Haemoglobinopathies and other rare anemias in Spain: ten years of a nationwide registry (REHem-AR).

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments.

Nutritional Ultrasonography, a Method to Evaluate Muscle Mass and Quality in Morphofunctional Assessment of Disease Related Malnutrition.

Nutritional ultrasonography is an emerging technique for measuring muscle mass and quality. The study aimed to evaluate the relationship between the parameters of body mass and quality of ultrasonography with other parameters of morphofunctional assessment in patients with disease-related malnutrition (DRM). METHODS: A cross-sectional study was developed on 144 patients diagnosed with DRM according to the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional evaluation was assessed with anthropometric variables, handgrip strength and bioelectrical impedanciometry (BIA). Nutritional ultrasonography of quadriceps rectus femoris (QRF) was made (muscle mass (Muscle Area of Rectus Femoris index (MARFI)), Y axis and muscle quality (X-Y index and echogenicity). RESULTS: The mean age of patients was 61.4 (17.34) years. The prevalence of sarcopenia in the sample was 33.3%. Patients with sarcopenia (S) had lower values of MARFI [(S: 1.09 (0.39) cm2/m2; NoS: 1.27 (0.45); p = 0.02), Y axis (S: 0.88 (0.27); NoS: 1.19 (0.60); p < 0.01) and X-Y index (S: 1.52 (0.61); NoS: 1.30 (0.53); p < 0.01)]. There was a correlation between BIA parameters (phase angle) and muscle mass ultrasonographic variables (MARFI) (r = 0.35; p < 0.01); there was an inverse correlation between muscle quality ultrasonographic variables (echogenicity) and handgrip strength (r = -0.36; p < 0.01). In the multivariate analysis adjusted by age, the highest quartile of the X-Y index had more risk of death OR: 4.54 CI95% (1.11-18.47). CONCLUSIONS: In patients with DRM and sarcopenia, standardized muscle mass and muscle quality parameters determined by ultrasonography of QRF are worse than in patients without sarcopenia. Muscle quality parameters had an inverse correlation with electric parameters from BIA and muscle strength. The highest quartile of the X-Y index determined by ultrasonography was associated with increased mortality risk.

Implications of Iron Deficiency in STEMI Patients and in a Murine Model of Myocardial Infarction.

In patients with a first anterior ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, iron deficiency (ID) was associated with larger infarcts, more extensive microvascular obstruction, and higher frequency of adverse left ventricular remodeling as assessed by cardiac magnetic resonance imaging. In mice, an ID diet reduced the activity of the endothelial nitric oxide synthase/soluble guanylate cyclase/protein kinase G pathway in association with oxidative/nitrosative stress and increased infarct size after transient coronary occlusion. Iron supplementation or administration of an sGC activator before ischemia prevented the effects of the ID diet in mice. Not only iron excess, but also ID, may have deleterious effects in the setting of ischemia and reperfusion.

Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases.

Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur de novo. Most cases of UHs are not detected by conventional testing, therefore diagnosis requires a high index of suspicion of the treating physician. Here, we highlight the importance of next generation sequencing (NGS) methodologies for the diagnosis of patients with dBTHAL and other less severe UH variants. We present five unrelated clinical cases referred with chronic hemolytic anemia, three of them with severe blood transfusion dependent anemia. Targeted NGS analysis was performed in three cases while whole exome sequencing (WES) analysis was performed in two cases. Five different UH variants were identified correlating with patients' clinical manifestations. Four variants were related to the beta-globin gene (Hb Bristol-Alesha, Hb Debrousse, Hb Zunyi, and the novel Hb Mokum) meanwhile one case was caused by a mutation in the alpha-globin gene leading to Hb Evans. Inclusion of alpha and beta-globin genes in routine NGS approaches for RADs has to be considered to improve diagnosis' efficiency of RAD due to UHs. Reducing misdiagnoses and underdiagnoses of UH variants, especially of the severe forms leading to dBTHAL would also facilitate the early start of intensive or curative treatments for these patients.

[Consensus document for the diagnosis and treatment of pyruvate kinase deficiency]. / Documento de consenso para el diagnóstico y tratamiento del déficit de piruvato quinasa.

