-41, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33295653

RESUMO

BACKGROUND: Renal failure and renal replacement therapy (RRT) affect the immune system and could therefore modulate red blood cell (RBC) alloimmunization after transfusion. STUDY DESIGN AND METHODS: We performed a nationwide multicenter case-control study within a source population of newly transfused patients between 2005 and 2015. Using conditional multivariate logistic regression, we compared first-time transfusion-induced RBC alloantibody formers (N = 505) with two nonalloimmunized recipients with similar transfusion burden (N = 1010). RESULTS: Renal failure was observed in 17% of the control and 13% of the case patients. A total of 41% of the control patients and 34% of case patients underwent acute RRT. Renal failure without RRT was associated with lower alloimmunization risks after blood transfusion (moderate renal failure: adjusted relative rate [RR], 0.82 [95% confidence interval (CI), 0.67-1.01]); severe renal failure, adjusted RR, 0.76 [95% CI, 0.55-1.05]). With severe renal failure patients mainly receiving RRT, the lowest alloimmunization risk was found in particularly these patients [adjusted RR 0.48 (95% CI 0.39-0.58)]. This was similar for patients receiving RRT for acute or chronic renal failure (adjusted RR, 0.59 [95% CI, 0.46-0.75]); and adjusted RR, 0.62 [95% CI 0.45-0.88], respectively). CONCLUSION: These findings are indicative of a weakened humoral response in acute as well as chronic renal failure, which appeared to be most pronounced when treated with RRT. Future research should focus on how renal failure and RRT mechanistically modulate RBC alloimmunization.


Assuntos
Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/imunologia , Insuficiência Renal/etiologia , Idoso , Transfusão de Sangue , Estudos de Casos e Controles , Correlação de Dados , Feminino , Humanos , Falência Renal Crônica/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/complicações , Insuficiência Renal/imunologia , Insuficiência Renal Crônica/etiologia , Terapia de Substituição Renal , Fatores de Risco , Reação Transfusional/complicações
9.
Clin Chem Lab Med ; 59(2): 315-323, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001847

RESUMO

Objectives: Hepcidin measurement advances insights in pathophysiology, diagnosis, and treatment of iron disorders, but requires analytically sound and standardized measurement procedures (MPs). Recent development of a two-level secondary reference material (sRM) for hepcidin assays allows worldwide standardization. However, no proficiency testing (PT) schemes to ensure external quality assurance (EQA) exist and the absence of a high calibrator in the sRM set precludes optimal standardization. Methods: We developed a pilot PT together with the Dutch EQA organization Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek (SKML) that included 16 international hepcidin MPs. The design included 12 human serum samples that allowed us to evaluate accuracy, linearity, precision and standardization potential. We manufactured, value-assigned, and validated a high-level calibrator in a similar manner to the existing low- and middle-level sRM. Results: The pilot PT confirmed logistical feasibility of an annual scheme. Most MPs demonstrated linearity (R2>0.99) and precision (duplicate CV>12.2%), although the need for EQA was shown by large variability in accuracy. The high-level calibrator proved effective, reducing the inter-assay CV from 42.0% (unstandardized) to 14.0%, compared to 17.6% with the two-leveled set. The calibrator passed international homogeneity criteria and was assigned a value of 9.07±0.24 nmol/L. Conclusions: We established a framework for future PT to enable laboratory accreditation, which is essential to ensure quality of hepcidin measurement and its use in patient care. Additionally, we showed optimized standardization is possible by extending the current sRM with a third high calibrator, although international implementation of the sRM is a prerequisite for its success.


Assuntos
Hepcidinas/sangue , Acreditação , Coleta de Amostras Sanguíneas , Calibragem , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Humanos , Laboratórios/normas , Garantia da Qualidade dos Cuidados de Saúde/normas , Controle de Qualidade , Padrões de Referência , Espectrometria de Massas em Tandem
10.
Clin Chem Lab Med ; 56(9): 1490-1497, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-29777607

