Largest comparison between onset and relapses of acquired thrombotic thrombocytopenic purpura reveals severe neurological involvement and worse analytic parameters at debut.

It has been proposed that the onset of Acquired Thrombotic Thrombocytopenic Purpura (iTTP) is more severe than subsequent relapses; however, existing studies have limitations. We conducted a retrospective observational study to compare analytical and clinical severity of onset and relapse aTTP cases between 2012 and 2023. A total of 370 episodes of aTTP were analyzed, comprising 272 at initial diagnosis and 98 relapses. At onset, analytical parameters indicative of severity (low hemoglobin, low platelet count, and increased LDH) were significantly worse; patients had severe neurological symptoms (p<0.001) and ≥ 3 points in the TMA mortality score (p<0.001). In conclusion, the onset of aTTP is associated with worse analytical parameters and severe neurological involvement.

Next generation sequencing for diagnosis of hereditary anemia: Experience in a Spanish reference center.

BACKGROUND AND AIMS: Hereditary anemia (HA) encloses a wide group of rare inherited disorders with clinical and hematologic overlaps that complicate diagnosis. MATERIALS AND METHODS: A 48-gene panel was developed to diagnose HA by Next Generation Sequencing (NGS) in a large cohort of 165 patients from 160 unrelated families. RESULTS: Patients were divided in: A) patients who had a suspicion of a specific type of HA (n = 109), and B) patients who had a suspicion of HA but with no clear type (n = 56). Diagnostic performance was 83.5% in group A and a change of the initial diagnosis occurred in 11% of these patients. In group B, 35.7% of patients achieved a genetic diagnosis. NGS identified 6 cases of xerocytosis, 6 of pyruvate kinase (PK) deficiency, 4 of G6PD, and 1 case of phytosterolemia with no initial suspicion of these pathologies, which is clinically relevant since they have specific treatment. Five patients were found to carry variants associated to two different pathologies (4 of them combining a metabolic deficiency and a membrane defect), and 44 new variants were identified in 41 patients. CONCLUSION: The use of NGS is a sensitive technique to diagnose HA and it shows better performance when patients are better characterized.

Hb Nivaria: A New Hemoglobin Variant with a Shortened α-Globin Chain [α139(HC1)Lys→Stop; HBA1: c.418A>T].

We report a novel hemoglobin (Hb) variant found in a Spanish individual from Santa Cruz de Tenerife, the Canary Islands in Spain. The proband was a 39-year-old male. High performance liquid chromatography (HPLC) displayed an unknown peak (19.3%) at a retention time of 1.3 min. eluting before Hb A0. Capillary zone electrophoresis (CZE) showed an abnormal peak (20.0%) in zone 12. Direct DNA sequencing of the α-globin genes revealed heterozygosity for a nonsense mutation at codon 139 (AAA>TAA), causing a lysine to stop codon substitution [α139(HC1)Lys→Stop; HBA1: c.418A>T]. We decided to name the variant Hb Nivaria (Tenerife) for the place of birth and residence of the proband.

Una causa infrecuente de saturación arterial de oxígeno baja: hemoglobinopatía de Rothschild / Hemoglobin Rothschild: A Rare Cause of Low Arterial Oxygen Saturation

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Hb Burgos (α 1 CD64(E13)(Asp→Asn)): una nueva variante de hemoglobina detectada durante la monitorización de pacientes con diabetes / Hb Burgos (α 1 CD64(E13)(Asp→Asn)): A new hemoglobin variant detected during follow-up of diabetic patients

Fundamento y objetivo: El control de la diabetes mellitus se realiza mediante la determinación de hemoglobina glucosilada (HbA1c) por cromatografía líquida de alta resolución. Algunas variantes estructurales de la hemoglobina (Hb) son conocidas por causar interferencia analítica en la medición de la HbA1c. Pacientes y métodos: En este estudio se ha caracterizado una nueva variante de Hb en 4 pacientes, que se detectó al realizarse un control de HbA1c. Resultados: La secuenciación selectiva del gen α1 mostró una mutación responsable del cambio de ácido aspártico (Asp) por asparagina (Asn) en el codón 64. El cambio de Asp por Asn no produce ninguna alteración funcional de la Hb y se comporta como una hemoglobinopatía silente. Conclusión: Las variantes estructurales de la Hb se pueden detectar durante la medición de la HbA1c y pueden alterar sus valores. Estos casos, aunque poco frecuentes, requieren examinar a fondo los cromatogramas para detectar posibles interferencias (AU)

