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

Abstract The diagnosis of Polycythemia Vera (PV) and Essential Thrombocythemia (ET) is currently performed by excluding possible causes of secondary erythrocytosis and thrombocythosis. Recently, new typical findings of Ph-negative myeloprolipherative syndromes have been described, such as the PRV-1 RNA over-expression and the Val617Phe JAK-2 mutation. In this study we evaluated the diagnostic value of endogenous erythroid colony-assay (EECs), PRV-1 RNA over-expression and JAK-2 mutation, in the screening of patients with thrombocytosys and erythrocytosis which are candidate to a more extensive diagnostic approach including bone marrow biopsy and red cell mass evaluation. Peripheral blood samples were obtained from 56 patients referring to the hematological day hospital of our institution for erythrocythosis or thrombocythosis. EECs assay and PRV-1 expression were evaluated as prevoiusly described (Teofili L. et al, JCO 2002); Jak-2 mutation was investigated by the method described by Baxter et al. (Lancet 2005). The diagnosis of PV and ET was performed according to the PV and ET Study Group criteria. Twenty-five patients were affected by PV (19 males and 6 females, median age 68 years, range 34–80), 20 by ET, (5 males and 15 females, median age 64 years, range 31–85) 5 patients (3 males and 2 females, median age 56 years, range 35–69) and 6 patients (1 male and 5 females, median age 31 years, range 12–83) were diagnosed affected by secondary erythrocytosis and thrombocytosis, respectively. Results obtained are shown in Table 1. In our series all PV cases were identified by means at least one positive test, whilst 20% of ET patients resulted negative to all three assays. Moreover, among PV patients, only 1 patient was positive at one single assay (JAK-2 mutation), and the vast majority of them resulted positive for two or three assays. On the contrary, among patients affected by ET, a high proportion of patients (35 %) showed only Jak-2 mutation (10%) or PRV-1 over-expression (25%).. Importantly, no false positive cases were detectable among patients with secondary erythrocytosis and thrombocythosis. In conclusion, these data confirm that PRV-1 over-expression is a feature typical not only of PV but also of ET. Nevertheless the combination of different used assays is more usefull in the differential diagnosis of erythrocythosis than of thrombocythosis. TABLE 1 PV (%) ET (%) SE (%) ST (%) EECs pos. 18 (72) 8 (40) 0 0 PRV-1 pos. 24 (96) 14 (70) 0 0 Jak-2 mutated 17 (68) 7 (35) 0 0 Full positive 14 (56) 4 (20) 0 0 Full negative 0 4 (20) 5 (100) 6 (100)

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Circulating red cell mass in polycythemia vera as determined by red blood cells tagged with the radio-active isotope of iron

The American Journal of Medicine ◽

10.1016/0002-9343(49)90616-6 ◽

1949 ◽

Vol 7 (2) ◽

pp. 254-255

Author(s):

George R. Meneely ◽

E.B. Wells ◽

Paul F. Hahn

Keyword(s):

Red Blood Cells ◽

Polycythemia Vera ◽

Blood Cells ◽

Cell Mass ◽

Red Cell ◽

Red Cell Mass ◽

Active Isotope

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

Blood ◽

10.1182/blood.v104.11.1525.1525 ◽

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.

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Masked Polycythemia Vera (mPV): Results Of An International Study

Blood ◽

10.1182/blood.v122.21.1581.1581 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1581-1581

Author(s):

Tiziano Barbui ◽

Jürgen Thiele ◽

Heinz Gisslinger ◽

Guido Finazzi ◽

Alessandra Carobbio ◽

...

Keyword(s):