RESUMO

BACKGROUND: Targeted quantification of protein biomarkers with liquid chromatography-tandem mass spectrometry (LC-MS/MS) has great potential, but is still in its infancy. Therefore, we elucidated the influence of charge state distribution and matrix effects on accurate quantification, illustrated by the peptide hormone hepcidin. METHODS: An LC-MS/MS assay for hepcidin, developed based on existing literature, was improved by using 5 mM ammonium formate buffer as mobile phase A and as an elution solution for solid phase extraction (SPE) to optimize the charge state distribution. After extensive analytical validation, focusing on interference and matrix effects, the clinical consequence of this method adjustment was studied by performing receiving operating characteristic (ROC)-curve analysis in patients with iron deficiency anemia (IDA, n=44), anemia of chronic disease (ACD, n=42) and non-anemic patients (n=93). RESULTS: By using a buffered solution during sample preparation and chromatography, the most abundant charge state was shifted from 4+ to 3+ and the charge state distribution was strongly stabilized. The matrix effects which occurred in the 4+ state were therefore avoided, eliminating bias in the low concentration range of hepcidin. Consequently, sensitivity, specificity and positive predictive value (PPV) for detection of IDA patients with the optimized assay (96%, 97%, 91%, respectively) were much better than for the original assay (73%, 70%, 44%, respectively). CONCLUSIONS: Fundamental improvements in LC-MS/MS assays greatly impact the accuracy of protein quantification. This is urgently required for improved diagnostic accuracy and clinical value, as illustrated by the validation of our hepcidin assay.


Assuntos
Biomarcadores/análise , Cromatografia Líquida de Alta Pressão/métodos , Hepcidinas/análise , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/patologia , Anemia Ferropriva/patologia , Área Sob a Curva , Proteína C-Reativa/análise , Doença Crônica , Feminino , Hepcidinas/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Extração em Fase Sólida , Adulto Jovem
11.
Scand J Clin Lab Invest ; 78(1-2): 1-5, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29148292

RESUMO

Idarucizumab, an antidote specific for dabigatran, became available recently. Dabigatran is not associated with increased risk of hepatotoxicity in comparison with warfarin, but it is seen as a rare side-effect. Cases of cholestatic liver injury due to dabigatran have not been reported previously. We present a case of severe gastro-intestinal bleeding with underlying dabigatran intoxication in a patient with renal failure and the effect of reversal of dabigatran using idaruzicumab on coagulation assays. International normalized ratio (INR) and activated partial thromboplastin time (APTT) results were elevated in a setting of sepsis, possibly due to liver failure. INR and APTT can be elevated if sepsis is complicated by disseminated intravascular coagulation (DIC) or liver failure, making it challenging to determine dabigatrans contribution to their prolongation. A rebound effect after administration of idarucizumab and slow elimination of dabigatran due to reduced kidney function could be detected using the Hemoclot® diluted thrombin time (dTT) in this situation, in contrast to with non-dilutional assays. Before admission, cholestatic liver injury started shortly after initiation of dabigatran etexilate therapy. As no other cause was found, this liver injury was likely to be drug-induced. Bleeding cessated promptly after administration of idarucizumab in dabigatran intoxication. In conclusion, the anticoagulant effect of dabigatran can be measured by Hemoclot® dTT in sepsis and cholestatic liver injury was seen as a possible rare side-effect of dabigatran treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Colestase/sangue , Dabigatrana/efeitos adversos , Hemorragia/tratamento farmacológico , Fígado/lesões , Sepse/tratamento farmacológico , Idoso , Testes de Coagulação Sanguínea , Dabigatrana/sangue , Evolução Fatal , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Fígado/patologia , Tromboelastografia
13.
Haematologica ; 102(1): 52-59, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27634204

RESUMO

Red cell alloimmunization may induce severe hemolytic side effects. Identification of risk-modifying conditions will help tailor preventative strategies. This study aims to quantify the associations of hematologic malignancies and solid cancers with red cell alloimmunization in patients receiving red cell transfusions. We performed a nested multicenter case-control study in a source population of 24,063 patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Cases (n=505), defined as patients developing a first transfusion-induced red cell alloantibody, were each compared with 2 non-alloimmunized controls (n=1010) who received a similar number of red cell units. Using multivariate logistic regression analyses, we evaluated the association of various malignancies and treatment regimens with alloimmunization during a delineated 5-week risk period. The incidence of alloimmunization among patients with acute (myeloid or lymphoid) leukemia and mature (B- or T-cell) lymphoma was significantly reduced compared to patients without these malignancies: adjusted relative risks (RR) with 95% confidence interval (CI) 0.36 (range 0.19-0.68) and 0.30 (range 0.12-0.81). Associations were primarily explained by immunosuppressive treatments [RR for (any type of) chemotherapy combined with immunotherapy 0.27 (95%CI: 0.09-0.83)]. Alloimmunization risks were similarly diminished in allogeneic or autologous stem cell transplanted patients (RR 0.34, 95%CI: 0.16-0.74), at least during the six months post transplant. Alloimmunization risks of patients with other hematologic diseases or solid cancers, and their associated treatment regimens were similar to risks in the general transfused population. Our findings suggest that, in contrast to malignancies in general, hemato-oncological patients treated with dose-intensive regimens have strongly diminished risk of red cell alloimmunization.