Background and objective: The glycated hemoglobin (HbA1c) test by high performance liquid chromatography is a useful tool for the follow-up of diabetes mellitus patients. Some structural hemoglobin (Hb) variants are known to cause interference in the analytical measurement of HbA1c. Patients and methods: In this study, it has been characterized a new Hb variant in 4 patients during their regular control of HbA1c. Results: Selective α1 gene sequencing showed a mutation GAC > AAC at codon 64 within exon 2. This produces a change of aspartic acid (Asp) by asparagine (Asn) that does not produce any functional alteration so the resultant molecule behaves as a silent hemoglobinopathy. Conclusion: The structural Hb variants can be detected during the analysis of HbA1c and may alter its values. Though rare, this occurrence signals the need to being aware when measuring HbA1 (AU)

[Hb Burgos (α1 CD64(E13)(Asp→Asn)): a new hemoglobin variant detected during follow-up of diabetic patients]. / Hb Burgos (α1 CD64(E13)(Asp→Asn)): una nueva variante de hemoglobina detectada durante la monitorización de pacientes con diabetes.

BACKGROUND AND OBJECTIVE: The glycated hemoglobin (HbA1c) test by high performance liquid chromatography is a useful tool for the follow-up of diabetes mellitus patients. Some structural hemoglobin (Hb) variants are known to cause interference in the analytical measurement of HbA1c. PATIENTS AND METHODS: In this study, it has been characterized a new Hb variant in 4 patients during their regular control of HbA1c. RESULTS: Selective α1 gene sequencing showed a mutation GAC>AAC at codon 64 within exon 2. This produces a change of aspartic acid (Asp) by asparagine (Asn) that does not produce any functional alteration so the resultant molecule behaves as a silent hemoglobinopathy. CONCLUSION: The structural Hb variants can be detected during the analysis of HbA1c and may alter its values. Though rare, this occurrence signals the need to being aware when measuring HbA1c.

Red blood cell disorders in recently arrived African immigrants to Gran Canaria, Spain.

BACKGROUND: In the last decade immigration to Europe has increased, with Africa being the source of a large number of immigrants. In addition to infections, this group has other less known health problems, such as erythrocyte abnormalities. METHODS: The objectives of this study were: the systematic evaluation of red cell abnormalities in 200 newly arrived asymptomatic African immigrants on the Canaries; the systematic evaluation of haemoglobinopathies and their characterization in this population; and the relationship of red blood cell disorders and parasitic infections. RESULTS: Of the studied immigrants 53 (26.5%) had red cell disorders according to their CBC parameters (Hb and/or MCV). In 48 people (24.0%) one or more etiologic diagnoses were made. Specifically, in order of frequency, a total of 26 structural haemoglobinopathies, 14 α-thalassemias, 2 ß-thalassemias and 14 iron deficiencies were diagnosed. There was a statistically significant association between the presence of anemia, microcytosis, structural haemoglobinopathies or α thalassemia and sub-Saharan origin. However, no statistically significant association between the abovementioned parameters and eosinophilia or helminthic infection was observed. CONCLUSIONS: These results suggest that, even in the presence of normal Hb and MCV values, including haemoglobinopathies in the initial screening of newly arrived sub-Saharan immigrants would be very useful.

[No deletion alpha thalassaemia in Spain. Abnormal hematological index and molecular study]. / Alpha talasemia no deleción en Espaia. indices hematológicos anormales y su estudio molecular.

The alpha thalassaemia diseases in most cases are caused by deletions that affect one or two of the alpha genes, being less frequent the cases due to punctual mutations, insertions or deletions of a few pairs of bases, which have been denominated no deletion a thalassaemias. The objective of this investigation was to determine the incidence of the no deletion alpha thalassaemia in patients with a thalassaemia using molecular biology techniques. We studied 517 individuals of the San Carlos Hospital (Thalassemia Molecular Research Center, Madrid-Spain) between January 2001 and December 2003, in whom iron deficiency anemia had been ruled out, that presented microcytosis and hypochromia and that presented normal HbA2, HbF and EEF from normal Hbs. The two types of no deletion a thalassaemia most frequently described in the Mediterranean were studied: 1) alpha Hph due to deletion of 5bp in the IVS I and 2) alphaNco due to a change in the initiation codon of the gene. Of the 517 cases studied, 40 (7.7% of the cases) represented a no deletion alpha thalassaemia. Of these cases, 28 were positive for alphaHph of the alpha2 gene, 24 in the heterozygote state, one homozygote and three double heterozygotes associated with the 3,7 kb deletion. The remaining 12 cases were positive for the alphaNco of the alpha2 gene, 10 heterozygotes, one homozygote and one double heterozygote associated with the 4,2 kb deletion. The no deletion alpha thalassaemias represent < 8% from the cases in our environment. The alphaHph is the most frequent type of no deletion a thalassaemia and its haematological abnormalities are more manifest that the ones present in the cases of alphaNco.

