Identification of Blood Erythroid Markers Useful in Revealing Erythropoietin Abuse in Athletes

Magnani, Mauro; Corsi, Dario; Bianchi, Marzia; Paiardini, Mirko; Galluzzi, Luca; Gargiullo, Elisa; Parisi, Attilio; Pigozzi, Fabio

doi:10.1006/bcmd.2001.0419

Cited by 18 publications

(20 citation statements)

References 26 publications

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“…Similarly, sTfR levels can be used to monitor how erythropoiesis subside after cessation of rHuEpo therapy [49]. Measurements of sTfR and calculated sTfR/ferritin ratios have also been proposed as possible probes to detect erythropoietin abuse in athletes [44], although lower rHuEpo doses inducing similar Hct changes over a longer period of time are not associated with sTfR changes [50]. Therefore, combining sTfR measurements into a multiparametric assessment of erythroid marrow function may improve the detection of rHuEpo abuse [50,51].…”

Section: Main Characteristicsmentioning

confidence: 99%

“…Measurements of sTfR and calculated sTfR/ferritin ratios have also been proposed as possible probes to detect erythropoietin abuse in athletes [44], although lower rHuEpo doses inducing similar Hct changes over a longer period of time are not associated with sTfR changes [50]. Therefore, combining sTfR measurements into a multiparametric assessment of erythroid marrow function may improve the detection of rHuEpo abuse [50,51]. However, intermittent or continuous hypoxia [52] as achieved by a ''living high-training low'' program [53] also induce endogenous Epo-driven elevated sTfR values.…”

Section: Main Characteristicsmentioning

confidence: 99%

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Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Béguin

2003

Clinica Chimica Acta

398

316

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Iron transport in the plasma is carried out by transferrin, which donates iron to cells through its interaction with a specific membrane receptor, the transferrin receptor (TfR). A soluble form of the TfR (sTfR) has been identified in animal and human serum. Soluble TfR is a truncated monomer of tissue receptor, lacking its first 100 amino acids, which circulates in the form of a complex of transferrin and its receptor. The erythroblasts rather than reticulocytes are the main source of serum sTfR. Serum sTfR levels average 5.0 F 1.0 mg/l in normal subjects but the various commercial assays give disparate values because of the lack of an international standard. The most important determinant of sTfR levels appears to be marrow erythropoietic activity which can cause variations up to 8 times below and up to 20 times above average normal values. Soluble TfR levels are decreased in situations characterized by diminished erythropoietic activity, and are increased when erythropoiesis is stimulated by hemolysis or ineffective erythropoiesis. Measurements of sTfR are very helpful to investigate the pathophysiology of anemia, quantitatively evaluating the absolute rate of erythropoiesis and the adequacy of marrow proliferative capacity for any given degree of anemia, and to monitor the erythropoietic response to various forms of therapy, in particular allowing to predict response early when changes in hemoglobin are not yet apparent. Iron status also influences sTfR levels, which are considerably elevated in iron deficiency anemia but remain normal in the anemia of inflammation, and thus may be of considerable help in the differential diagnosis of microcytic anemia. This is particularly useful to identify concomitant iron deficiency in a patient with inflammation because ferritin values are then generally normal. Elevated sTfR levels are also the characteristic feature of functional iron deficiency, a situation defined by tissue iron deficiency despite adequate iron stores. The sTfR/ferritin ratio can thus describe iron availability over a wide range of iron stores. With the exception of chronic lymphocytic leukemia (CLL) and high-grade non-Hodgkin's lymphoma and possibly hepatocellular carcinoma, sTfR levels are not increased in patients with malignancies. We conclude that soluble TfR represents a valuable quantitative assay of marrow erythropoietic activity as well as a marker of tissue iron deficiency. D

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Section: Main Characteristicsmentioning

confidence: 99%

Section: Main Characteristicsmentioning

confidence: 99%

Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Béguin

2003

Clinica Chimica Acta

398

316

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“…64,[107][108][109] Some investigators have attempted to enrich the screened parameters for altered erythropoiesis with the determination of messenger RNA of erythroid target genes such as b-globin, ferritin-light chain, and ornithine decarboxylase antizyme by quantitative polymerase chain reaction. 42,110 b-Globin is considered a selective marker of erythroid activity and its expression (upregulated during erythropoiesis stimulation) appears to change most significantly after rhEpo intake as described by Magnani et al 110 Moreover, considering its occurrence in the reticulocyte library, the estimated b-globin level was 30% of total mRNA and represents the major reticulocyte transcript. As for ferritin-light chain, the red cell pool incorporates iron during erythroid expansion.…”

Section: Alternative Approaches To the Direct Recombinant Human Erythmentioning

confidence: 99%

Applications and Biomonitoring Issues of Recombinant Erythropoietins for Doping Control