Assuntos
Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Isoanticorpos/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Terapia Combinada , Feminino , Neoplasias Hematológicas/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunização , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Países Baixos/epidemiologia , Vigilância da População , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
14.
Clin Chem Lab Med ; 55(12): 2002-2009, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28328523

RESUMO

BACKGROUND: Dabigatran is prescribed to increasing numbers of patients with atrial fibrillation (AF). Although routine monitoring is not considered to be useful, measuring drug concentrations can be clinically relevant in specific situations. The aim of this study was the comparison of different functional and non-functional assays for determination of dabigatran concentrations at different timepoints in a real-life patient population with AF. We focused on the differences between assays in identifying patients with low drug concentrations. Furthermore, we studied the effect of glucuronidation on the established concentration as determined with different assays. METHODS: This study established dabigatran concentration ranges in 40 real-life AF patients by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) reference method and compared these with results from coagulation assays (Hemoclot dTT, LD-dTT and ECA). Samples were taken just before and 2 and 4 h after taking the drug. RESULTS: A wide range of concentrations at different time points was found in this patient group. Coagulation assays correlate best with UPLC-MS/MS results that include the glucuronidated metabolites, showing that the pharmacologically active glucuronides are also measured in coagulation testing. The LD-dTT has the best agreement with UPLC-MS/MS and combines good sensitivity with high specificity. Several patients show consistently low or high drug concentrations, implying that drug exposure differs between patients. CONCLUSIONS: Based on the association of dabigatran concentrations with bleeding and thromboembolic risk, we believe that dabigatran monitoring could be beneficial for further optimizing anticoagulation therapy in AF.


Assuntos
Fibrilação Atrial/sangue , Fibrilação Atrial/metabolismo , Variação Biológica Individual , Dabigatrana/sangue , Dabigatrana/metabolismo , Idoso , Antitrombinas/sangue , Antitrombinas/metabolismo , Testes de Coagulação Sanguínea , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
15.
JAMA ; 318(15): 1471-1478, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29049654

RESUMO

Importance: Transfusion of red blood cells from female donors has been associated with increased mortality in male recipients. Objective: To quantify the association between red blood cell transfusion from female donors with and without a history of pregnancy and mortality of red blood cell recipients. Design, Setting, and Participants: Retrospective cohort study of first-time transfusion recipients at 6 major Dutch hospitals enrolled from May 30, 2005, to September 1, 2015; the final follow-up date was September 1, 2015. The primary analysis was the no-donor-mixture cohort (ie, either all red blood cell transfusions exclusively from male donors, or all exclusively from female donors without a history of pregnancy, or all exclusively from female donors with a history of pregnancy). The association between mortality and exposure to transfusions from ever-pregnant or never-pregnant female donors was analyzed using life tables and time-varying Cox proportional hazards models. Exposures: Red blood cell transfusions from ever-pregnant or never-pregnant female donors, compared with red blood cell transfusions from male donors. Main Outcomes and Measures: All-cause mortality during follow-up. Results: The cohort for the primary analyses consisted of 31 118 patients (median age, 65 [interquartile range, 42-77] years; 52% female) who received 59 320 red blood cell transfusions exclusively from 1 of 3 types of donors (88% male; 6% ever-pregnant female; and 6% never-pregnant female). The number of deaths in this cohort was 3969 (13% mortality). For male recipients of red blood cell transfusions, all-cause mortality rates after a red blood cell transfusion from an ever-pregnant female donor vs male donor were 101 vs 80 deaths per 1000 person-years (time-dependent "per transfusion" hazard ratio [HR] for death, 1.13 [95% CI, 1.01-1.26]). For receipt of transfusion from a never-pregnant female donor vs male donor, mortality rates were 78 vs 80 deaths per 1000 person-years (HR, 0.93 [95% CI, 0.81-1.06]). Among female recipients of red blood cell transfusions, mortality rates for an ever-pregnant female donor vs male donor were 74 vs 62 per 1000 person-years (HR, 0.99 [95% CI, 0.87 to 1.13]); for a never-pregnant female donor vs male donor, mortality rates were 74 vs 62 per 1000 person-years (HR, 1.01 [95% CI, 0.88-1.15]). Conclusions and Relevance: Among patients who received red blood cell transfusions, receipt of a transfusion from an ever-pregnant female donor, compared with a male donor, was associated with increased all-cause mortality among male recipients but not among female recipients. Transfusions from never-pregnant female donors were not associated with increased mortality among male or female recipients. Further research is needed to replicate these findings, determine their clinical significance, and identify the underlying mechanism.


