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Clinical and Experimental Medicine Jan 2024Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no...
Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
Topics: Humans; Polycythemia; Polycythemia Vera; Mutation; Iron; Germ Cells
PubMed: 38244120
DOI: 10.1007/s10238-023-01283-y -
CMAJ : Canadian Medical Association... Aug 2020
Review
Topics: Aspirin; Diagnosis, Differential; Erythropoietin; Humans; Janus Kinase 2; Polycythemia
PubMed: 32778603
DOI: 10.1503/cmaj.191587 -
Annals of Saudi Medicine 2009
Topics: Anti-Dyskinesia Agents; Chorea; Haloperidol; Humans; Male; Middle Aged; Phlebotomy; Polycythemia
PubMed: 19139620
DOI: 10.4103/0256-4947.51815 -
Frontiers in Endocrinology 2022TEMPI (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) syndrome is... (Review)
Review
TEMPI (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) syndrome is a rare and newly defined multisystemic disease, which belongs to "monoclonal gammopathy of clinical significances". Due to its rarity, the etiology, pathogenesis, and clinical features of this disease remain largely unknown. Owing to its hidden and diverse clinical manifestations, missed diagnosis and misdiagnosis are common. In recent years, as more patients (including three fatal cases) were identified, some special clinical manifestations other than the typical pentad of TEMPI syndrome have been reported. Meanwhile, several studies attempting to identify the pathogenesis of TEMPI syndrome were conducted. In this review, we summarize the reported clinical characteristics of TEMPI syndrome and discuss the current and potential treatment options for patients with TEMPI syndrome, including those with relapsed/refractory disease. Furthermore, we provide an overview of current knowledge on the pathophysiology of TEMPI syndrome.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Polycythemia; Syndrome; Telangiectasis
PubMed: 35663307
DOI: 10.3389/fendo.2022.886961 -
Ultrasound in Obstetrics & Gynecology :... Feb 2016Twin anemia-polycythemia sequence (TAPS) is recognized increasingly antenatally by the demonstration of an anemic twin and a polycythemic cotwin using the middle... (Review)
Review
Review of the correlation between blood flow velocity and polycythemia in the fetus, neonate and adult: appropriate diagnostic levels need to be determined for twin anemia-polycythemia sequence.
Twin anemia-polycythemia sequence (TAPS) is recognized increasingly antenatally by the demonstration of an anemic twin and a polycythemic cotwin using the middle cerebral artery peak systolic velocity (MCA-PSV). While the MCA-PSV has been shown to correlate well with anemia in singleton fetuses, the evidence to support its use to diagnose fetal polycythemia appears to be less clear-cut. We aimed to evaluate fetal, neonatal and adult literature used to support the use of MCA-PSV for the diagnosis of polycythemia. Comprehensive literature searches were performed for ultrasound evidence of polycythemia in the human fetus, neonate and adult using key search terms. Only manuscripts in the English language with an abstract were considered for the review, performed in June 2014. Fifteen manuscripts were found for the human fetus, including 38 cases of TAPS. Nine of these defined fetal polycythemia as MCA-PSV < 0.8 multiples of the median (MoM), five used < 1.0 MoM and one used 0.8-1.0 MoM. Only two studies, involving a total of 15 cases, proposed a diagnostic level, acknowledging false-positive and -negative cases, though neither reported sensitivities or specificities. Six neonatal studies (96 neonates) demonstrated evidence of decreased cerebral velocities in polycythemia and a consequent increase with hemodilution. In the adult, five studies (57 polycythemic adults) demonstrated increased flow or velocity with hemodilution. Neither neonatal nor adult studies conclusively defined levels for screening for polycythemia. Despite widespread adoption of a cut-off of < 0.8 MoM in the published literature for the polycythemic fetus in TAPS, this is based upon minimal evidence, with unknown sensitivity and specificity. We recommend caution in excluding TAPS based purely upon the absence of a reduced MCA-PSV.
Topics: Adult; Anemia; Blood Flow Velocity; Diseases in Twins; Female; Fetal Diseases; Humans; Infant, Newborn; Middle Cerebral Artery; Polycythemia; Pregnancy; Pregnancy, Twin; Reference Values; Sensitivity and Specificity; Ultrasonography, Prenatal
PubMed: 25580896
DOI: 10.1002/uog.14782 -
EBioMedicine Jan 2022Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this...
BACKGROUND
Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients.
METHODS
IgAN-PE patients' serum was collected, analyzed and used to study IgA1 effect on proliferation and differentiation of erythroid progenitors. Hematological parameters of transgenic mice for human alpha1 heavy chain were studied. Multicentric observational cohorts of chronic kidney disease (CKD) patients, including both native kidney diseases and renal transplants, were studied to analyze patient hemoglobin levels.
FINDINGS
We retrospectively identified 6 patients with IgAN and unexplained PE. In large CKD cohorts, IgAN was associated with PE in 3.5% of patients (p<0.001 compared to other nephropathies). IgAN was an independent factor associated with higher hemoglobin levels (13.1g/dL vs 12.2 g/dL, p=0.01). During post-transplant anemia, anemia recovery was faster in IgAN patients. Elevated polymeric/monomeric IgA1 ratio as well as high Gd-IgA1 rate were observed in circulating IgA1 of the 6 IgAN-PE patients as compared with control or IgAN patients without PE. IgA1 from these patients increased the sensitivity of erythroid progenitors to Epo. In mice, we also observed an elevation of hematocrit in alpha1 knock-in mice compared to wild type controls.