Pyruvate kinase (PK) deficiency is the second most frequent enzymopathy and the most common cause of chronic hereditary non-spherocytic haemolytic anaemia. Its global prevalence is underestimated due to low clinical suspicion of mild cases, associated with difficulties in the performance and interpretation of PK enzymatic activity assays. With the advent of next generation sequencing techniques, a better diagnostic approach is achieved. Treatment remains based on red blood cell transfusions and splenectomy, with special attention to iron overload, not only in transfusion-dependent patients. Nowadays, allogeneic hematopoietic stem cell transplantation is the only curative treatment, recommended only in selected cases of severely affected patients with an HLA-identical donor. Novel pharmacological and gene therapies are in clinical trials, with promising results. In this article, the Spanish Erythropathology Group reviews the current situation of PK deficiency, paying special attention to the usefulness of different diagnostic techniques and to actual and emerging treatments.

Actualización del registro español de hemoglobinopatías de niños y adultos / Update of the Spanish registry of haemoglobinopathies in children and adults

ANTECEDENTES Y OBJETIVO: Los pacientes con talasemia mayor (TM) y enfermedad de células falciformes (ECF) en España se han empezado a contabilizar desde la creación del registro español de hemoglobinopatías (REHem). El objetivo del trabajo es actualizar los datos publicados previamente, tras el aumento de casos por la inclusión de adultos y la introducción del cribado neonatal en casi todo el país. MATERIAL Y MÉTODOS: Estudio observacional, descriptivo, multicéntrico y ambispectivo, que incluye pacientes con hemoglobinopatías registrados en REHem, iniciado en enero de 2014 y de seguimiento anual. Los datos presentados corresponden hasta el 31 de diciembre de 2017. RESULTADOS: Se recogieron 959 pacientes. Se registraron 75 casos de talasemia (62 TM), 826 de ECF y 58 de otro tipo de hemoglobinopatías. El motivo de diagnóstico principal en la TM fue la clínica de anemia (70,6%), con una media de edad al diagnóstico de 0,7 años; en la ECF fue el cribado neonatal (33,1%), con una media de edad al diagnóstico de 2,7 años; 26 pacientes con TM (41,9%) y 30 con ECF (3,6%) fueron sometidos a trasplante. Hubo 2 fallecimientos (3,2%) con TM y 19 (2,3%) con ECF. La supervivencia global fue del 96,7% en la TM y del 97,5% en la ECF a los 15 años. CONCLUSIONES: Desde la publicación previa y tras la difusión del cribado neonatal, el método diagnóstico más frecuente, en la mayoría de comunidades autónomas, y la inclusión de pacientes adultos al registro, el REHem se ha visto incrementado en más de 240 casos, llegando hasta un total de 959 registros

BACKGROUND AND OBJECTIVE: Patients with thalassaemia major (TM) and sickle cell disease (SCD) in Spain have been counted since the creation of the Spanish registry of haemoglobinopathies (REHem). The objective of this paper is to update the published data after the increase in cases due to the inclusion of adults and introduction of new-born screening in almost the whole country. MATERIAL AND METHODS: An observational, descriptive, multicentre and ambispective study that included patients with haemoglobinopathies registered in the REHem, started in January 2014 and followed up annually. The data presented correspond until December 31, 2017. RESULTS: Nine hundred and fifty-nine patients were collected. There were 75 cases of thalassaemia (62 TM), 826 of ECF and 58 of other types of haemoglobinopathies. The main diagnostic reason in the TM cohort was anaemia symptoms (70.6%), with a mean age at diagnosis of .7 years; in the SCD cohort it was neonatal screening (33.1%), with a mean age at diagnosis of 2.7 years; 26 patients with TM (41.9%) and 30 with SCD (3.6%) underwent a transplant. There were 2 deaths (3.2%) with TM and 19 (2.3%) with SCD. Overall survival was 96.7% in the TM and 97.5% in the SCD cases at 15 years. CONCLUSIONS: Since the previous publication and after the diffusion of new-born screening, the most frequent diagnostic method, to the majority of autonomous regions, and the inclusion of adult patients to the registry, the REHem has increased by more than 240 cases, reaching a total of 959 records

Anemias hemolíticas autoinmunes: estudio retrospectivo de 93 pacientes / Autoimmune haemolytic anaemias: A retrospective study of 93 patients

