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Leukemia & Lymphoma, 2014; Early Online: 1–2© 2014 Informa UK, Ltd.ISSN: 1042-8194 print / 1029-2403 onlineDOI: 10.3109/10428194.2014.966243

Correspondence: Richard T. Silver, MD, Department of Hematology-Oncology, Weill Cornell Medical College, 1305 York Ave, Box # 403, New York, NY 10021, USA. Tel: 646-962-2255. Fax: 646-962-1607. E-mail: rtsilve@med.cornell.edu

Received 28 July 2014 ; revised 9 September 2014 ; accepted 9 September 2014

LETTER TO THE EDITOR

The hematocrit value in polycythemia vera: caveat utilitor

Richard T. Silver & Stefani Gjoni

Division of Hematology/Medical Oncology, Weill Cornell Medical College, New York, NY, USA

In patients with polycythemia vera (PV), phlebotomy performed to a target hematocrit (Hct) value of less than 45% resulted in a signifi cantly lower rate of cardiovascular death and major thrombosis compared to those patients who had a target Hct of 45 – 50% [1]. In an accompanying editorial, Spivak [2] also stressed the importance of phlebotomy guided by the Hct value, but adjusted for gender.

Th e Hct value now widely used in clinical settings is a derived value, i.e. red blood cell count (RBC) � mean cor-puscular volume (MCV). Since the great majority of regularly phlebotomized patients with PV either are or become iron defi cient, for a given RBC a lower MCV will yield a lower Hct value compared to the RBC. Th us, examining the Hct only may yield an erroneous interpretation regarding the need for phlebotomy.

In addition to its importance as a guide in treating patients with PV, the Hct value has been suggested as a surrogate marker for an increased red cell mass (RCM) for the diagnosis of PV [3]. Th us, consideration of certain pitfalls pertaining to the use of this widely employed test is timely and important.

We now report our fi ndings regarding relative values of the Hct in patients with PV with either microcytic or normo-cytic RBC and comment on other factors aff ecting the clini-cal accuracy of its use.

Th e study was approved by our Institutional Review Board, and written consent was obtained for permission to collect a blood specimen and pertinent medical information in accordance with the Declaration of Helsinki. Ten cubic centimeters of blood was collected in BD Vacutainer Venous Blood Collection EDTA ™ tubes for sample measurement of the RBC and hemoglobin (Hb). Two methods were used for determining the Hct values: the derived Hct from an auto-mated blood count and the microcentrifuge method. Th e latter employed 75 mm Hct tubes spun in the usual timed fashion in an Adams ™ microcentrifuge and a Damon IEC/Division ™ microcapillary reader. Th e average Hct value was determined from three collected specimens. No adjustments were made for trapped plasma [4].

Th e automated counts were performed in duplicate, and the derived Hct was measured electronically by multiplying the average MCV by the RBC, thus: Hct (%) � [RBC ( � 10 6 / μ L) � MCV � 10 � 15 ]/10.

Random blood specimens were collected from 94 diff erent patients with PV, 33 of whom had an MCV � 80 fL (10 � 15 /L), the cut-off value for “ microcytosis ” at our institution. Sixty-one of the 94 samples had an MCV � 80 fL, and normocytic and normochromic RBC on review of the peripheral blood smear. Retrospective review of these 61 patients indicated that they were in a complete or partial remission, and phle-botomy-free for at least 6 months, or men who had received four or fewer phlebotomies in the prior year (four patients). Of the 33 patients with microcytosis, all were receiving phle-botomies or had been within the previous 6 months.

A good correlation was obtained by plotting Hct vs. RBC for normocytic, normochromic cells [ R 2 � 0.86, Figure 1(a)]. Similar plots of Hct vs. Hb, MCV vs. RBC and MCV vs. Hb also showed good correlations (data not shown). A poor correla-tion plotting Hct vs. RBC was obtained for microcytic, hypo-chromic cells [ R 2 � 0.54, Figure 1(b)]. Similar plots of Hct vs. Hb, MCV vs. RBC and MCV vs. Hb for hypochromic, micro-cytic cells likewise showed a poor correlation ( R 2 � 0.51, data not shown). No signifi cant diff erences were observed between the microcentrifuged and derived Hct values (data not shown).

For microcytic cells, the diff erence in RBC counts for a given Hct is apparent. Examination of the potential inac-curacy of using the Hct instead of RBC value is illustrated in Figure 1(b). For example, Hct values between 44.5% and 45.5% yielded RBC counts ranging between 5.6 and 7.7 � 10 6 / μ L.

Importantly, other factors in addition to microcytosis aff ect the Hct value, including postural [5] and seasonal changes [6] and the site of obtaining the blood specimen [7]. An increase of 11.0 � 3.6% occurred in Hct values from lying to standing [4], and regional variations [5] occur due to mean environmental temperature (lower values in warm climates and higher values in cold). Th ese diff erences are due to intravascular fl uid shifts [5,6]. More commonly appreciated is the10% diff erence in Hct value that occurs between the body Hct and venous Hct, depending upon whether fi ngerstick or venous blood is used [7]. However, venous Hct becomes less representative of body Hct as patients with PV develop increasing splenomegaly, refl ect-ing splenic blood pooling [8,9].

