Detection of JAK2 V617F in the Diagnosis of Erythrocytosis: Feasibility and Diagnostic Value in Clinical Practice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2595-2595
Author(s):  
Chloé James ◽  
François Delhommeau ◽  
Christophe Marzac ◽  
Irène Teyssandier ◽  
Jean-Pierre Le Couédic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mass Measurement ◽  
Cell Mass ◽  
Jak2 V617f ◽  
Diagnostic Value ◽  
Red Cell ◽  
Myeloproliferative Disease ◽  
Isotopic Methods ◽  
Serum Erythropoietin Level ◽  
Red Cell Mass

Abstract Polycythemia Vera (PV) is a myeloproliferative disorder (MPD), whose diagnosis is currently based on an association of clinical and biological criteria following the WHO or the PVSG classification. It is characterized by a primitive absolute erythrocytosis, and formation of endogenous erythroid colonies (EEC). Recently, we described a point mutation in JAK2 (JAK2 V617F) and showed that this activating mutation was the cause of the disease (James et al, Nature, 2005). This molecular abnormality was therefore likely to be a diagnostic marker of PV, as bcr-abl for chronic myeloid leukemia (CML). Nevertheless, JAK2 V617F is also found in other MPDs, sharing some common features with PV, as essential thrombocythemia, idiopathic myelofibrosis, and other rare MPDs. One major criterion for the diagnosis of PV requires the demonstration of increased red cell mass as measured by isotopic methods. We assessed the value of detection of JAK2 V617F as a first intention diagnostic test in 88 patients with hematocrit values above 51% (=erythrocytosis) and showed that the mutation correlated with the diagnosis of PV according to the WHO (R=0.879) and the PVSG (R=0.717) criteria, with a positive predictive value of 100% in the context of erythrocytosis. Besides, the presence of the mutation strongly correlated with EEC formation in 81/87 patients (R=0.824) and only weakly with the serum erythropoietin level (R=0,416). PCR-based genotyping techniques are less time-consuming, less expensive, than DNA sequencing and are easier to perform in hematology diagnostic laboratories. Therefore, we studied the feasibility of the detection of JAK2 V617F with widespread instruments commonly used in routine. We analyzed 119 samples from patients with a suspicion of myeloproliferative disease and showed that JAK2 V617F was efficiently detected by LightCycler® and TaqMan® genotyping technologies, these latter being a little more sensitive than sequencing. For 50 patients, peripheral blood and bone marrow samples were both available. In all cases (34 mutated, 16 non-mutated) the mutation was identically detected. Based on these results, we propose that the detection of JAK2 V617F in granulocytes has a first place in the diagnostic chart of an erythrocytosis, as bcr-abl in CML, avoiding, if positive, an isotopic red cell mass measurement and bone marrow EEC assays. The presence of JAK2 V617F in a patient with erythrocytosis would then lead to the diagnosis of MPD of PV type. Further prospective studies will be necessary to assess if all the MPDs patients bearing JAK2 V617F can be grouped in a new subset within the MPD entity, especially in term of thrombotic and neoplasic risk.

Red Cell Mass Measurement in Polycythemia: Evaluation of Performance and Added Value.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1525-1525
Author(s):  
Shireen Sirhan ◽  
Ayalew Tefferi
Keyword(s):  
Bone Marrow ◽  
Plasma Volume ◽  
Test Performance ◽  
Mass Measurement ◽  
Cell Mass ◽  
Added Value ◽  
Study Cohort ◽  
Red Cell ◽  
Disease Category ◽  
Red Cell Mass

