174 Polycythemia Vera
Review
Polycythemia Vera: A Comprehensive Review and Clinical Recommendations
AYALEW TEFFERI, MD
More than a century has elapsed since the appearance of
the modern descriptions of polycythemia vera (PV). Dur-
ing this time, much has been learned regarding disease
pathogenesis and PV-associated molecular aberrations.
New information has allowed amendments to traditional
diagnostic criteria. Phlebotomy remains the cornerstone
treatment of PV, whereas myelosuppressive agents may
augment the benefit of using phlebotomy for thrombosis
prevention in high-risk patients. Excessive aspirin use is
contraindicated in PV, although the use of lower-dose aspi-
rin has been shown to be safe and effective in alleviating
microvascular symptoms including erythromelalgia and
headaches. Recent studies have shown the utility of selec-
tive serotonin receptor antagonists for treating PV-associ-
ated pruritus. Nevertheless, many questions remain unan-
swered. What is the specific genetic mutation or altered
molecular pathway that is causally related to the disease?
In the absence of a specific molecular marker, how is a
working diagnosis of PV made? What evidence supports
current practice in the management of PV? This article
summarizes both old and new information on PV; pro-
T he clinical phenotype of polycythemia vera (PV)
(plethora, engorged veins) was appreciated long be-
fore the disease was formally described by Vaquez1 in 1892
and subsequently by Osler2 in 1903.3-7 By 1910, it was
evident that erythrocytosis in PV was often associated with
leukocytosis, thrombocytosis, and panmyeloid hyperplasia
of the bone marrow.8-10 The development of myelofibrosis
and acute leukemia as part of the natural history of PV was
first reported in 1935 and 1938, respectively.11,12
In 1951, Dameshek13 classified PV as a chronic myelo-
proliferative disorder (CMPD) along with other related
myeloid disorders, including chronic myeloid leukemia
(CML) and agnogenic myeloid metaplasia (AMM), be-
cause of similarities in both clinical and laboratory fea-
tures. Between 1967 and 1981, Fialkow et al14-21 showed
that CMPDs are biologically interrelated on the basis of
being clonal stem cell disorders with involvement of both
myeloid and lymphoid lineage.
Phlebotomy used as treatment of PV was recommended
by Osler22 in the first decade of the 20th century. During
From the Division of Hematology and Internal Medicine, Mayo Clinic,
Rochester, Minn.
Address reprint requests and correspondence to Ayalew Tefferi, MD,
Division of Hematology, Mayo Clinic, 200 First St SW, Rochester,
MN 55905 (e-mail: tefferi.ayalew@mayo.edu).
Mayo Clin Proc. 2003;78:174-194
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Mayo Clin Proc, February 2003, Vol 78
poses a modern diagnostic algorithm to formulate a work-
ing diagnosis; and provides recommendations for patient
management, relying whenever possible on an evidence-
based approach.
Mayo Clin Proc. 2003;78:174-194
ACE = angiotensin-converting enzyme; ADP = adenosine di-
phosphate; AMM = agnogenic myeloid metaplasia; CML =
chronic myeloid leukemia; CMPD = chronic myeloprolifera-
tive disorder; COPD = chronic obstructive pulmonary dis-
ease; EORTC = European Organisation for Research and
Treatment of Cancer; EPO = erythropoietin; EPOR = EPO
receptor; ET = essential thrombocythemia; GP = glycopro-
tein; IFN-αα = interferon α; IGF-1 = insulin-like growth factor
1; MMM = myelofibrosis with myeloid metaplasia; 32P = radio-
active phosphorus 32; PRTE = post–renal transplant erythro-
cytosis; PRV-1 = polycythemia rubra vera-1; PTP = protein
tyrosine phosphatase; PV = polycythemia vera; PVSG = Poly-
cythemia Vera Study Group; RCM = red blood cell mass;
SH2 = Src (family of tyrosine kinases) homology 2; SP =
secondary polycythemia; STAT = signal transducer and acti-
vator of transcription; TPO = thrombopoietin
this early period, external beam irradiation of the spleen,
long bones, and vertebrae also was being used in the treat-
ment of PV23 until the introduction of intravenous therapy
with radioactive phosphorus 32 (32P) by Lawrence24 in
1938. By the early 1950s, alkylating agents and antime-
tabolites were introduced to the therapeutic armamen-
tarium of PV, and the additional benefit of these agents in
reducing thrombotic complications was touted.25 However,
questions were raised and needed to be resolved about the
validity of such claims as well as the possible leukemoge-
nicity of both 32P and chemotherapeutic agents.26 This and
other factors led to the formation of an international Poly-
cythemia Vera Study Group (PVSG) in 1967, under the
auspices of the National Cancer Institute with Dr Louis R.
Wasserman as principal investigator.27 The objectives of
the PVSG were to describe the natural history of PV and
to define optimal therapy through the institution of long-
term therapeutic trials. It is reasonable to consider the
period that started with the PVSG studies as the modern era
in PV.
