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We describe presenting features, treatment strategies, and follow-up events involving 41 patients (median age 39 years, range 1-81; 54% males) with high oxygen affinity (HOA) hemoglobinopathy-associated erythrocytosis, seen at our institution (1973-2020). Thirty-four (83%) patients carried β-chain (13 Malmo, 4 Olympia, 3 San Diego, 2 Wood) and 7 (17%) α-chain (4 Dallas and one each Columbia-Missouri, Jackson, and Wayne) variants. Median (range) hemoglobin (Hgb)/hematocrit (Hct), serum erythropoietin and p50 were 18 g/dL/52.9% (16-21.9/48-66), 10.4 mIU (4-36.3), and 20 mmHg (12-25), respectively. Family history was documented in 24 patients and history of thrombosis in two (5%). Treatment included phlebotomy in 23 and antiplatelet therapy in 21 patients. At a median follow-up of 10 years, 23 (56%) patients reported one or more symptoms that were thought to be related to their increased Hct while thrombosis was documented in 10 (24%) patients. Neither Hgb/Hct level nor active phlebotomy showed a significant correlation with either thrombotic or nonthrombotic symptoms (p > .1 in all instances). Among 23 pregnancies recorded, 78% resulted in live births and no fetal loss was attributed to erythrocytosis. The current study does not implicate Hgb/Hct level as a major contributor of morbidity in HOA hemoglobinopathy-associated erythrocytosis and suggests limited therapeutic value for phlebotomy.

Low serum erythropoietin (EPO) is a minor criterion of Polycythaemia Vera (PV) but its diagnostic usefulness relies on studies performed before the discovery of JAK2 V617F mutation. The objective of the present study was to evaluate the diagnostic accuracy of serum EPO and JAK2 V617F allele burden as markers of PV as well as the combination of different diagnostic criteria in 287 patients (99 with PV, 137 with Essential Thrombocythaemia and 51 with non-clonal erythrocytosis). Low EPO showed good diagnostic accuracy as a marker for PV, with the area under the curve (AUC) of the chemiluminescent-enhanced enzyme immunoassay (CEIA) being better than that of radioimmunoassay (RIA) (0·87 and 0·76 for CEIA and RIA, respectively). JAK2 V617F quantification displayed an excellent diagnostic accuracy, with an AUC of 0·95. A haematocrit >52% (males) or >48% (females) plus the presence of the JAK2 V617F mutation had a sensitivity and specificity of 79% and 97%, respectively. Adding low EPO or the JAK2 V617F allele burden did not improve the diagnostic accuracy for PV whereas the inclusion of both improved the sensitivity up to 83% and maintaining 96% specificity. Haematocrit and qualitative JAK2 V617F mutation allow a reliable diagnosis of PV. Incorporation of EPO and/or JAK2 V617F mutant load does not improve the diagnostic accuracy.

Objectives: To determine the effect of sildenafil for dogs with Eisenmeger's syndrome and secondary erythrocytosis. Methods: This is a prospective, single arm, open-label study. Five clinical dogs with Eisenmeger's syndrome and secondary erythrocytosis were included. New York Heart Association functional class, packed cell volume, pulmonary artery acceleration time to ejection time ratio and serum erythropoietin concentration were evaluated before and after sildenafil therapy (0·5 mg/kg, twice a day). Results: New York Heart Association functional class was significantly improved after one (median 2; range 1 to 2, P=0·031) and three months (median 2; range 1 to 2, P=0·031) of sildenafil therapy, compared with the baseline (median 3, range 2 to 3). Packed cell volume was significantly decreased after three months (median 59%; range 56 to 63, P=0·031) of therapy, compared with the baseline (median 71%; range 58 to 74). Acceleration time to ejection time ratio had increased and serum erythropoietin concentration had decreased particularly after 1 month of therapy, but there was no statistical significance. Clinical Significance: Sildenafil improved the clinical signs and secondary erythrocytosis in dogs with Eisenmeger's syndrome. Sildenafil therapy could be a useful treatment for dogs with Eisenmeger's syndrome.