Abstract Background : Current diagnosis of polycythemia vera (PV) is based on a set of clinical and laboratory criteria that were adopted more by consensus rather than because of support from systematic evidence. Accordingly, one major criterion for the diagnosis of PV requires the demonstration of increased red cell mass (RCM) as measured by radionuclide dilution methods. In order to adjust for the influence of obesity on RCM expressed in mL/kg, an expert radionuclide panel of the International Committee for Standardization in Haematology (ICHS) has recommended that the results be expressed in reference to body surface area and specific formulae for the prediction of normal values as well as guidelines for the interpretation of measured values have been proposed (J Nuclear Med1980;21:793, BJH1995;89:748). Nevertheless, there is limited data on either the performance or added value of RCM measurement, following these revised recommendations, for the diagnosis of PV in current clinical practice. Methods : The current study looks at a single institution experience with RCM measurement over the last 10 years involving patients in whom the test was performed to consider the diagnosis of PV. The study excluded patients that were previously treated with either phlebotomy or cytoreduction. Designation of diagnostic categories was based on both a retrospective and prospective analysis of clinical data, bone marrow histology, and other laboratory parameters including leukocyte count, platelet count, serum erythropoietin (EPO) level, serum B12 level, and leukocyte alkaline phospatase (LAP) score. A diagnosis of secondary polycythemia (SP) required the presence of a condition known to be associated with SP. Apparent polycythemia (AP) was represented by patients in whom the diagnosis of either PV or SP could not be made and the stability of hematocrit values was documented by serial measurements. Measurement and interpretation of RCM values were according to the aforementioned published criteria and separate analyses were performed for males and females. Results : i) Evaluation of test performance : The study cohort consisted of 105 patients (60 males; median age 62 years, range 16–89) including 25 with PV, 35 with SP, 38 with AP, and 7 with essential thrombocythemia (ET). Table 1 outlines the percentage of patients, in each disease category, whose measured values exceeded the 98–99% limits of the reference range (i.e. ±25% of the normal predicted mean for an individual patient). Table 1 Diagnosis % with increased RCM (m2) % with normal RCM (m2) % with decreased plasma volume % with increased plasma volume PV (n=25) 80 20 0 20 ET (n=7) 57.1 42.9 0 29 SP (n=35) 20 80 2.9 5.7 AP (n=38) 21.6 78.4 5.4 5.4 The results reveal that RCM measurement was neither adequately sensitive nor specific in distinguishing PV from the other disease categories. In addition, based on the aforementioned ICHS criteria, chronically contracted plasma volume appears to be an infrequent phenomenon in AP. ii) Evaluation of added value for the diagnosis of PV : Among the 19 PV patients with elevated RCM, serum EPO was measured in 17 and the results showed decreased levels in 16 (94%). Bone marrow biopsy was available for review in 9 patients and the results were consistent with PV in all instances (100%). LAP score was performed in 12 patients and 11 had LAP scores above 130 (92%). In none (0%) of the 19 patients was RCM measurement found to be vital for the diagnosis of PV. Conclusion : In the current retropsective study, RCM measurement was found to be neither diagnostically accurate nor essential for the diagnosis of PV.

scholarly journals Oxymetholone Treatment for the Anemia of Bone Marrow Failure

Blood ◽  
1972 ◽  
Vol 40 (3) ◽  
pp. 353-365 ◽  
Author(s):  
Raymond Alexanian ◽  
Judith Nadell ◽  
Clarence Alfrey
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Cell Mass ◽  
Iron Concentration ◽  
Response To Therapy ◽  
Red Cell ◽  
Bone Marrow Disease ◽  
Subsequent Response ◽  
Red Cell Mass ◽  
Complicating Factors

Abstract Oxymetholone was given to 28 adults with chronic anemia from bone marrow disease. Changes in hematocrit and red cell mass were correlated with serial assessments of erythropoietin and erythropoiesis. Erythropoietin excretion was enhanced more than five-fold over the level expected for the hematocrit in 70% of the patients. Only 23% of the patients with an evaluable treatment trial increased their red cell mass by at least 20%. In all responders, the T½ of 59Fe disappearance ranged from 86-136 min and erythron iron turnover exceeded 0.25 mg/100 ml blood/day. A decline in serum iron concentration to the 50-100 µg/100 ml range after 1 mo of oxymetholone was frequently associated with a subsequent response to therapy. Patients with severe bone marrow failure, for whom frequent red cell transfusions were required, did not improve. The failure of other patients to respond was attributed to complicating factors that either impaired maximal erythropoietin production or restricted iron supply to the bone marrow. Hepatic toxicity was detected in less than 10% of treated patients. Results support the use of oxymetholone in the treatment of patients with moderate degrees of bone marrow failure and symptomatic anemia.

scholarly journals Effect of Transfusion Polycythemia upon Bone Marrow Activity and Erythrocyte Survival in Man