a talasemia no deleción en España: Índices hematológicos anormales y su estudio molecular / No Deletion a Thalassaemia in Spain: Abnormal hematological index and molecular study

Las a talasemias en la mayoría de los casos es debida a deleciones que afectan a uno o a los dos genes a, siendo poco frecuente los casos debidos a mutaciones puntuales, inserciones o deleciones de pocos pares de bases, los cuales se han denominado a talasemias no deleción. Se determinó la incidencia de la a talasemia no deleción en los pacientes con a talasemia, mediante biología molecular. Se estudiaron 517 individuos remitidos al Hospital Clínico San Carlos, centro de referencia de estudios moleculares de Talasemias en Madrid- España, entre Enero del 2001 a Diciembre del 2003, en los que se había descartado ferropenia y presentaban microcitosis, hipocromía, Hb A2, Hb F y EEF de Hbs normales. Se estudiaron los 2 tipos de a talasemia no deleción más descritas en el Mediterráneo: 1) aHph debida a la deleción de 5 bp en el IVS I y 2) aNco a un cambio en el codón de iniciación del gen. De los 517, 40 presentaban una a talasemia no deleción (7,7%). De éstos, 28 fueron positivos para aHph del gen a2, 24 en estado heterocigoto, 1 homocigoto y 3 dobles heterocigotos asociados con la deleción 3,7 kb. Los 12 restantes resultaron positivos para la aNco del gen a2, 10 heterocigotos, 1 homocigoto y 1 doble heterocigoto asociado con la deleción 4,2 kb. La a talasemia no deleción representa < 8% de los casos de a talasemia en nuestro medio. La aHph es el tipo de a talasemia no deleción más frecuente y cuyas anormalidades hematológicas son más manifiestas que las presentadas en los casos de aNco.

The a thalassaemia diseases in most cases are caused by deletions that affect one or two of the a genes, being less frequent the cases due to punctual mutations, insertions or deletions of a few pairs of bases, which have been denominated no deletion a thalassaemias. The objective of this investigation was to determine the incidence of the no deletion a thalassaemia in patients with a thalassaemia using molecular biology techniques. We studied 517 individuals of the San Carlos Hospital (Thalassemia Molecular Research Center, Madrid-Spain) between January 2001 and December 2003, in whom iron deficiency anemia had been ruled out, that presented microcytosis and hypochromia and that presented normal HbA2, HbF and EEF from normal Hbs. The two types of no deletion a thalassaemia most frequently described in the Mediterranean were studied: 1) a Hph due to deletion of 5bp in the IVS I and 2) aNco due to a change in the initiation codon of the gene. Of the 517 cases studied, 40 (7.7% of the cases) represented a no deletion a thalassaemia. Of these cases, 28 were positive for aHph of the a2 gene, 24 in the heterozygote state, one homozygote and three double heterozygotes associated with the 3,7 kb deletion. The remaining 12 cases were positive for the aNco of the a2 gene, 10 heterozygotes, one homozygote and one double heterozygote associated with the 4,2 kb deletion. The no deletion a thalassaemias represent < 8% from the cases in our environment. The aHph is the most frequent type of no deletion a thalassaemia and its haematological abnormalities are more manifest that the ones present in the cases of aNco.

Hemoglobin Seville [α2 ß2 81(EF5) Leu→Phe] a silent phenotypic variant that interferes in hemoglobin A1c measurement by ion-exchange HPLC method.

OBJECTIVES: The aim of the study was to investigate hemoglobin (Hb) species in a 61 year-old male with diabetes mellitus type II and a low value of Hb A(1c). DESIGN AND METHODS: Hb species were analyzed by electrophoresis and chromatography methods. Functional properties were determined by oxygen equilibrium studies. ß-globin gene was amplified by PCR and sequenced. RESULTS AND CONCLUSIONS: A novel clinically silent Hb (Hb Seville), that results in falsely low Hb A(1c) measurement, was detected. This Hb variant presented a single base mutation at codon 81 (C→T) of the ß-globin gene. This case points out the necessity of careful inspection of the chromatograms and the use of additional methods to Hb A(1c) measurement when the presence of aberrant peaks is detected.