The etiology of posttransplant erythrocytosis (PTE) remains unclear, and the most frequently suggested causative factors are still a matter of controversy. We aimed to investigate serum-soluble stem cell factor (sSCF) along with serum erythropoietin (EPO) levels in renal transplant recipients (RTRs) with PTE. Thirteen RTRs with PTE, 42 RTRs without PTE, and 42 healthy controls were included. Serum sSCF and EPO levels were determined using an enzyme-linked immunosorbent assay kit. Expected and observed/expected EPO levels were calculated. Serum sSCF levels and observed/expected EPO were significantly higher in RTRs with PTE than both RTRs without PTE and controls. In RTRs with PTE, sSCF level was significantly correlated with hematocrit and observed/expected EPO, respectively. Significant correlation was also observed between hematocrit level and observed/expected EPO in RTRs with PTE. Increased sSCF level and inadequate suppression of EPO production seem to have a role in the pathogenesis of PTE.

Serial serum erythropoietin levels were measured in 10 consecutive patients undergoing allogeneic bone marrow transplantation. Observed erythropoietin levels are compared with those predicted from a large control population of anaemic patients not receiving chemotherapy. There was an initial acute rise in serum erythropoietin, peaking between days 1 and 4 after marrow transfusion, which was unrelated to changes in haemoglobin concentration. Patients maintained serum erythropoietin concentrations at around twice the predicted level for the first 2 weeks following transplantation, with a gradual fall into the expected range by wk 3. Erythropoietin levels did not change with episodes of bacterial infection or acute graft-versus-host disease. A patient with severe aplastic anaemia had initial successful engraftment with normalisation of erythropoietin levels, but showed a marked and amplified rise in erythropoietin 2 wk before falling peripheral blood counts indicated failure of the bone marrow graft.

Erythropoietin activity in serum was measured using 59Fe incorporation into erythrocytes in protein-starved, hypoxic mice. The activity in serum from 20 patients with untreated myelomatosis was not significantly different from that in 31 saline controls. Only three patients had detectable erythropoietin levels in serum: 0.24 IU/ml, 0.27 IU/ml and 0.50 IU/ml (standard B), respectively. The venous haematocrit was correlated positively with the glomerular filtration rate as measured by 51Cr EDTA-clearance. No correlation could be established between venous haematocrit and serum albumin or serum transferrin. The results are in agreement with the assumption of a defective erythropoietin activity due to renal failure in myelomatosis.

A patient with leiomyomata of the skin and erythrocytosis is reported. After surgical removal of the larger skin tumours there was remission of the haematologic abnormalities and the erythrocytosis and the red cell mass decreased to normal levels. The raised serum erythropoietin levels were reduced but remained slightly elevated and less than those recorded prior to surgery. Tumour extracts contained significant erythropoietic activity. This seems to be the first documented case of erythrocytosis associated with skin leiomyomata.

Serum levels of transferrin receptor and erythropoietin were determined in 2 patients with hereditary hemochromatosis undergoing phlebotomy therapy. The objective of the study was to determine changes in serum transferrin receptor and serum erythropoietin occurring during therapy, and to investigate if such changes could be useful to monitor the therapy. The study showed that serum transferrin receptor, and to a lesser extent serum erythropoietin, may be better parameters than serum ferritin as indicators of when phlebotomy should be discontinued. The most sensitive parameter, however, appeared to be the serum transferrin receptor/ferritin ratio.

A survey was sent to laboratories participating in the United Kingdom External Quality Assessment Service (UKNEQAS) Haematinics Scheme about the measurement of serum erythropoietin (EPO). Six laboratories, from a total of 120 that returned the survey, were measuring serum EPO concentrations by commercially available immunoassays on site in the United Kingdom. The workload of the laboratories varied from up to 100 specimens per month to more than 100 specimens analysed per week. All laboratories included control material in the assays and none of the laboratories was participating in an external quality assessment scheme for serum EPO. Four laboratories agreed to take part in the first sample distribution programme, with five and six laboratories participating in distributions 2 and 3 respectively. The results from eight kits were compared from the three distributions over a 2-year period. The serum EPO concentrations for the methods showed some variation across the range of 2.9-200 U/l when the serum EPO concentrations for each method were compared with the whole method mean. The results from this scheme have identified a role for an external quality assessment scheme for serum EPO measurements.