CURRENT DISEASE CLASSIFICATION
Discordant with the traditional scheme proposed by
Dameshek,13 current classification systems consider CML
separate from the other CMPDs because of its specific
174 © 2003 Mayo Foundation for Medical Education and Research
Mayo Clin Proc, February 2003, Vol 78 Polycythemia Vera 175

Figure 1. Operational classification of the chronic myeloid disorders. *Atypical chronic

myeloid disorders include chronic neutrophilic leukemia, chronic eosinophilic leukemia/
hypereosinophilic syndrome, systemic mast cell disease, juvenile myelomonocytic leuke-
mia, chronic myelomonocytic leukemia, and a chronic myeloid process that displays
overlapping features of both myelodysplastic syndrome and chronic myeloproliferative
disorder. Reprinted with permission from Tefferi.31 Copyright ©2000 Massachusetts Medi-
cal Society. All rights reserved.

association with the Philadelphia chromosome transloca-
tion (bcr-abl tyrosine kinase)28 as well as its unique treat-
ment response to both interferon α (IFN-α)29 and imatinib
mesylate.30 Therefore, the term chronic myeloproliferative
disorder is currently reserved for only PV, essential throm-
bocythemia (ET), and myelofibrosis with myeloid meta-
plasia (MMM). However, the CMPDs are joined by CML
and myelodysplastic syndrome as members of a broader
category of chronic myeloid disorders that also includes a
fourth category that groups unclassified myeloprolifera-
tive/myelodysplastic disorders, chronic myelomonocytic
leukemia, juvenile myelomonocytic leukemia, hyper-
eosinophilic syndrome, systemic mast cell disease, and
chronic neutrophilic leukemia under an operational desig-
nation of atypical chronic myeloid disorders (Figure 1).31
All 3 CMPDs, including PV, are characterized by vari-
able degrees of bone marrow hypercellularity and atypical
megakaryocytic hyperplasia and clustering.32 In addition,
all 3 disorders may or may not display splenomegaly,
leukocytosis, thrombocytosis, and clonal cytogenetic ab-
normalities. The clinical distinction among the CMPDs is
made by the demonstration of clonal erythrocytosis in
PV,26 substantial bone marrow fibrosis in AMM,31 and
clonal thrombocytosis that is not associated with either
erythrocytosis or high-grade myelofibrosis in ET.33,34
Note that currently there is no specific disease marker,
molecular or otherwise, for PV or the other CMPDs and
that a working diagnosis is made on the basis of the
constellation of clinical and bone marrow histological
findings.
EPIDEMIOLOGY
Population-based epidemiological studies done in Roches-
ter, Minn, have suggested a stable incidence trend for PV of
approximately 2.3/100,000.35,36 Other studies have reported
either similar37,38 or lower39-43 incidence figures. A higher
disease incidence has been suggested in persons of Jewish
ancestry44-48 and among parent-offspring pairs.49,50 Median
age at diagnosis of PV is approximately 60 years with a
slight (1.2:1) male preponderance.51 Approximately 7% of
patients are diagnosed before age 40 years,51 and children
are rarely diagnosed with PV.52-54

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176 Polycythemia Vera
No strong evidence supports disease association with
environmental exposure,55 although an excess risk has been
suggested in embalmers and funeral directors,56 as well as
in persons exposed to benzene,57 petroleum refineries,58
and low doses of radiation.59 In contrast to patients with
acute leukemias and CML,60 a high risk of developing PV
in atomic-bomb survivors of Hiroshima and Nagasaki has
not been shown.
PATHOGENETIC MECHANISMS
Origin of the PV Clone
It is now well established that PV is a clonal stem cell
disease with trilineage myeloid involvement.16,61 However,
some studies have suggested clonal heterogeneity includ-
ing clonal involvement of B lymphocytes62 and polyclonal
granulopoiesis in certain patients.63-66 Also, normal he-
matopoietic stem cells are known to coexist with clonal
stem cells in PV and may gain growth advantage under
experimental conditions.67,68 Regardless, unlike with CML,
the clonogenic molecular lesion in PV remains elusive.
Recall that cytogenetic studies have played a major role in
deciphering the causal genetic mutation in CML.28,69-73
However, karyotypic abnormalities in PV are infrequent
(13%-18% in chemotherapy-naïve patients) and nonspe-
cific, and they include trisomies of chromosomes 9 and 8
and deletions of the long arms of chromosomes 13 and
20.74-76 Not surprisingly, these chromosomes were targeted
for further studies that showed cryptic interstitial deletions
on chromosome 20q,66 9p chromosomal gains that are not
apparent by conventional techniques,77,78 and a high inci-
dence of heterozygosity loss involving chromosome 9p.79
Whether further inquiry into these preliminary observa-
tions leads to specific pathogenetic information remains to
be seen.