Assuntos
Doadores de Sangue , Transfusão de Eritrócitos/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Eritrócitos/imunologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem
16.
Br J Haematol ; 175(5): 956-966, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27539877

RESUMO

Red cell alloantigen exposure can cause alloantibody-associated morbidity. Murine models have suggested that inflammation modulates red cell alloimmunisation. This study quantifies alloimmunisation risks during infectious episodes in humans. We performed a multicentre case-control study within a source population of patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Patients developing a first transfusion-induced red cell alloantibody (N = 505) were each compared with two similarly exposed, but non-alloimmunised controls (N = 1010) during a 5-week 'alloimmunisation risk period' using multivariate logistic regression analysis. Transfusions during 'severe' bacterial (tissue-invasive) infections were associated with increased risks of alloantibody development [adjusted relative risk (RR) 1·34, 95% confidence interval (95% CI) 0·97-1·85], especially when these infections were accompanied with long-standing fever (RR 3·06, 95% CI 1·57-5·96). Disseminated viral disorders demonstrated a trend towards increased risks (RR 2·41, 95% CI 0·89-6·53), in apparent contrast to a possible protection associated with Gram-negative bacteraemia (RR 0·58, 95% CI 0·13-1·14). 'Simple' bacterial infections, Gram-positive bacteraemia, fungal infections, maximum C-reactive protein values and leucocytosis were not associated with red cell alloimmunisation. These findings are consistent with murine models. Confirmatory research is needed before patients likely to develop alloantibodies may be identified based on their infectious conditions at time of transfusion.


Assuntos
Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/imunologia , Isoanticorpos/biossíntese , Idoso , Animais , Bacteriemia/imunologia , Estudos de Casos e Controles , Feminino , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Viroses/imunologia
17.
Clin Chem Lab Med ; 54(7): 1211-9, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26587745

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab (IFX, Remicade®) can aid to optimize therapy efficacy. Many assays are available for this purpose. However, a reference standard is lacking. Therefore, we evaluated the analytical performance, agreement and clinically relevant differences of three commercially available IFX ELISA kits on an automated processing system. METHODS: The kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 µg/mL and determining assay concordance. RESULTS: Within-run and between-run imprecision were acceptable (≤12% and ≤17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved. CONCLUSIONS: Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization.


Assuntos
Monitoramento de Medicamentos/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Fármacos Gastrointestinais/sangue , Infliximab/sangue , Kit de Reagentes para Diagnóstico , Humanos , Países Baixos , Valor Preditivo dos Testes
18.
Hemodial Int ; 28(1): 72-76, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37962053

RESUMO

PURPOSE: Apixaban is a factor Xa inhibitor used in patients undergoing hemodialysis treatment. The objective of this study is to investigate the effect of hemodialysis on apixaban plasma concentrations. METHODS: This observational study is on patients treated with apixaban 2.5 mg twice daily on conventional hemodialysis with standard low-molecular-weight heparin (LMWH) anticoagulation (nadroparin 3800-7600 IU). Plasma blood samples were collected before starting dialysis (t1), 2 h after starting dialysis (t2), and directly after dialysis (t3). Apixaban concentration was measured before and after dialysis. Anti-Xa activity was measured for all three samples. RESULTS: A significant difference was observed between the apixaban concentration before and after dialysis (mean before dialysis 141.03 ng/mL; mean after dialysis 102.71 ng/mL; p = 0.003). Nonetheless, both apixaban plasma concentrations and anti-Xa levels remained within the reference range. Anti-Xa levels had a strong correlation with the apixaban concentrations (r = 0.935, p = 0.000). Thus, anti-Xa activity might be used as a surrogate for apixaban plasma concentration. CONCLUSION: There seems to be no need for dose adjustments of apixaban; co-administration of LMWH next to apixaban might also be unnecessary.