For more than 15 years recombinant human erythropoietin (r-HuEPO) has been used for the treatment of renal anemia benefiting patients with improved quality of life and reduced need for blood transfusions. It is still early in the history of r-HuEPO treatment; therapy has changed little and there have been few investigations into whether current treatment strategies are optimal. Of note, current therapy makes little attempt to mimic normal erythropoietin biology. Large doses of drug are administered episodically resulting in great fluxes in serum erythropoietin levels. It is unlikely that this approach is very efficient from the erythropoietic standpoint. Furthermore the effects of these nonbiologic kinetics on extraerythroid organs that express erythropoietin receptors are unknown. In this review the current state of r-HuEPO treatment is compared to the normal biology of erythropoietin and potential pitfalls caused by divergences are explored.

Serum erythropoietin levels (s-[epo]), haemoglobin concentration ([Hb]), haematocrit (hct), and ferritin concentration ([fer]) were measured in seven healthy male volunteers (20-23 years) exposed continuously to hypoxia (PO(2) 14 kPa) for 10 days. Serum erythropoietin concentration increased significantly from 9.5 +/- 3.51 to 33.6 +/- 11.64 U L(-1) (P < 0.05) after 2 days of hypoxia. Thereafter, s-[epo] decreased. However, after 10 days s-[epo] was 18.7 +/- 5.83 U L(-1) which was still increased above the pre-hypoxia level (P < 0.05). Serum haemoglobin concentration and hct increased over the 10 days of hypoxia, [Hb] from 152 +/- 8.9 to 168 +/- 9.2 gL(-1) (P < 0.001), and hct from 43 +/- 2.4 to 49 +/- 2.6% (P < 0.001). Ferritin concentration decreased significantly during the hypoxic exposure from 82 +/- 46.9 to 44 +/- 31.7 mmol L(-1) after 10 days (P < 0.01). In conclusion, the initial increase of s-[epo] under controlled normobaric hypoxia was marked, 353%, and levelled off after 5-10 days at 62-97% above normoxia level. There was also a significant increase in [Hb] and hct and a decrease in [fer] after 10 days of exposure to normobaric hypoxia.

In refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) a discrepancy is observed between the decreased in vitro erythroid colony formation and the normal or increased number of normoblasts in the bone marrow. To study the in vivo and in vitro erythropoiesis in more detail erythron transferrin uptake (ETU), soluble transferrin receptor (sTfR) and erythroid in vitro colony formation were performed in 24 patients with BA and five patients with RARS. These results were correlated with bone marrow morphology and transfusion dependency. Increased (mean, 124.9; range, 74-225 mu mol/l blood/day) and normal (mean, 60.6; range, 50-71) ETU values were observed in 51% and 28% of the cases, whereas 21% of the cases demonstrated a diminished ETU value (mean, 35.8; range, 28-46), which correlated significantly with sTfR in cases with RE (P

Summary: Three separate high molecular weight fractions, designated as FI, FII and FIII, were isolated from sera of chronic renal failure (CRF) patients by precipitate with ammonium sulfate of different concentrations and DEAE celluose. All fractions had obvious suppressive effect on red blood cell growth, both erythroid colony (CFU-E) and BFU-E in vitro, but the maximal inhibitory rate that may be found in Fl or in FII and FIII depends entirely on individuals. the study also showed that none of these fractions was a homogeneous substance in SDS-PAGE electrophoresis. As well, a close correlationship between serum erythropoietin level and the inhibitory rate of the isolated fractions was observed. It is suggested that the inhibitory factors might exist in CRF sera and play a role in triggering the anaemia of CFR.