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2 R. T. Silver & S. Gjoni

Th us, although we agree with Marchioli et al . [1] regard-ing the appropriate target Hct in patients with PV and with Spivak [2] regarding gender specifi city, our data show that for hypochromic microcytic cells, the Hct does not refl ect true RCM. Th e danger of stroke occurring in a patient with a nor-mal Hct but increased RBC has been reported [8]. Th us, a tar-get RBC of 5.0 � 10 6 / μ L for men and 4.5 � 10 6 / μ L for women for microcytic cells is probably safer. Although microcytic hypochromic RBCs have reduced deformability [10], specifi c comparisons of the viscosity of microcytic and normocytic RBCs have not been published.

Our second caveat relates to the Hct value as a potential diagnostic marker, recently suggested [3] and currently under consideration by the World Health Organization (WHO). Th e 2008 WHO recommendations for Hb values have been repeatedly shown to be inaccurate as a surrogate marker for RCM [8,9], and Hct values likewise [9,11,12], since iron defi ciency is most often present at diagnosis [13]. Th us, RBC may be underestimated for reasons discussed. Years ago, Pearson et al . found a discordant rate of nearly 20% for Hct values between 50 and 53% and true RCM [11,12,14]. Th us, 51 Cr RCM remains the only critical measurement of red cell volume [7,8,11,12,14] for the early diagnosis of PV.

Th erefore, the Hct value must be interpreted carefully when used for diagnosis or for following phlebotomy need, especially in the presence of microcytosis. A target RBC count

of 5.0 � 10 6 / μ L for men and 4.5 � 10 6 / μ L for women may be more accurate than using the derived Hct. In addition, terms such as “ masked ” PV [15] further obfuscate the diagnosis and pathogenesis of PV due to an emphasis on Hb values rather than the RBC, fi rst employed by Sir William Osler [16].

Acknowledgments

Th is study was supported in part by the William and Judy Higgins Trust of the Cancer Research and Treatment Fund, Inc., New York, NY, USA. We acknowledge and thank Paul Christos, Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research for statisti-cal advice and Vasilios Avlonitis, Department of Nuclear Medicine for technical assistance .

Richard T. Silver. MD designed the study, cared for the patients, reviewed smears, analyzed data and wrote the paper .

Stefani Gjoni collected specimen, analyzed data and wrote the paper .

Potential confl ict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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and intensity of treatment in polycythemia vera . N Engl J Med 2013 ; 368 : 22 – 33 .

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Barbui T , Th iele J , Vannucchi AM , et al . Rethinking the diagnostic [3] criteria of polycythemia vera . Leukemia 2014 ; 28 : 1191 – 1195 .

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Jacob G , Raj SR , Ketch T , et al . Postural pseudoanemia: posture-[5] dependent change in hematocrit . Mayo Clin Proc 2005 ; 80 : 611 – 614 .

Sebok MA , Notari EP , Chambers LA , et al . Seasonal temperature [6] variation and the rate of donor deferral for low hematocrit in the American Red Cross . Transfusion 2007 ; 47 : 890 – 894 .

Cable RG , Steele WR , Melmed RS . Th e diff erence between [7] fi ngerstick and venous hemoglobin and hematocrit varies by sex and iron stores . Transfusion 2012 ; 52 : 1031 – 1040 .

Spivak J , Silver RT . Th e revised World Health Organization diagnostic [8] criteria for polycythemia vera, essential thrombocytosis and primary myelofi brosis: an alternative proposal . Blood 2008 ; 112 : 231 – 239 .

Silver RT , Chow W , Orazi A , et al . Evaluation of WHO criteria [9] for diagnosis of polycythemia vera: a prospective analysis . Blood 2013 ; 122 : 1881 – 1886 .

Pearson TC . Rheology of the absolute polycythaemias . Balliere ’ s [10] Clin Haematol 1987 ; 1 : 637 – 664 .

Pearson TC , Botterill CA , Glass UH , et al . Interpretation of [11] measured red cell mass and plasma volume in males with elevated venous PCV values . Scand J Hematol 1984 ; 33 : 68 – 74 .

Guthrie DL , Pearson TC . PCV measurement in the management [12] of polycythaemic patients . Clin Lab Haematol 1982 ; 4 : 257 – 265 .

Ellis JT , Silver RT , Coleman M , et al . Th e bone marrow in [13] polycythemia vera . Semin Hematol 1975 ; 12 : 433 – 444 .

Pearson TC . Apparent polycythaemia . Blood Rev 1991 ; 5 : 205 – 213 . [14] Barbui T , Th iele J , Gisslinger H , et al . Masked polycythemia vera [15]

(mPV): results of an international study . Am J Hematol 2014 ; 89 : 52 – 54 . Osler W . Chronic cyanosis, with polycythaemia and enlarged [16]

spleen: a new clinical entity . Am J Med Sci 1903 ; 126 : 187 – 201 .

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Figure 1. Derived Hct vs. RBC count in (a) normocytic and (b) microcytic patients.

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