Tsitsimpikou¹,

Kouretas²,

Tsarouhas³

et al. 2011

Therapeutic Drug Monitoring

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The biochemical actions and side effects of recombinant erythropoietins (rhEPOs), their analogs and mimetics, their misuse as doping agents, and the principal analytical strategies developed to identify them in athletes' biologic fluids are reviewed. Patients who experience a range of pathologies have benefited from the administration of rhEPOs to correct severe anemia. Currently, monitoring the biologic effect of rhEPO in patients under treatment is by measuring the hemoglobin concentration. However, it may be valuable to directly monitor the actual levels of the administered drug and determine a dose-dependent correlation with any clinical adverse effect observed. This may permit the adoption of a patient-specific administration regime. Currently, the method of detecting EPO approved for doping control is an isoelectric-focusing, double-blotting, chemiluminescence assay based on charge differences between isoforms of rhEPOs and endogenous EPO in urine. The advantages and limitations of this method are presented. A new approach using sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a complementary tool to the established method is discussed. The application of matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography combined with tandem mass spectrometry for the direct detection of the rhEPO molecules may prove to be promising. Indirect evidence of rhEPO abuse by athletes is based on the analysis of blood parameters (hemoglobin hematocrit, reticulocytes, macrocytes, etc) and serum markers (concentration of EPO and serum transferrin receptors, etc). Enrichment of the screened parameters with gene or biochemical markers revealing altered erythropoiesis and adoption of longitudinal monitoring of athletes' hematologic and biochemical parameters could also be a complementary approach in the fight against doping.

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“…The simultaneous application of upper limits for both Hb and HCT, however, is redundant and does not have any scientific basis. Several authors have proposed the utilization of alternative and more sophisticated approaches for detection of blood doping, such as the percentage of macrocytes [5] and the measurement of Hb concentration or mean corpuscular volume, or Hb concentration of reticulocytes [48,49]. In healthy subjects receiving rhEPO, it is possible to detect an increase of the amounts of β-globin mRNA by RT-PCR in whole blood [49].…”

Section: Hematological Parameters: the Threshold Strategymentioning

confidence: 99%

“…Several authors have proposed the utilization of alternative and more sophisticated approaches for detection of blood doping, such as the percentage of macrocytes [5] and the measurement of Hb concentration or mean corpuscular volume, or Hb concentration of reticulocytes [48,49]. In healthy subjects receiving rhEPO, it is possible to detect an increase of the amounts of β-globin mRNA by RT-PCR in whole blood [49]. Some of these parameters have been included in mathematical models (see below); although interesting from a scientific standpoint, their practical utility has not been definitively proven.…”

Section: Hematological Parameters: the Threshold Strategymentioning

confidence: 99%

Blood doping: present procedures and detection techniques

Melioli¹,

D’Onofrio²

2006

Expert Review of Endocrinology & Metabolism

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Blood doping represents a serious risk in endurance athletes. Blood transfusion practices (either autologous or homologous) have been used since 1960 and, despite the significant improvement in the laboratory methods, only homologous blood transfusion can be detected currently, while for autologous blood transfusion, no validated methods exist. In the last 15 years, a number of drugs have been developed to treat anemic patients. From recombinant erythropoietin to synthetic hemoglobin, all the developed tools are potentially useful to increase the oxygen transport to peripheral tissues in endurance athletes. Thus, the availability of doping-detection methods can only be sustained by the knowledge of any novel therapeutic approach in this field. The identification of the doping molecule is the gold standard of any antidoping campaign; despite this, indirect methods based on the detection of the effects induced by the doping procedure will be a very powerful tool in the near future. Nevertheless, while direct methods are only affected by the sensitivity and the specificity of the method itself (deterministic methods), indirect approaches are affected by the statistic weight of the results (probabilistic methods). Thus, blood doping will be better controlled by the combination of the two approaches.Expert Rev. Endocrinol. Metab. 1(6), 793-800 (2006) Despite the legend that Roman legions, as well as mythical vampires, drank the blood of their adversaries to gain strength, rumors report that the first attempts of blood doping began back in the 1960s with athletes withdrawing their own blood, storing it and reinjecting it prior to a competition. This procedure was carried out since it was expected that any increase in the transport of oxygen may result in a significant improvement of the performance of endurance athletes. Along this line, the effects of blood doping were well defined in late 1980s [1] and, in the same period, attempts to detect this procedure were reported [2]. Following that pioneering period, the human recombinant (rh) erythropoietin (EPO) era began. rhEPO was developed for the treatment of severely anemic patients, but was rapidly introduced in endurance sports. In the early and mid-1990s, a number of tests were proposed to detect the abuse of such a molecule in athletes. However, these approaches were, in general, based on the laboratory evidence of the effects of rhEPO administration, such as identification of threshold levels for hematocrit (HCT) and/or hemoglobin (Hb), increase of the soluble transferring receptor [3], reticulocytes [4] and large red blood cells (RBCs) [5], and inhibition of endogenous EPO secretion [101]. Only at the beginning of this millennium was a method to detect the presence of rhEPO in urine samples developed, validated and used in elite competitions, such as the Olympic games [6]. In the same period, an algorithm to calculate the probability of rhEPO abuse was originally described [7]. Present state of blood dopingDespite all these tools and the repeatedly reported ...

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Identification of Blood Erythroid Markers Useful in Revealing Erythropoietin Abuse in Athletes

Cited by 18 publications

References 26 publications

Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Applications and Biomonitoring Issues of Recombinant Erythropoietins for Doping Control

Blood doping: present procedures and detection techniques

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