[Molecular characterization of heterozygous beta-thalassemia in Lanzarote, Spain]. / Caracterización molecular de la betatalasemia en Lanzarote.

BACKGROUND AND OBJECTIVE: The aim of this study was to determine the molecular defects of heterozygous beta thalassaemia and to ascertain their distribution in Lanzarote. PATIENTS AND METHOD: Molecular characterization was achieved by real time polymerase chain reaction (RT-PCR LightCycler, Roche), PCR-ARMS (PCR-amplification reaction mutations system) and DNA sequencing on an automated DNA sequencer. RESULTS: Two hundred forty-three heterozygous beta thalassaemia carriers were included between July 1991 and February 2007. RT-PCR detected the molecular defect in 81% of the beta thalassaemia chromosomes analyzed [113 codon CD 39 (C --> T); 41 IVS-1-nt-110 (G --> A), 25 IVS 1-nt-1 (G --> A) and 19 IVS 1-nt-6 (T --> C)]. The remaining 12 molecular defects included the deletion 619 bp (7.8%) and the mutations -28 (A --> G), IVS1-nt-2 (T --> G), CD 41/42 (-TTCT), CD 8/9 (+G), CD 51 (-C), CD 22 (G --> T) and CD 24 (T --> A), CD 67 (-TG) and the novel mutation CD 20/21-TGGA. CONCLUSIONS: The distribution of the mutations is similar to that found in the Mediterranean area. The increasing migratory flow received in the Canary Islands may explain the emergence of new mutations not reported before in our area.

Caracterización molecular de la betatalasemia en Lanzarote / Molecular characterization of heterozygous b-thalassemia in Lanzarote, Spain

Fundamento y objetivo: Caracterizar los defectos moleculares y estudiar su distribución en los portadores de betatalasemia de Lanzarote. Pacientes y método: El estudio molecular del gen beta de la globina se llevó a cabo con la técnica de reacción en cadena de la polimerasa (PCR) en tiempo real (RT-PCR LyghtCycler, Roche), PCR con amplificación de alelos específicos (PCR-ARMS) y secuenciación automática del ADN del gen beta de la globina. Resultados: Se incluyó en el estudio a 243 portadores diagnosticados de betatalasemia heterocigota entre julio de 1991 y febrero de 2007. La RT-PCR identificó la lesión molecular en el 81% de los cromosomas [113 codón CD 39 (C * T); 41 IVS-1-nt-110 (G * A), 25 IVS 1-nt-1 (G * A) y 19 IVS 1-nt-6 (T * C)]. Las 12 alteraciones moleculares restantes incluyeron la deleción 619 bp (7,8%) y las mutaciones ­28 (A * G), IVS1-nt-2 (T * G), CD 41/42 (­TTCT), CD 8/9 (+G), CD 51 (­C), CD 22 (G * T), CD 24 (T * A), CD 67 (­TG), además de una nueva mutación CD 20/21-TGGA. Conclusiones: La distribución de las mutaciones de la betatalasemia heterocigota en Lanzarote es similar a la descrita en la zona mediterránea. El aumento de los flujos migratorios a la comunidad canaria puede explicar la presencia de mutaciones no descritas antes en nuestra comunidad

Background and objective: The aim of this study was to determine the molecular defects of heterozygous b thalassaemia and to ascertain their distribution in Lanzarote. Patients and method: Molecular characterization was achieved by real time polymerase chain reaction (RT-PCR LightCycler, Roche), PCR-ARMS (PCR-amplification reaction mutations system) and DNA sequencing on an automated DNA sequencer. Results: Two hundred forty-three heterozygous b thalassaemia carriers were included between July 1991 and February 2007. RT-PCR detected the molecular defect in 81% of the b thalassaemia chromosomes analyzed [113 codon CD 39 (C * T); 41 IVS-1-nt-110 (G * A), 25 IVS 1-nt-1 (G * A) and 19 IVS 1-nt-6 (T * C)]. The remaining 12 molecular defects included the deletion 619 bp (7.8%) and the mutations ­28 (A * G), IVS1-nt-2 (T * G), CD 41/42 (­TTCT), CD 8/9 (+G), CD 51 (­C), CD 22 (G * T) and CD 24 (T * A), CD 67 (­TG) and the novel mutation CD 20/21-TGGA. Conclusions: The distribution of the mutations is similar to that found in the Mediterranean area. The increasing migratory flow received in the Canary Islands may explain the emergence of new mutations not reported before in our area

Distribución geográfica de las mutaciones del gen HFE en España / Geographical distribution of HFE C282Y and H63D mutation in Spain

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