INTRODUCCIÓN: Las anemias hemolíticas autoinmunes (AHAI) son enfermedades poco frecuentes y heterogéneas en su fisiopatología y comportamiento clínico, siendo el manejo de las mismas fundamentalmente empírico. PACIENTES Y MÉTODOS: Realizamos un estudio observacional, retrospectivo y multicéntrico de 93 pacientes diagnosticados de AHAI en 9 hospitales españoles entre 1987 y 2017, con una mediana de seguimiento de 28 meses. RESULTADOS: Mediana de edad de 67 años; un 85% de AHAI por anticuerpos calientes y un 64% AHAI primarias. Los valores de hemoglobina más bajos al diagnóstico se relacionaron con edad<45 años y el tipo serológico IgG+C. Un 92% recibieron tratamiento de primera línea, un 54% de segunda línea y un 27% de tercera línea. Las AHAI calientes fueron tratadas en primera línea con esteroides, con respuestas globales del 83% y completas del 58%. El rituximab en monoterapia o asociado a esteroides se administró a 34 pacientes con respuestas globales cercanas al 100% (respuestas completas 40-60%), relegando la esplenectomía a tercera línea. El tratamiento inmunosupresor se administró en pacientes con enfermedades autoinmunes o en dependientes de corticoides. DISCUSIÓN: Encontramos altas tasas de respuesta a esteroides, con tratamientos muy prolongados que provocan efectos secundarios y corticodependencia en un tercio de los pacientes. La asociación de esteroides con rituximab en primera línea podría estar indicada en pacientes con bajos niveles de hemoglobina y tipo serológico IgG+C. Las altas tasas de recaída hacen necesario el desarrollo de estudios aleatorizados con nuevos fármacos o la asociación con los ya existentes, que permitan mayor duración de las respuestas y con menores efectos secundarios

INTRODUCTION: Autoimmune haemolytic anaemia (AIHA) is an infrequent and heterogeneous disease in its pathophysiology and clinical behaviour, therefore it is generally managed empirically. PATIENTS AND METHODS: We conducted an observational, retrospective and multicentre study of 93 patients diagnosed with AHAI in 9 Spanish hospitals between 1987 and 2017, with a median follow-up of 28 months. RESULTS: Median age of 67 years; 85% AHAI for hot antibodies and 64% primary AHAI. The lowest haemoglobin values at diagnosis related to patients under 45 years of age and serological type IgG+C. Of the patients, 92% received first line treatment, 54% second line, and 27% third line. The warm AHAI were treated in first line with steroids, with overall responses of 83% and complete of 58%. Rituximab in monotherapy or in association with steroids was administered to 34 patients with overall responses close to 100% (complete responses 40-60%), relegating splenectomy to the third line. The immunosuppressive treatment was administered in patients with autoimmune diseases or in corticoid-dependent patients. DISCUSSION: We found high rates of response to steroids, with very prolonged treatments that cause side effects and corticoid dependence in a third of patients. The combination of steroids with rituximab in the first line, could be indicated in patients with low levels of haemoglobin and serological type IgG+C. The high relapse rates make necessary the development of randomised studies with new drugs or the combination with existing ones, which allow longer response times and with fewer side effects

Update of the Spanish registry of haemoglobinopathies in children and adults. / Actualización del registro español de hemoglobinopatías de niños y adultos.

BACKGROUND AND OBJECTIVE: Patients with thalassaemia major (TM) and sickle cell disease (SCD) in Spain have been counted since the creation of the Spanish registry of haemoglobinopathies (REHem). The objective of this paper is to update the published data after the increase in cases due to the inclusion of adults and introduction of new-born screening in almost the whole country. MATERIAL AND METHODS: An observational, descriptive, multicentre and ambispective study that included patients with haemoglobinopathies registered in the REHem, started in January 2014 and followed up annually. The data presented correspond until December 31, 2017. RESULTS: Nine hundred and fifty-nine patients were collected. There were 75 cases of thalassaemia (62 TM), 826 of ECF and 58 of other types of haemoglobinopathies. The main diagnostic reason in the TM cohort was anaemia symptoms (70.6%), with a mean age at diagnosis of .7 years; in the SCD cohort it was neonatal screening (33.1%), with a mean age at diagnosis of 2.7 years; 26 patients with TM (41.9%) and 30 with SCD (3.6%) underwent a transplant. There were 2 deaths (3.2%) with TM and 19 (2.3%) with SCD. Overall survival was 96.7% in the TM and 97.5% in the SCD cases at 15 years. CONCLUSIONS: Since the previous publication and after the diffusion of new-born screening, the most frequent diagnostic method, to the majority of autonomous regions, and the inclusion of adult patients to the registry, the REHem has increased by more than 240 cases, reaching a total of 959 records.

Autoimmune haemolytic anaemias: A retrospective study of 93 patients. / Anemias hemolíticas autoinmunes: estudio retrospectivo de 93 pacientes.

INTRODUCTION: Autoimmune haemolytic anaemia (AIHA) is an infrequent and heterogeneous disease in its pathophysiology and clinical behaviour, therefore it is generally managed empirically. PATIENTS AND METHODS: We conducted an observational, retrospective and multicentre study of 93 patients diagnosed with AHAI in 9 Spanish hospitals between 1987 and 2017, with a median follow-up of 28 months. RESULTS: Median age of 67 years; 85% AHAI for hot antibodies and 64% primary AHAI. The lowest haemoglobin values at diagnosis related to patients under 45 years of age and serological type IgG+C. Of the patients, 92% received first line treatment, 54% second line, and 27% third line. The warm AHAI were treated in first line with steroids, with overall responses of 83% and complete of 58%. Rituximab in monotherapy or in association with steroids was administered to 34 patients with overall responses close to 100% (complete responses 40-60%), relegating splenectomy to the third line. The immunosuppressive treatment was administered in patients with autoimmune diseases or in corticoid-dependent patients. DISCUSSION: We found high rates of response to steroids, with very prolonged treatments that cause side effects and corticoid dependence in a third of patients. The combination of steroids with rituximab in the first line, could be indicated in patients with low levels of haemoglobin and serological type IgG+C. The high relapse rates make necessary the development of randomised studies with new drugs or the combination with existing ones, which allow longer response times and with fewer side effects.

Paciente con betatalasemia mayor y 2 embarazos a término / Beta-thalassemia major and pregnancy to term

No disponible

Clopidogrel y déficit de glucosa-6-fosfato deshidrogenasa / Clopidrogrel and deficiency of glucose 6 phosphate dehydrogenase

No disponible

Heterozygous Hb Hope [beta136(H14)Gly --> Asp] in association with heterozygous beta0-thalassemia with apparent homozygous expression, in a Spanish patient.

Hb Hope [beta136(H14)Gly --> Asp (GGT --> GAT)] has been found alone or in combination with other globin gene mutations in several African-American families, as well as in Japanese, Thai, Laotian, Cuban and Mauritanian families. We report the hematological and molecular characteristics of a heterozygous association of Hb Hope with beta0-thalassemia (thal) in a Spanish patient, in whom the level of expression of abnormal hemoglobin (Hb) by cation exchange high performance liquid chromatography (HPLC) and electrophoresis suggested initially a homozygous expression of the abnormal Hb, although sequencing of the polymerase chain reaction (PCR)-amplified beta-globin gene demonstrated a heterozygous genotype for Hb Hope. To the best of our knowledge, this is the first description of a case of Hb Hope in a Spanish family.

CD38 expression in B-chronic lymphocytic leukemia: association with clinical presentation and outcome in 155 patients.

BACKGROUND AND OBJECTIVES: To investigate whether CD38 expression at diagnosis is an independent predictor of survival and assess its associations with other clinical parameters used in the staging of B-cell chronic lymphocytic leukemia (B-CLL). DESIGN AND METHODS: CD38 expression was analyzed in 155 consecutive unselected patients newly diagnosed with B-CLL from January 1991 to July 1997. In all cases CD38 expression was evaluated at diagnosis and patients were classified into two groups: those with > or = 30% were considered positive (CD38+) and those with < 30% were considered negative (CD38-). Statistical differences between each group were analyzed using c2 tests for categorical variables and Student's t-tests for continuous variables. Survival analysis was performed at the univariate level by the Kaplan Meier technique and at the multivariate level by Cox hazard models. RESULTS: Thirty (19%) patients were CD38+. CD38+ was associated with atypical morphology (p=0.004), a diffuse bone marrow pattern (p=0.016), Rai stage > or =2 (p=0.009), high lactate dehydrogenase (p=0.02), high b2 microglobulin (p=0.004), and higher lymphocyte count (p=0.02). Furthermore, CD38+ patients required treatment more frequently (p=0.006) and CLL-related mortality was significantly higher (p=0.012). When we divided the study group into patients with Rai 0-1 and Rai 2-4 stages, CD38 positivity was only significantly associated with mortality in the early stage patients (p= 0.012 vs p= 0.68). CD38 expression in the multivariate analysis lost its statistical significance. None of these results was modified when the CD38 cut-off was set at 20%. INTERPRETATION AND CONCLUSIONS: CD38 expression identifies a subgroup of B-CLL patients with aggressive clinical presentation and worse outcome. Its expression is probably associated with other prognostic factors, but the feasibility of determining this parameter makes it easily reproducible and adds prognostic information at diagnosis to aid prediction of the clinical course and outcome of B-CLL.