Overall Survival ◽

Polycythemia Vera ◽

Thrombotic Event ◽

Cell Mass ◽

Annual Rate ◽

World Health ◽

Rapid Progression ◽

Red Cell ◽

Who Criteria ◽

Red Cell Mass

Abstract Introduction Patients with masked polycythemia vera (mPV) present with hemoglobin (HB) values borderline inferior to those required by the World Health Organization (WHO) diagnostic criteria (HB >16.5g% and >18.5 g% in female and male respectively) but are suspected to have PV for presenting clinico-hematological features. The diagnostic HB values required by the WHO guidelines have been considered surrogate of increased red cell mass (RCM). However, in both males and females HB values are not always equal to an absolute erythrocytosis and conversely a HB concentration below the required cut off level could be associated with an increased red cell mass. We believe that bone marrow (BM) morphology may play an important role in differentiating PV from other MPN entities and reactive changes. In this study we investigated JAK2V617/Exon12-positive patients showing BM features characteristic for PV and classified as mPV or overt PV according to their hemoglobin levels and evaluated their respective outcomes including thrombosis, progression to myelofibrosis (MF), acute leukemia (AL) and overall survival with the purpose to support the diagnosis of PV also in patients presenting with lower HB levels than required by WHO criteria. Materials and Methods A clinicopathological database of patients who were diagnosed and treated for PV was created by clinicians and hematopathologists from seven international centers of excellence for MPNs. Eligibility criteria for entry included the presence of JAK2V617F (or Exon12) mutation, EPO measurement, no evidence of subnormal ferritin levels and the availability of representative, treatment-naive BM biopsies (hematoxylin-eosin staining and silver impregnation after Gomori or Gordon-Sweet). All BM biopsies were centrally re-reviewed by one of the authors (J.T.) who was completely blinded to outcome data. In both mPV and overt PV patients, phlebotomy and cytoreductive therapy were used with the same frequency (p=0.101). Results and Discussion Among 397 mutated patients, with PV BM morphology as defined by WHO, 257 (65%) met the full WHO-2008 criteria. The remaining 140 patients (35%) were classified as mPV for levels of HB at diagnosis, ranging from 16.5 to 18.5 g/dL in men and from 15.0 to 16.5 g/dL in women, and frequent presence of subnormal EPO levels (65%). At baseline, mPV patients were more males, had more previous arterial thrombosis and presented more frequently with platelet counts exceeding the required level of WHO-defined ET (450 x 109/L), often mimicking clinically this entity at onset. After a median follow-up of 3.8 (0-29.8) and 4.5 (0-21.1) years in mPV and overt PV, respectively, time to the first thrombotic event was superimposable in the two groups while time to progression to MF and AL was significantly different .These combined events were recorded in 10% of mPV and 5.8% of overt PV, corresponding to an annual rate of 1.60 % pts/year in mPV and 0.97 % pts/year in overt PV, respectively (p=0.010). In addition, an inferior overall survival was documented in mPV patients in comparison with overt PV (p=0.011). The annual rate of death in mPV was almost twice that of overt PV, mainly due to an excess of hematological transformation (overt MF and AL). Multivariable analysis identified age older than 65 years (hazard ratio (HR) 6.63, P<.0001), WBC >10 x109/L (HR 2.99, P=.005) and diagnosis of mPV (HR 2.38, P=.036) as independent risk factors for survival in these patients. These results show that in JAK2 mutated patients with borderline HB levels, BM features may be a valid support to confirm the suspicion of PV diagnosis. Of interest, recent data demonstrated that all patients with increased RCM also had BM morphology typical of PV. It is tempting to speculate that the clinico-hematologic phenotype of mPV may represent an early stage of a JAK2 mutated MPN, presenting as a variant of PV, with a more rapid progression to MF and AL. The recognition of these early PV patients has an important clinical impact since, in spite of not meeting the full WHO criteria, mPV share the same vascular risk as overt PV. In conclusion, these data suggest that mPV is not necessarily only an early form of classical PV but a distinct entity with disease outcomes akin to primary myelofibrosis. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.5249.5249 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5249-5249 ◽

Cited By ~ 1

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.

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IMPACT OF THE CONSENSUS CONFERENCE ON POLYCYTHEMIA VERA

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462399153145 ◽

1999 ◽

Vol 15 (3) ◽

pp. 602-607 ◽

Cited By ~ 3

Author(s):

Lionel Pazart ◽

Françoise Carpentier ◽

Alain Durocher ◽

Chrystelle Mougeot ◽

Yves Najean ◽

...

Keyword(s):

Polycythemia Vera ◽

Plasma Volume ◽

Diagnostic Tests ◽

Cell Mass ◽

Consensus Conference ◽

Red Cell ◽

Consensus Conferences ◽

Red Cell Mass ◽

Time Series Analyses ◽

The Impact

Objective: To assess the impact of guidelines on drug use issued by a consensus conference on polycythemia vera held in Paris in June 1993. 32Phosphorus (32P) was recommended for patients over 70 and/or at risk, whereas pipobroman and hydroxyurea were recommended for patients under 70.Methods: A questionnaire was sent to all 119 departments of nuclear medicine in France 1 year after the conference to find out whether and how often they measured plasma volume and red cell mass (the recommended diagnostic tests for polycythemia vera). Time-series analyses were performed on sales of 32P, pipobroman (both virtually exclusively prescribed for polycythemia), and hydroxyurea over a 4-year span (January 1992–December 1995).Results: The average number of plasma volume determinations per year did not change significantly after the conference (22 ± 26 before vs 21 ± 25 after). 32P and pipobroman sales were stable until July 1993, when 32P sales decreased while pipobroman sales rose steadily. Hydroxyurea sales increased over the whole period with no change in trend after the guidelines were published.Conclusions: The guidelines apparently influenced clinical practice since sales of drugs that are specifically used to treat polycythemia vera showed clear changes in trend after publication of the guidelines. This type of study seems to be an effective way of assessing the impact of consensus conferences.

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Erythropoietin-dependent primary pure erythrocytosis

Blood ◽

10.1182/blood.v53.6.1076.1076 ◽

1979 ◽

Vol 53 (6) ◽

pp. 1076-1084 ◽

Cited By ~ 28

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.

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