The prevalence of anemia in the elderly raises the question of an inappropriate secretion of erythropoietin in response to increased demands. Therefore, the serum erythropoietin concentration of elderly patients (74-95 years) with iron deficiency anemia was measured and compared to that of iron deficiency anemic adults (25-60 years). A lowered erythropoietin secretion in response to anemia was observed in elderly patients in comparison with adults. However, the serum erythropoietin of the anemic elderly was inversely correlated with hemoglobin levels as shown for the anemic adults. The progressive reduction of the renal function observed with aging could explain the decreased capacity of erythropoietin secretion in elderly patients.

Birgegard et al (1989) have demonstrated rapid increases in serum erythropoietin (EPO) concentration following cyto-reductive therapy for bone marrow transplantation and acute leukaemia. We have also observed similar increases although our conclusions concerning the underlying mechanisms are different

Summary To investigate the pathogenesis of polycythaemia in a child with isolated, primary erythrocytosis, we measured serum erythropoietin activity and in vitro erythroid progenitor cell responsiveness to erythropoietin. Unstimulated erythropoietin activity was markedly elevated (1.8 IU/ml), and isovolaemic phlebotomy induced a four-fold increment above this level. In contrast to findings in our index case with this syndrome, normal erythroid colony growth patterns were present in patient marrow cultures. The primary mechanism of polycythaemia in this individual is similar to that reported in the index case: an inappropriately elevated regulatory set point for erythropoietin production. Since an additional defect of progenitor cell hypersensitivity to erythropoietin is not always present, we conclude that abnormalities at single or multiple sites of the erythropoietic regulatory axis may occur in primary erythropoietin-dependent erythrocytosis.

Serum erythropoietin (s-Epo) was measured with a sensitive radioimmunoassay method in 58 patients with classical rheumatoid arthritis (n = 41) or seronegative spondyloarthropathies (n = 17). Epo was significantly (P less than 0.001) increased and on an average two times higher than in a healthy population. A correlation was found between Hb and s-Epo (r = -0.46, P less than 0.005), indicating that these patients respond to anaemia with an increase in s-Epo. In order to investigate if inflammation has a direct influence on s-Epo levels a short period of corticosteroid treatment was given to rapidly decrease inflammatory activity. No increase in s-Epo was seen after 1 week. Furthermore, there was a correlation between s-Epo and ESR in all patients (r = 0.59, P less than 0.01). These results indicate that s-Epo is directed by the Hb level, which in turn is influenced by the inflammatory activity: a higher inflammatory activity gives a lower Hb and an increase in s-Epo. In comparison to previously published figures for the relation between Hb and s-Epo these patients seem to have an ordinary Epo response. We conclude that the anaemia of patients with chronic inflammatory joint disease is not caused by a diminished Epo production.

SUMMARY Marked diurnal variation in serum immunoreactive erythropoietin was seen in a healthy man both during a 4-day control period and following acute loss of 450 g of blood by venesection. The highest concentrations of erythropoietin occurred around midnight and the lowest around noon. These findings emphasize the need to take account of diurnal changes in serum erythropoietin when assays for this hormone are used or assessed for their potential as diagnostic tools.

Multiple retroperitoneal functioning paraganglioma complicated by polycythemia is reported in the case of a girl who, at the age of 13 years complained of headache, palpitation, and faintness preoperatively. In the retroperitoneal cavity, there were 21 paragangliomas larger than 1 cm in diameter. All were removed surgically in two sections, the first in 1979 and the second in 1983. Bilateral adrenals were macroscopically normal, and her symptoms disappeared. Now the recurrence of retroperitoneal paraganglioma is likely, although there have been no symptoms for 8 years, since the first operation. It is difficult to conclude that the tumors were benign or malignant in this case. Though complication of polycythemia had been diagnosed before the operation, the symptom continued even with the serum erythropoietin level kept in the normal range. Association of polycythemia with paraganglioma is extremely rare, and it is also rare to find more than 10 paragangliomas. Only a limited number of reports have been made on each case in the literature.