Diagnosis and Treatment of Erythrocytosis

2010 ◽  
Vol 00 (04) ◽  
pp. 55 ◽  
Author(s):  
Mary Frances McMullin ◽  
Keyword(s):  
Cell Mass ◽  
Erythropoietin Receptor ◽  
Congenital Defects ◽  
Intrinsic Defect ◽  
Haematocrit Level ◽  
Polycythaemia Vera ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Number Of Patients ◽  
Secondary Causes

An erythrocytosis arises when the red cell mass is increased. This can be due to a primary intrinsic defect in the erythroid progenitor cells or secondary to erythropoietin production from some source. Primary and secondary causes can be congenital or acquired. Rare, primary congenital defects are due to mutations leading to truncation of the erythropoietin receptor. The main acquired, primary erythrocytosis is polycythaemia vera. Among the congenital secondary causes, a number of defects in the genes in the oxygen-sensing pathway have recently been described, which lead to a secondary erythrocytosis. An extensive list of acquired secondary causes needs to be considered. A number of patients do not have an identifiable cause of erythrocytosis and are therefore described as having idiopathic erythrocytosis. Investigation should commence with careful clinical evaluation. Determination of the erythropoietin level is then a first step to guide the further direction of investigation. In those with congenital defects, a number of serious thromboembolic events have been described, but there is little information available about outcomes in these individuals and, therefore, no evidence to guide management. In this group, consideration should be given to the use of venesection to attain an achievable haematocrit level, and also low-dose aspirin therapy.

Idiopathic erythrocytosis: a disappearing entity

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 629-635 ◽  
Author(s):  
Mary Frances McMullin
Keyword(s):  
Progenitor Cell ◽  
Cell Mass ◽  
Young Patients ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitor ◽  
Best Management ◽  
Number Of Patients ◽  
Clinical Consequences ◽  
The Common ◽  
Idiopathic Erythrocytosis

Abstract Erythrocytosis results when there is an increased red cell mass and thus an increased hemoglobin. The causes can be divided into primary intrinsic defects of the erythroid progenitor cell and secondary defects, where factors external to the erythroid compartment are responsible. Both can then be further divided into congenital and acquired categories. Congenital causes include mutations of the erythropoietin receptor and defects of the oxygen-sensing pathway including VHL, PHD2 and HIF2A mutations. When fully investigated there remain a number of patients in whom no cause can be elucidated who are currently described as having idiopathic erythrocytosis. Investigation should start with a full history and examination. Having eliminated the common entity polycythemia vera, further direction for investigation is guided by the erythropoietin level. Clinical consequences of the various erythrocytoses are not clear, but in some groups thromboembolic events have been described in young patients. Evidence is lacking to define best management, but aspirin and venesection to a target hematocrit should be considered.

scholarly journals Genetic Background of Congenital Erythrocytosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1151
Author(s):  
Mary Frances McMullin
Keyword(s):  
Receptor Gene ◽  
Cell Mass ◽  
Oxygen Affinity ◽  
Young Age ◽  
Erythropoietin Receptor ◽  
Congenital Defects ◽  
History Of ◽  
Genetic Mechanisms ◽  
High Oxygen Affinity ◽  
Hemoglobin Variants

True erythrocytosis is present when the red cell mass is greater than 125% of predicted sex and body mass, which is reflected by elevated hemoglobin and hematocrit. Erythrocytosis can be primary or secondary and congenital or acquired. Congenital defects are often found in those diagnosed at a young age and with a family history of erythrocytosis. Primary congenital defects mainly include mutations in the Erythropoietin receptor gene but SH2B3 has also been implicated. Secondary congenital erythrocytosis can arise through a variety of genetic mechanisms, including mutations in the genes in the oxygen sensing pathway, with high oxygen affinity hemoglobin variants and mutations in other genes such as BPMG, where ultimately the production of erythropoietin is increased, resulting in erythrocytosis. Recently, mutations in PIEZ01 have been associated with erythrocytosis. In many cases, a genetic variant cannot be identified, leaving a group of patients with the label idiopathic erythrocytosis who should be the subject of future investigations. The clinical course in congenital erythrocytosis is hard to evaluate as these are rare cases. However, some of these patients may well present at a young age and with sometimes catastrophic thromboembolic events. There is little evidence to guide the management of congenital erythrocytosis but the use of venesection and low dose aspirin should be considered.

scholarly journals A constitutively activated erythropoietin receptor stimulates proliferation and contributes to transformation of multipotent, committed nonerythroid and erythroid progenitor cells.