Assuntos
Anticoagulantes , Heparina de Baixo Peso Molecular , Pirazóis , Piridonas , Humanos , Anticoagulantes/uso terapêutico , Diálise Renal/efeitos adversos , Coagulação Sanguínea
19.
J Pharm Biomed Anal ; 249: 116381, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39067280

RESUMO

Fluorouracil is among the most used antimetabolite drugs for the chemotherapeutic treatment of various types of gastrointestinal malignancies. Dihydropyrimidine dehydrogenase (DPYD) genotyping prior to fluorouracil treatment is considered standard practice in most European countries. Yet, current pre-therapeutic DPYD genotyping procedures do not identify all dihydropyrimidine dehydrogenase (DPD)-deficient patients. Alternatively, DPD activity can be estimated by determining the DPD phenotype by quantification of plasma concentrations of the endogenous uracil and thymine concentrations and their respective metabolites dihydrouracil (DHU) and dihydrothymine (DHT). Liquid chromatography - mass spectrometry (LC-MS) detection is currently considered as the most adequate method for quantification of low-molecular weight molecules, although the sample preparation method is highly critical for analytical outcome. It was hypothesized that during protein precipitation, the recovery of the molecule of interest highly depends on the choice of precipitation agent and the extent of protein binding in plasma. In this work, the effect of protein precipitation using acetonitrile (ACN) compared to strong acid perchloric acid (PCA) on the recovery of uracil, thymine, DHU and DHT is demonstrated. Upon the analysis of plasma samples, PCA precipitation showed higher concentrations of uracil and thymine as compared to ACN precipitation. Using ultrafiltration, it was shown that uracil and thymine are significantly (60-65 %) bound to proteins compared to DHU and DHT. This shows that before harmonized cut-off levels of DPD phenotyping can be applied in clinical practice, the analytical methodology requires extensive further optimization.


Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Fenótipo , Ligação Proteica , Timina , Uracila , Timina/metabolismo , Uracila/análogos & derivados , Uracila/metabolismo , Uracila/sangue , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/genética , Humanos , Cromatografia Líquida/métodos , Fluoruracila/metabolismo , Fluoruracila/sangue , Genótipo , Deficiência da Di-Hidropirimidina Desidrogenase/metabolismo , Espectrometria de Massas em Tandem/métodos
20.
Lung Cancer ; 189: 107477, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38271919

RESUMO

OBJECTIVES: Timely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed. MATERIALS AND METHODS: 1096 patients with suspected LC were enrolled in this multicenter prospective study (NL9146). The overall survival, time from referral to the first appointment with the pulmonologist, time to diagnosis and treatment, and the number of imaging and invasive procedures were evaluated. Patients were divided into different diagnostic groupsearly- and advanced stage non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), patients without LC and patients without a definitive diagnosis. RESULTS: The majority of patients (66 %) received a definitive diagnosis within 5 weeks, although the time to diagnosis of early-stage LC patients and patients without LC was significantly longer comparted to advanced stage LC. An increase in invasive procedures was seen for early-stage LC compared to advanced stage LC and for 13 % of the advanced stage non-squamous NSCLC patients up to three additional invasive procedures were performed solely to obtain sufficient material for NGS. For patients without a definitive diagnosis, 50 % did undergo at least one invasive procedure, while 11 % did not wish to undergo any invasive procedures. CONCLUSION: These insights could aid in improved LC diagnostics and efficient implementation of new techniques like liquid biopsy and artificial intelligence. This may lead to more timely LC care, a decreased number of invasive procedures, less variability between the diagnostic trajectory of different patients and aid in obtaining a definitive diagnosis for all patients.


Assuntos
Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Inteligência Artificial , Estudos Prospectivos , Hospitais , Pulmão
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA