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1.
Blood ; 136(4): 480-488, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32374875

RESUMO

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Cloridrato de Bendamustina/administração & dosagem , Rituximab/administração & dosagem , Vidarabina/análogos & derivados , Adulto , Idoso , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Vidarabina/administração & dosagem
2.
Blood ; 136(17): 1956-1967, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32693407

RESUMO

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.


Assuntos
Grânulos Citoplasmáticos/patologia , Heterogeneidade Genética , Síndrome da Plaqueta Cinza , Sistema Imunitário/patologia , Fenótipo , Biópsia , Proteínas Sanguíneas/genética , Estudos de Casos e Controles , Estudos de Coortes , Grânulos Citoplasmáticos/metabolismo , Diagnóstico Diferencial , Frequência do Gene , Estudos de Associação Genética , Síndrome da Plaqueta Cinza/classificação , Síndrome da Plaqueta Cinza/genética , Síndrome da Plaqueta Cinza/imunologia , Síndrome da Plaqueta Cinza/patologia , Humanos , Sistema Imunitário/fisiologia , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Mutação
3.
Int J Exp Pathol ; 102(1): 45-50, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32929772

RESUMO

Testing for the CALR mutation is included in the updated WHO criteria for essential thrombocythaemia (ET) and primary myelofibrosis (PMF). We report on the application of the CAL2 monoclonal antibody, raised against the mutated CALR gene to myeloid cases. The immunostain was used on 116 acute myeloid leukaemias (AML) and 66 myeloproliferative neoplasms (MPN) or myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). None of AML cases was stained by the CAL2 antibody, while 20/66 MPNs and MDS/MPNs appeared positive. Fourteen of the latter cases were studied by molecular techniques, and all showed aberrations of the CALR gene. In addition, CAL2 positivity was found in some small-sized elements besides megakaryocytes. By double staining, these elements corresponded to small megakaryocytes as well as both erythroid and myeloid precursors. This finding suggests possible occurrence of CALR gene abnormalities in a stem cell.


Assuntos
Anticorpos Monoclonais , Calreticulina/genética , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Eritrócitos/metabolismo , Granulócitos/metabolismo , Humanos , Megacariócitos/metabolismo , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética
4.
Haemophilia ; 26(3): 401-408, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32243025

RESUMO

AIMS: The occurrence of AIDS in 1980s posed difficult problems for haemophilia clinicians worldwide. The impact of these events is substantial, and the events continue to be subject to judicial proceedings and publications. The stance of haemophilia physicians, particularly their professional resilience, is of importance and remains unexamined. METHODS: Deploying oral histories informed by literature review of scientific publications and past inquiry reports, this qualitative study addresses how physicians continued to work in haemophilia during those years and attributes that contributed to their resilience. RESULTS AND CONCLUSIONS: Experience and role in laboratory aspects were of value in handling and communicating uncertainty. Collegiality, peer support and scholarship were important in sustaining their roles, in clinical decision-making and re-instating confidence in the therapeutic relationship during the toughest years of their practice.


Assuntos
Hemofilia A/psicologia , Médicos/psicologia , Resiliência Psicológica , Hemofilia A/terapia , História do Século XX , Humanos
5.
Transfusion ; 59(1): 160-168, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30383912

RESUMO

BACKGROUND: Patients with prolonged neutropenia caused by chemotherapy or underlying marrow disorders are at risk of invasive bacterial and fungal infections. New treatment options alongside targeted antimicrobial therapy that might improve outcomes include granulocyte transfusions (GTX). To inform the research agenda, a prospective observational cohort study was performed in the Netherlands and United Kingdom. The aim was to describe the incidence, characteristics, and outcomes of patients developing invasive infections and assess patients fulfilling criteria for GTX. STUDY DESIGN AND METHODS: All patients receiving myeloablative chemotherapy and anticipated to develop 7 or more days of neutropenia (<0.5 × 109 /L) were eligible and followed for the development of invasive infections according to a defined algorithm and mortality up to 100 days. Secondary outcomes were types of infection and eligibility for GTX. RESULTS: A total of 471 patients enrolled at six hematology-oncology departments were followed for 569 neutropenic episodes. Overall, 32.5% of patients developed invasive infections during their first episode. Significant baseline risk factors for developing infections were high comorbidity scores (WHO performance status ≥ 2, hazard ratio [HR], 2.6 [1.7-3.9]; and hematopoietic cell transplantation-comorbidity index score ≥ 2 HR 1.3 [0.9-1.8]). Infections were bacterial (59.4%) and fungal (22.3%). Despite 34 patients (6.3% of all episodes) appearing to meet criteria to receive GTX, only nine patients received granulocytes. The HR for death was 5.8 (2.5-13.0) for patients with invasive infections. CONCLUSION: This study documents that invasive infections are associated with significant mortality. There is a need for new strategies to prevent and treat infections, which may include better understanding of use GTX.


Assuntos
Granulócitos/citologia , Transfusão de Leucócitos/métodos , Neutropenia/epidemiologia , Neutropenia/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
6.
Gut ; 72(8): 1471-1543, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36038198
8.
Liver Int ; 36(4): 522-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26537012

RESUMO

BACKGROUND & AIMS: Cirrhosis is a complex acquired disorder of coagulation and frequent indication for transfusion of blood components. We characterised blood component use in patients with cirrhosis and compared this to transfusion guidelines. METHODS: All National Health Service trusts with representation on the British Society of Gastroenterology membership list were invited to take part. Data were collected prospectively on consecutive, unselected, hospitalised admissions with cirrhosis over 28 days. Detailed information was recorded for patients receiving blood components including indication (for bleeding or prophylaxis), type of component, laboratory indices triggering transfusion, complications, thromboembolic events and clinical outcome to day 28. RESULTS: Data on 1313 consecutive patients with cirrhosis were collected from 85 hospitals. A total of 391/1313 (30%) were transfused a blood component; in 238/391 (61%), this was for treatment of bleeding and in 153/391 (39%) for prophylaxis of bleeding. In 48/185 (26%) cases with bleeding, the haemoglobin threshold was >80 g/L prior to red blood cell transfusion. In the prophylaxis group, 238/391 (61%) received transfusion in response to an abnormal haematological value in the absence of any planned procedure. In patients transfused for procedural prophylaxis, 10/34 (29%) received fresh frozen plasma at an International Normalised Ratio lower than the threshold where a benefit would be anticipated. An in-patient thromboembolic event was recorded in 3% (35/1313) and 10% (138/1313) died by day 28. CONCLUSIONS: One-third of hospitalised patients with cirrhosis were transfused. Strategies for Patient Blood Management should include ensuring transfusion practice is consistent with guidelines and greater emphasis on alternatives to transfusion.


Assuntos
Transfusão de Componentes Sanguíneos/tendências , Hemorragia Gastrointestinal/terapia , Cirrose Hepática/terapia , Padrões de Prática Médica/tendências , Idoso , Biomarcadores/sangue , Transfusão de Componentes Sanguíneos/efeitos adversos , Transfusão de Componentes Sanguíneos/normas , Feminino , Hemorragia Gastrointestinal/sangue , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Fidelidade a Diretrizes/tendências , Pesquisas sobre Atenção à Saúde , Hemoglobinas/metabolismo , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/tendências , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Valor Preditivo dos Testes , Fatores de Risco , Medicina Estatal , Tromboembolia/etiologia , Fatores de Tempo , Resultado do Tratamento , Reino Unido
14.
Curr Res Transl Med ; 72(1): 103420, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38262189

RESUMO

BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of disorders of clonal haemopoiesis associated with an inherent risk of arterial and venous thrombotic complications. The prevalence of thrombotic complications and the impact of cardiovascular risk factors (CVRFs) in contemporary patient cohorts within the current era of MPN treatments have not been completely defined. OBJECTIVES: We aim to characterise the cardiovascular risk of patients with MPN by identifying the prevalence of CVRFs and describing the pattern of thrombotic events. We also aim to utilise the QRISK3 algorithm, which is a validated model used to estimate an individual's risk of developing cardiovascular disease, to further phenotype this cohort of patients. METHODS: We perform a retrospective analysis on a single-centre cohort of 438 patients with MPN. RESULTS: MPN patients continue to carry a high burden of vascular morbidity with a prevalence of arterial thrombotic events in 15.8 % (69/438) and venous thrombotic events in 13.2 % (58/438) of the cohort. The novel use of the QRISK3 algorithm, which showed a mean score of 13.7 % across the MPN population, provides further evidence to suggest an increased cardiovascular risk in MPN patients. CONCLUSION: With an increased risk of cardiovascular disease in patients with MPN, we propose an integrated approach between primary and specialised healthcare services using risk stratification tools such as QRISK3, which will allow aggressive optimisation of CVRFs to prevent thrombosis and reduce the overall morbidity and mortality in patients with MPN.


Assuntos
Doenças Cardiovasculares , Transtornos Mieloproliferativos , Neoplasias , Trombose , Humanos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/complicações , Estudos Retrospectivos , Fatores de Risco , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/genética , Trombose/etiologia , Trombose/genética , Fatores de Risco de Doenças Cardíacas , Neoplasias/complicações
15.
Br J Haematol ; 162(6): 730-47, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23855810

RESUMO

Splanchnic vein thrombosis (SVT) is one of the most important complications of myeloproliferative neoplasms (MPN). Although MPN are common causes of SVT, the pathophysiological mechanisms underlying this predisposition, their epidemiology and natural history are not fully understood. Studies have concentrated on the generalized prothrombotic environment generated by MPN and their relationship with abnormal blood counts, thereby furthering our knowledge of arterial and venous thrombosis in this population. In contrast, there are few studies that have specifically addressed SVT in the context of MPN. Recent research has demonstrated in patients with MPN the existence of factors increasing the risk of SVT such as the presence of the JAK2 V617F mutation and its 46/1 haplotype. Features unique to the circulating blood cells, splanchnic vasculature and surrounding micro-environment in patients with MPN have been described. There are also abnormalities in local haemodynamics, haemostatic molecules, the spleen, and splanchnic endothelial and endothelial progenitor cells. This review considers these important advances and discusses the contribution of individual anomalies that lead to the development of SVT in both the pre-neoplastic and overt stage of MPN. Clinical issues relating to epidemiology, recurrence and survival in these patients have also been reviewed and their results discussed.


Assuntos
Transtornos Mieloproliferativos/sangue , Circulação Esplâncnica , Trombose Venosa/patologia , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Fatores de Risco , Trombose Venosa/sangue , Trombose Venosa/genética
16.
Nat Commun ; 14(1): 7725, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38001082

RESUMO

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Neoplasias/metabolismo , Tamoxifeno/uso terapêutico , Tamoxifeno/metabolismo , Mutação , Calreticulina/genética , Calreticulina/metabolismo
17.
Br J Haematol ; 158(4): 453-71, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22651893

RESUMO

The guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the 'GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post-PV MF) and post-thrombocythemic myelofibrosis (post-ET MF) in both adult and paediatric patients.


Assuntos
Mielofibrose Primária/diagnóstico , Mielofibrose Primária/terapia , Anemia/etiologia , Anemia/terapia , Transplante de Medula Óssea/métodos , Inibidores Enzimáticos/uso terapêutico , Medicina Baseada em Evidências/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/uso terapêutico , Janus Quinases/antagonistas & inibidores , Mielofibrose Primária/complicações , Mielofibrose Primária/genética , Prognóstico , Esplenectomia
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