INTERPRETATION
These data identify a new etiology of erythrocytosis and demonstrate the role of pIgA1 in human erythropoiesis. This syndrome of IgA-related erythrocytosis should be investigated in case of unexplained erythrocytosis and renal disease.
FUNDING
This work was supported by INSERM (French national institute for health and medical research), Labex GRex and Imagine Institute (Paris, France).
Topics: Animals; Biomarkers; Galactose; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Mice; Polycythemia; Retrospective Studies
PubMed: 34959131
DOI: 10.1016/j.ebiom.2021.103785 -
Blood Transfusion = Trasfusione Del... Nov 2021Erythrocytosis is a blood disorder characterised by an increased red blood cell mass. The most common causes of erythrocytosis are acquired and caused by diseases and... (Review)
Review
Erythrocytosis is a blood disorder characterised by an increased red blood cell mass. The most common causes of erythrocytosis are acquired and caused by diseases and conditions that are accompanied by hypoxaemia or overproduction of erythropoietin. More rarely, erythrocytosis has a known genetic background, such as for polycythaemia vera and familial erythrocytosis. The majority of cases of polycythaemia vera are associated with acquired variants in JAK2, while familial erythrocytosis is a group of congenital disorders. Familial erythrocytosis type 1 is associated with hypersensitivity to erythropoietin (variants in EPOR), types 2-5 with defects in oxygen-sensing pathways (variants in VHL, EGLN1, EPAS1, EPO), and types 6-8 with an increased affinity of haemoglobin for oxygen (variants in HBB, HBA1, HBA2, BPGM). Due to a heterogenic genetic background, the causes of disease are not fully discovered and in more than 70% of patients the condition remains labelled idiopathic.The transfer of next-generation sequencing into clinical practice is becoming a reality enabling detection of various variants in a single rapid test. In this review, we describe the current research on erythrocytosis gene variants and the mechanisms associated with disease development, along with the currently used diagnostic tests.
Topics: Erythropoietin; Hemoglobins; Humans; Mutation; Oxygen; Polycythemia
PubMed: 33370224
DOI: 10.2450/2020.0197-20 -
BMC Medical Genomics Jul 2023As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood.
BACKGROUND
As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood.
METHODS
37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis.
RESULTS
The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent.
CONCLUSION
This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.
Topics: Humans; Altitude Sickness; Altitude; Polycythemia; Erythrocytes
PubMed: 37507679
DOI: 10.1186/s12920-023-01613-9 -
Haematologica Oct 2018Pathological erythropoiesis with consequent anemia is a leading cause of symptomatic morbidity in internal medicine. The etiologies of anemia are complex and include... (Review)
Review
Pathological erythropoiesis with consequent anemia is a leading cause of symptomatic morbidity in internal medicine. The etiologies of anemia are complex and include reactive as well as neoplastic conditions. Clonal expansion of erythroid cells in the bone marrow may result in peripheral erythrocytosis and polycythemia but can also result in anemia when clonal cells are dysplastic and have a maturation arrest that leads to apoptosis and hinders migration, a constellation typically seen in the myelodysplastic syndromes. Rarely, clonal expansion of immature erythroid blasts results in a clinical picture resembling erythroid leukemia. Although several mechanisms underlying normal and abnormal erythropoiesis and the pathogenesis of related disorders have been deciphered in recent years, little is known about specific markers and targets through which prognosis and therapy could be improved in anemic or polycythemic patients. In order to discuss new markers, targets and novel therapeutic approaches in erythroid disorders and the related pathologies, a workshop was organized in Vienna in April 2017. The outcomes of this workshop are summarized in this review, which includes a discussion of new diagnostic and prognostic markers, the updated WHO classification, and an overview of new drugs used to stimulate or to interfere with erythropoiesis in various neoplastic and reactive conditions. The use and usefulness of established and novel erythropoiesis-stimulating agents for various indications, including myelodysplastic syndromes and other neoplasms, are also discussed.
Topics: Adult; Anemia; Erythroid Cells; Erythropoiesis; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Polycythemia
PubMed: 30076180
DOI: 10.3324/haematol.2018.192518 -
Fetal Diagnosis and Therapy 2010Monochorionic twins share a single placenta with intertwin vascular anastomoses, allowing the transfer of blood from one fetus to the other and vice versa. These... (Review)
Review
Monochorionic twins share a single placenta with intertwin vascular anastomoses, allowing the transfer of blood from one fetus to the other and vice versa. These anastomoses are the essential anatomical substrate for the development of several complications, including twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). TTTS and TAPS are both chronic forms of fetofetal transfusion. TTTS is characterized by the twin oligopolyhydramnios sequence, whereas TAPS is characterized by large intertwin hemoglobin differences in the absence of amniotic fluid discordances. TAPS may occur spontaneously in up to 5% of monochorionic twins and may also develop after incomplete laser treatment in TTTS cases. This review focuses on the pathogenesis, incidence, diagnostic criteria, management options and outcome in TAPS. In addition, we propose a classification system for antenatal and postnatal TAPS.
Topics: Female; Fetal Diseases; Fetofetal Transfusion; Humans; Incidence; Placenta; Polycythemia; Pregnancy; Prenatal Diagnosis; Treatment Outcome
PubMed: 20339296
DOI: 10.1159/000304512