1994 ◽  
Vol 14 (4) ◽  
pp. 2266-2277 ◽  
Author(s):  
G D Longmore ◽  
P N Pharr ◽  
H F Lodish
Keyword(s):  
Cell Line ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Leukemia Virus ◽  
Active Form ◽  
Erythropoietin Receptor ◽  
Mutant Form ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

If the env gene of spleen focus-forming virus (SFFV) is replaced by a cDNA encoding a constitutively active form of the erythropoietin receptor, EPO-R(R129C), the resultant recombinant virus, SFFVcEPO-R, induces transient thrombocytosis and erythrocytosis in infected mice. Clonogenic progenitor cell assays of cells from the bone marrow and spleens of these infected mice suggest that EPO-R(R129C) can stimulate proliferation of committed megakaryocytic and erythroid progenitors as well as nonerythroid multipotent progenitors. From the spleens of SFFVcEPO-R-infected mice, eight multiphenotypic immortal cell lines were isolated and characterized. These included primitive erythroid, lymphoid, and monocytic cells. Some expressed proteins characteristic of more than one lineage. All cell lines resulting from SFFVcEPO-R infection contained a mutant form of the p53 gene. However, in contrast to infection by SFFV, activation of PU.1 gene expression, by retroviral integration, was not observed. One cell line had integrated a provirus upstream of the fli-1 gene, in a location typically seen in erythroleukemic cells generated by Friend murine leukemia virus infection. This event led to increased expression of fli-1 in this cell line. Thus, infection by SFFVcEPO-R can induce proliferation and lead to transformation of nonerythroid as well as very immature erythroid progenitor cells. The sites of proviral integration in clonal cell lines are distinct from those in SFFV-derived lines.

A Minimal Cytoplasmic Subdomain of the Erythropoietin Receptor Mediates Erythroid and Megakaryocytic Cell Development

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3381-3387 ◽  
Author(s):  
Chris P. Miller ◽  
Zi Y. Liu ◽  
Constance T. Noguchi ◽  
Don M. Wojchowski
Keyword(s):  
Progenitor Cells ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Cell Development ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitor ◽  
Epo Receptor ◽  
Receptor Complexes ◽  
Erythroid Progenitor Cells ◽  
Fetal Liver Cells

Signals provided by the erythropoietin (Epo) receptor are essential for the development of red blood cells, and at least 15 distinct signaling factors are now known to assemble within activated Epo receptor complexes. Despite this intriguing complexity, recent investigations in cell lines and retrovirally transduced murine fetal liver cells suggest that most of these factors and signals may be functionally nonessential. To test this hypothesis in erythroid progenitor cells derived from adult tissues, a truncated Epo receptor chimera (EE372) was expressed in transgenic mice using a GATA-1 gene-derived vector, and its capacity to support colony-forming unit-erythroid proliferation and development was analyzed. Expression at physiological levels was confirmed in erythroid progenitor cells expanded ex vivo, and this EE372 chimera was observed to support mitogenesis and red blood cell development at wild-type efficiencies both independently and in synergy with c-Kit. In addition, the activity of this minimal chimera in supporting megakaryocyte development was tested and, remarkably, was observed to approximate that of the endogenous receptor for thrombopoietin. Thus, the box 1 and 2 cytoplasmic subdomains of the Epo receptor, together with a tyrosine 343 site (each retained within EE372), appear to provide all of the signals necessary for the development of committed progenitor cells within both the erythroid and megakaryocytic lineages.

scholarly journals During EPO or anemia challenge, erythroid progenitor cells transit through a selectively expandable proerythroblast pool

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5334-5346 ◽  
Author(s):  
Arvind Dev ◽  
Jing Fang ◽  
Pradeep Sathyanarayana ◽  
Anamika Pradeep ◽  
Christine Emerson ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Progenitor Cell ◽  
Ex Vivo ◽  
Erythropoietin Receptor ◽  
Erythroid Cell ◽  
Short Term ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Stage Development ◽  
Bcl2 Expression