Blood ◽  
1951 ◽  
Vol 6 (11) ◽  
pp. 1021-1033 ◽  
Author(s):  
FREDERICK ROSS BIRKHILL ◽  
MARY A. MALONEY ◽  
STANLEY M. LEVENSON
Keyword(s):  
Bone Marrow ◽  
Cell Mass ◽  
White Blood Cells ◽  
Red Cell ◽  
Adult Males ◽  
Erythrocyte Survival ◽  
Red Cell Mass ◽  
Post Infusion ◽  
Cell Synthesis ◽  
Marrow Activity

Abstract 1. The effect of transfusion polycythemia upon bone marrow activity and erythrocyte survival has been studied in 4 normal young adult males. 2. Plasma volumes did not change significantly throughout the period of study. 3. Total red cell masses increased to the "expected" levels, i.e., to the total of the subjects’ cells plus the transfused cells immediately after the transfusions. Thereafter these fell progressively, reaching the control levels in about forty days. 4. Survival of the infused cells was normal. 5. The subjects’ own red cell masses fell progressively at first. This was due to decreased erythropoiesis rather than to increased destruction. This is indicated by (a) no consistent significant elevation in hemolytic indexes; (b) change of the myeloid-erythroid ratio from normal values of 4 to 7:1 to about 20:1 two weeks post-infusion; (c) consistent decrease in circulating reticulocytes. 6. The depression of erythropoiesis was directly related to the quantity of red cells infused; almost complete cessation of red cell synthesis followed an increase of the red cell mass by forty per cent. 7. The depression of erythropoiesis was only temporary. As soon as the total circulating red cell mass returned to the pre-injection level, erythropoiesis proceeded at a normal rate. 8. No consistent changes in the circulating white blood cells, totals and differentials were noted. 9. Mild abnormalities in some liver functions were observed. Whether these should be attributed to the effects of the transfusions directly, or to the mild febrile responses experienced by the subjects shortly after the infusions cannot be stated with certainty at present.

The Red Cell Mass (RCM) Value In Polycythaemia Vera Disease In The JAK2 V617F Era

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5249-5249 ◽  
Author(s):  
Hassan A. Al-Jafar ◽  
Leena M Aytoglu ◽  
Issa Loutfi ◽  
Iman Al-Shemmari ◽  
Salem H Alshemmari
Keyword(s):  
Polycythemia Vera ◽  
Cell Mass ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Jak2 V617f Mutation ◽  
Polycythaemia Vera ◽  
Red Cell ◽  
Red Cell Mass ◽  
V617f Mutation ◽  
Idiopathic Erythrocytosis

Abstract Introduction In Polycythaemia Vera (PV), the RBC lineage is involved with increased haemoglobin, RBC count and haematocrit. WHO diagnostic criteria for PV are JAK2 V617F mutation and elevated red cell mass (RCM) > 25% of mean normal value. In addition, tests of marrow hypercellularity, blood erythropoietin and colony formation, are minor criteria. However, the diagnostic role of RCM test is still controversial and requires clarification. In this work, PV patients who had both an RCM study and JAK2 V617F mutation test, and routine laboratory tests, are evaluated to check if RCM was essential in the diagnostic work up for PV. Methods Over 2 years, 75 patients with abnormal haematocrit (men ≥ 0.50, women ≥ 0.45) had RCM and JAK2 V617F mutation tests (except JAK2 exon 12 mutation). All subjects consented to the study approved by the ethics committee. RCM was done by Cr-51 RBC radiolabeling method (no prior venesection at least 1 month). Statistical analysis involved descriptive statistics and chi-square test. Results There were 71 males and 4 females, mean age 46 y (range 17-75 y). Increased RCM was found in 41/75 (55%). Positive JAK2 V617F was found in 13/75 patients (17%), who also had RCM above the mean normal predicted value, however, when the WHO RCM criteria were applied, only 7/13 (54%) could be considered as having “truly” increased RCM. In the patient group with negative JAK2 V617F test, 12/28 (43%) had RCM results as per WHO criteria. There was no statistical association between presence of JAK2 V617F and the RCM values. Conclusion In patients with negative JAK2 V617F but with high clinical suspicion for PV and all other causes of secondary and idiopathic erythrocytosis excluded, an increase in RCM would support the diagnosis of PV (about 10 % PV cases). In patients with JAK2 positive mutation and high haematocrit but RCM below the WHO cut-off level, an increased RCM would still count to confirm the diagnosis as the current standard level seems too stringent. References James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005; 434(7037): 1144-8. Kralovics R, Passamonti F, Buser AS, Soon-Siong T, Tiedt R, Passweg JR, et al. A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders. Merck Manual of Diagnosis and Therapy. 16th Edition, 1992 McMullin MF, Bareford D, Campbell P, Green AR, Claire Harrison C, Hunt B, Oscier D, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British Journal of Haematology 2005; 130(2): 174-95. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459-468. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007;21:1960-1963. Pancrazzi A, Guglielmelli P, Ponziani V, et al. A sensitive detection method for MPLW515L or MPLW515K mutation in chronic myeloproliferative disorders with locked nucleic acid-modified probes and real-time polymerase chain reaction. J Mol Diagn. 2008;10:435-441. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Erythropoietin-dependent primary pure erythrocytosis