Abstract Investigations of bone marrow (BM) erythroblast development are important for clinical concerns but are hindered by progenitor cell and tissue availability. We therefore sought to more specifically define dynamics, and key regulators, of the formation of developing BM erythroid cell cohorts. A unique Kit−CD71highTer119− “stage E2” proerythroblast pool first is described, which (unlike its Kit+ “stage E1” progenitors, or maturing Ter119+ “stage E3” progeny) proved to selectively expand ∼ 7-fold on erythropoietin challenge. During short-term BM transplantation, stage E2 proerythroblasts additionally proved to be a predominantly expanded progenitor pool within spleen. This E1→E2→E3 erythroid series reproducibly formed ex vivo, enabling further characterizations. Expansion, in part, involved E1 cell hyperproliferation together with rapid E2 conversion plus E2 stage restricted BCL2 expression. Possible erythropoietin/erythropoietin receptor proerythroblast stage specific events were further investigated in mice expressing minimal erythropoietin receptor alleles. For a hypomorphic erythropoietin receptor-HM allele, major defects in erythroblast development occurred selectively at stage E2. In addition, stage E2 cells proved to interact productively with primary BM stromal cells in ways that enhanced both survival and late-stage development. Overall, findings reveal a novel transitional proerythroblast compartment that deploys unique expansion devices.

scholarly journals Erythropoietin-induced tyrosine phosphorylations in a high erythropoietin receptor-expressing lymphoid cell line

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 1923-1932 ◽  
Author(s):  
J Damen ◽  
AL Mui ◽  
P Hughes ◽  
K Humphries ◽  
G Krystal
Keyword(s):  
Cell Surface ◽  
Cell Line ◽  
Tyrosine Phosphorylation ◽  
Erythropoietin Receptor ◽  
Biologically Active ◽  
Erythroid Progenitor ◽  
Retroviral Gene Transfer ◽  
Molecular Weights ◽  
Erythroid Progenitor Cells ◽  
Major Species

Abstract Retroviral gene transfer of the murine erythropoietin receptor (EpR) cDNA into the pro-B-cell line, Ba/F3, was used to generate cells expressing high EpR levels. One of the resulting clones, Ba/F3 clone C5, contained 5 integrated copies of the gene and expressed, at the cell surface, a single affinity class of EpRs at 10 to 15 times the level present on spleen cells from phenylhydrazine-treated mice. Cross- linking studies with clone C5, using 125I-Ep, yielded the same two 105- and 88-Kd major species as that seen with typical erythroid cells. This was distinct from that obtained with EpR-transfected COS cells or L cells, which gave species of 88 and 65 Kd. This suggests that the biologically active EpR complex generated in this Ba/F3 cell line may closely resemble that present in native Ep-responsive erythroid progenitor cells. Tyrosine phosphorylation experiments showed that several proteins in clone C5 cells were rapidly phosphorylated on tyrosine residues in response to Ep, one being the EpR itself. The proportion of cell surface EpRs tyrosine phosphorylated in response to Ep was substantial, reaching a maximum of approximately 10% within 30 minutes of incubation at 37 degrees C. A comparison of Ep- and murine interleukin-3 (mIL-3)-induced tyrosine phosphorylation patterns in clone C5 cells showed that both growth factors stimulated the tyrosine phosphorylation of proteins with molecular weights of 135, 93, 70, and 55 Kd. This could suggest that the Ep and mIL-3 receptors are capable of using the same tyrosine kinase in these cells.

Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2073-2080 ◽  
Author(s):  
Bojana B. Beleslin-Cokic ◽  
Vladan P. Cokic ◽  
Xiaobing Yu ◽  
Babette B. Weksler ◽  
Alan N. Schechter ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Oxygen Tension ◽  
Cell Mass ◽  
Erythropoietin Receptor ◽  
Guanosine Monophosphate ◽  
No Production ◽  
Low Oxygen ◽  
Erythroid Progenitor ◽  
Low Oxygen Tension

Abstract Erythropoietin (EPO), a hypoxia-inducible cytokine, is required for survival, proliferation, and differentiation of erythroid progenitor cells. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors (EPORs). In this study we investigated the EPO response of vascular endothelial cells at reduced oxygen tension (5% and 2%), in particular the effect of EPO on nitric oxide (NO) release. Endothelial nitric oxide synthase (eNOS) produces NO, which maintains blood pressure homeostasis and blood flow. We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air. We found a corresponding increase in eNOS expression and NO production in response to EPO during hypoxia. Stimulation of NO production was dose dependent on EPO concentration and was maximal at 5 U/mL. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to EPO by induction of both EPOR and eNOS. This effect of EPO on eNOS may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell mass. (Blood. 2004;104:2073-2080)

Gab1 Is Involved in Erythropoietin Receptor-Mediated Survival Signal through Activation of the Erk Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2207-2207
Author(s):  
Tetsuya Fukumoto ◽  
Yoshitsugu Kubota ◽  
Akira Kitanaka ◽  
Fusako Waki ◽  
Osamu Imataki ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Adaptor Protein ◽  
Annexin V ◽  
Erythropoietin Receptor ◽  
Erk Pathway ◽  
Biological Functions ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Survival Signal ◽  
Survival Signals

Abstract Erythropoietin (EPO) is required for the survival, proliferation and differentiation of erythroid progenitor cells. The scaffolding adaptor protein Grb2-associated binder-1 (Gab1) is tyrosine phosphorylated upon stimulation of EPO in several cell lines and erythroid progenitor cells, and interacts with signaling molecules such as SHP2 phosphatase and the p85 subunit of phosphatidylinositol 3-kinase (PI3K). However, biological functions of Gab1 in EPO receptor (EPOR)-mediated signaling has not yet been established. In this study, to explore the biological functions of Gab1 in vivo, Gab1-deficient F-36P human erythroleukemia cells were generated by means of transfection of the expression vector of siRNA against Gab1. WST-1 assay revealed that growth of Gab1-deficient F-36P cells was reduced to 61% and 77%, respectively, 5 days after incubation with lower concentrations of EPO (0.001 and 0.01 ng/ml), compared with that of mock-transfected F-36P (F-36P-mock) cells. In contrast, growth of Gab1-deficient F-36P cells at sufficient concentration of EPO (10 ng/ml) was similar to that of F-36P-mock cells. Analysis of apoptosis by flow cytometry using FITC-labeled annexin-V showed that the percentage of annexin-V-positive apoptotic cells in Gab1-deficient F-36P and F-36P-mock cells was increased to 19% and 34%, and 8% and 17%, respectively, 72 h after incubation with 0.01 and 0.001 ng/ml of EPO. These results indicate that Gab1 plays a crucial role in transducing EPOR-mediated survival signals. Next, we examined the molecular mechanism of EPOR-mediated signaling involved in survival of erythroid cells through Gab1. Western blot analysis showed that EPO-induced phosphorylation of threonine 202/ tyrosine 204 on Erk-1 and Erk-2 in Gab1-deficient F-36P but not in F-36P-mock cells was significantly suppressed. Interestingly, phosphorylation of serine 473 on Akt in Gab1-deficient F-36P cells in response to EPO was slightly suppressed in comparison with that in F-36P-mock cells. Therefore, Gab1-mediated survival signals appear to be mainly transmitted to downstream through activation of the Erk pathway, although the PI3K/Akt pathway may be involved in EPO-initiated survival signal transduction mediated by Gab1. Furthermore, EPO induced the association of SHP2 with EPOR in Gab1-deficient F-36P cells. Gab1 was associated with SHP2 in EPO-treated F-36P cells. In addition, Gab1 was constitutively associated with Grb2 in F-36P cells. Taken together, EPO induces the recruitment of Gab1 to EPOR through binding of Gab1 to SHP2, which is associated with EPOR. Because the guanine nucleotide exchange factor SOS1 is known to bind to the SH3 domain of Grb2, SOS1-Grb2 complex is recruited to vicinity of Ras at the plasma membrane to activate this GTP-binding protein through the interaction of Grb2 with Gab1, leading to activation of Erk.

Erythropoietin Increases Erythropoiesis, Metabolism and Weight Loss In Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 946-946
Author(s):  
Constance Tom Noguchi ◽  
Heather Marie Rogers ◽  
Li Wang ◽  
Ruifeng Teng
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Progenitor Cells ◽  
White Adipose Tissue ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Erythropoietin Treatment ◽  
Expected Increase

Abstract Erythropoietin is required for erythroid progenitor cell survival, proliferation and differentiation. Increasing evidence suggests that erythropoietin treatment in mice can stimulate erythropoiesis and also affect metabolic processes in a dose dependent manner. For example, medium to high dose erythropoietin treatment (600 U/kg or 3000 U/kg) in leptin deficient obese (ob/ob) mice three times a week for three weeks or more results in the expected increase in hematocrit as well as decrease in accumulated body fat and improved glucose tolerance. Phlebotomy to maintain normal hematocrit demonstrated that erythropoietin regulation of body weight was not dependent on increased red cell mass. In non-obese wild type C57BL/6 mice, erythropoietin treatment also demonstrated the expected increase in hematocrit as well as a 15% reduction in body weight and decreased fasting blood glucose. Erythropoietin receptor is expressed at the highest level in erythroid progenitor cells. The link between increased metabolism and erythropoietin stimulated erythroid differentiation was suggested by the increased oxygen consumption rate observed in vitro in primary cultures of erythropoietin stimulated erythroid progenitor cells. Erythropoietin also stimulated glucose uptake in differentiating erythroid progenitor cells in a dose dependent manner. Glucose uptake decreased with the down regulation of erythropoietin receptor during terminal differentiation. Relatively high erythropoietin receptor expression and erythropoietin activity that may also contribute to erythropoietin metabolic activity has been observed in non-hematopoietic mouse tissue including the hypothalamus and white adipose tissue (Teng R, Gavrilova O et al., Nat Commun 2011). The hypothalamus contributes importantly to appetite regulation and mice treated with erythropoietin exhibited a decrease in food intake compared with saline control. We found that pair-feeding decreased body weight and fat mass, and improved glucose tolerance, but no more than half that observed with erythropoietin treatment, providing evidence that erythropoietin regulation of food intake accounts for only part of the metabolic response observed with erythropoietin treatment. Adipocytes isolated from white adipose tissue in erythropoietin treated mice showed an increase in oxygen consumption compared with vehicle treated or pair-fed mice. To assess the role of direct erythropoietin response of white adipose tissue in regulation of fat mass accumulation, we engineered mice with targeted deletion of erythropoietin receptor in adipose tissue. Erythropoietin treatment gave rise to the expected increase in hematocrit but resulted in a reduced decrease in body weight compared with saline treatment. These data show that erythropoietin treatment can stimulate cell oxygen consumption and can contribute to regulation of metabolism and body weight in mice. Erythropoietin receptor expression on erythroid progenitor cells provides for erythropoietin response to promote erythropoiesis and increase cell metabolic activity including glucose uptake and oxygen consumption. In non-hematopoietic tissue, erythropoietin receptor expression further contributes to erythropoietin regulated metabolic activity such as control of food intake attributed in part to hypothalamus response and modulation of fat mass affected by direct erythropoietin response in white adipose tissue. Therefore, in addition to its critical role in promoting erythropoiesis, erythropoietin can contribute to metabolic homeostasis via its activity in erythroid tissue and beyond. Disclosures: No relevant conflicts of interest to declare.

Erythropoietin Receptor Mutations Associated With Familial Erythrocytosis Cause Hypersensitivity to Erythropoietin in the Heterozygous State

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2530-2532 ◽  
Author(s):  
Stephanie S. Watowich ◽  
Xiaoling Xie ◽  
Ursula Klingmuller ◽  
Juha Kere ◽  
Mikael Lindlof ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Negative Control ◽  
Erythropoietin Receptor ◽  
Heterozygous State ◽  
Wild Type ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Swedish Family ◽  
Inherited Mutations ◽  
Low Serum

Inherited mutations in the erythropoietin receptor (EPOR) causing premature termination of the receptor cytoplasmic region are associated with dominant familial erythrocytosis (FE), a benign clinical condition characterized by hypersensitivity of erythroid progenitor cells to EPO and low serum EPO (S-EPO) levels. We describe a Swedish family with dominant FE in which erythrocytosis segregates with a new truncation in the negative control domain of the EPOR. We show that cells engineered to concomitantly express the wild-type (WT) EPOR and mutant EPORs associated with FE (FE EPORs) are hypersensitive to EPO-stimulated proliferation and activation of Jak2 and Stat5. These results demonstrate that FE is caused by hyperresponsiveness of receptor-mediated signaling pathways and that this is dominant with respect to WT EPOR signaling.

Sign in / Sign up

Export Citation Format

Share Document