Blood ◽  
1979 ◽  
Vol 53 (6) ◽  
pp. 1076-1084 ◽  
Author(s):  
N Dainiak ◽  
R Hoffman ◽  
AI Lebowitz ◽  
L Solomon ◽  
L Maffei ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Cell Mass ◽  
Red Cell ◽  
Extensive Search ◽  
Erythropoietin Production ◽  
Red Cell Mass ◽  
Marrow Cells

Abstract We investigated the pathogenesis of isolated erythrocytosis of 14 yr duration in a 28-yr-old man. The increase in red cell mass was attributed to increased erythropoietin production. An extensive search for recognized causes of secondary erythrocytosis was unrevealing. Family members were found to be hematologically normal. After reduction of the circulating red cell mass by 20%, erythropoietin activity nearly quadrupled, thus suggesting a normal erythropoietin response to phlebotomy. When bone marrow cells of the patient were cultured in plasma clots in the absence of added erythropoietin, endogenous erythroid colony formation was observed, a pattern previously believed to be specific for polycythemia vera bone marrow cells. Our observations suggest that the erythrocytosis in this individual is best explained by an abnormal “servoregulatory” mechanism of erythropoietin production. In addition, this is the first instance in which the rule that endogenous erythroid colony formation is correlated with the diagnosis of polycythemia vera has not held.

Hematological measurements in rats flown on Spacelab shuttle, SL-3

1987 ◽  
Vol 252 (2) ◽  
pp. R216-R221 ◽  
Author(s):  
R. D. Lange ◽  
R. B. Andrews ◽  
L. A. Gibson ◽  
C. C. Congdon ◽  
P. Wright ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Life Science ◽  
Bone Marrow Cells ◽  
Cell Mass ◽  
Red Cell ◽  
Cell Counts ◽  
Animal Bone ◽  
Red Cell Mass ◽  
And Control ◽  
First Time

Previous studies have shown that a decrease in red cell mass occurs in astronauts, and some studies indicate a leukocytosis occurs. A life science module housing young and mature rats was flown on shuttle mission Spacelab 3 (SL-3), and the results of hematology studies of flight and control rats are presented. Statistically significant increases in the hematocrit, red blood cell counts, and hemoglobin determinations, together with a mild neutrophilia and lymphopenia, were found in flight animals. No significant changes were found in bone marrow and spleen cell differentials or erythropoietin determinations. Clonal assays demonstrated an increased erythroid colony formation of flight animal bone marrow cells at erythropoietin doses of 0.02 and 1.0 U/ml but not 0.20 U/ml. These results agree with some but vary from other previously published studies. Erythropoietin assays and clonal studies were performed for the first time.

scholarly journals Red cell mass measurement in patients with clinically suspected diagnosis of polycythemia vera or essential thrombocythemia

Haematologica ◽  
2012 ◽  
Vol 97 (11) ◽  
pp. 1704-1707 ◽  
Author(s):  
A. Alvarez-Larran ◽  
A. Ancochea ◽  
A. Angona ◽  
C. Pedro ◽  
F. Garcia-Pallarols ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Mass Measurement ◽  
Cell Mass ◽  
Red Cell ◽  
Red Cell Mass ◽  
Suspected Diagnosis
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