Growth Factor Independence and Hypersensitivity
of Erythroid Progenitor Cells
A frequent area of pathogenetic investigation in PV
involves erythropoietin (EPO) and its relationship to the
growth of erythroid progenitor cells in affected patients. It
has been almost 30 years since the initial observation that
in vitro erythroid colony formation in patients with PV may
require no additional exogenous EPO, unlike in normal
controls or in patients with secondary polycythemia (SP).80
However, reports conflict about whether clonal erythroid
growth in PV is completely independent of EPO81-83 or
retains some degree of EPO dependency including hyper-
sensitivity.84-86 Regardless, several studies have shown that
the particular phenomenon is not specific to PV, EPO, or
erythroid progenitor cells.
For example, endogenous (ie, without the addition of
exogenous growth factors) erythroid and megakaryocyte
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Mayo Clin Proc, February 2003, Vol 78
colony formation has been shown not only in PV87 but
also in other CMPDs, including ET88-90 and MMM.88 Simi-
larly, growth factor hypersensitivity of clonal progenitor
cells has been shown in ET,91 whereas erythroid progenitor
cells in PV display growth factor hypersensitivity also
to insulin-like growth factor (IGF)-1,92 interleukin 3,86,93
granulocyte-monocyte colony-stimulating factor,94 stem
cell factor,95 and thrombopoietin (TPO).96 The consistently
observed IGF-1 hypersensitivity of erythroid cells in PV
has been attributed to alterations in IGF-1 binding pro-
teins.97 Regardless, the phenomena of growth factor in-
dependence and hypersensitivity may be nonspecific,
intrinsic cell properties that are generic to many clonal
processes.
Molecular Studies At and Beyond the Level of the
EPO Receptor
Signal transducers that are important in physiological,
EPO-dependent erythropoiesis involve both enhancing
and regulatory molecules and include the EPO recep-
tor (EPOR),98,99 Janus kinase 2,100 signal transducers and
activators of transcription (STATs; STAT1, STAT3,
STAT5),101-105 Src (family of tyrosine kinases) homology 2
(SH2) domain-containing protein tyrosine phosphatases
(SH-PTPs; SH-PTP1, SH-PTP2),106 Src,107 phosphoino-
sitide 3 kinase,108 and mitogen-activated protein kinases
and their kinases.109 Therefore, a defect in any one of these
molecules could conceivably underlie EPO-independent
erythroid proliferation.
Regarding the EPOR, both its encoding gene and its
structure have been shown to be intact in PV,110-112 in con-
trast to those of some forms of familial polycythemia in
which EPOR is truncated at the C-terminal as a result of
EPOR gene mutations.113-117 Such modification of the
EPOR structure is believed to enhance signal transduction
as a result of the loss of a regulatory domain that is nor-
mally located distal to the truncation site. It is interesting
but not verified that expression of differentially truncated
EPOR isoforms that result from alternative splicing may
play a role in the pathogenesis of PV.118
Post–receptor molecular variations that have been re-
ported in PV include increased baseline phosphorylation of
the IGF-1 receptor,119 decreased activity of SH-PTP1,120
increased activity of membrane-associated SH-PTP,121
constitutive activation of STAT3,122 up-regulation of nega-
tive control elements of the cell cycle (p16/p14),123 and an
abundance of antiapoptotic proteins (Bcl-xL) in erythroid
precursors.124 Similarly, constitutive activation of phospho-
inositide 3 kinase has been shown in EPO-independent
erythroid cells that are infected with Friend spleen focus-
forming virus.125 Furthermore, mice that genetically lack
SH-PTP activity as a result of an SHP-1 null mutation
Mayo Clin Proc, February 2003, Vol 78
(motheaten) or deletion of the catalytic domain of SHP-1
(motheaten viable) display among other abnormalities a
PV phenotype (increased myelopoiesis and growth factor
hypersensitivity of myeloid cells including erythroid pro-
genitors).126 However, it is currently difficult to formulate a
unifying hypothesis on the pathogenesis of PV on the basis
of the aforementioned observations because they are often
isolated, may represent nonspecific events in a clonal cell
regardless of cell type, and are not always reproduced by
other investigators.97,122,127
TPO and the TPO Receptor in PV
Thrombopoietin is the key growth factor for physiologi-
cal megakaryocytopoiesis and is essential for platelet
production.128-132 Normal TPO production is constitutive,133
and circulating TPO is regulated by TPO receptor (c-mpl)–
mediated platelet binding, internalization, and catabo-
lism.134-138 As such, plasma TPO levels usually are inversely
proportional to total megakaryocyte/platelet mass.139,140
However, in PV and other CMPDs, plasma levels of
TPO are either elevated or normal, despite the associated
increase in megakaryocyte/platelet mass.141-145 This cur-
rently is believed to be the result of a defective TPO
clearance caused by an abnormally reduced membrane
expression of c-mpl in PV and other CMPDs. This phe-
nomenon was first reported in ET146 and subsequently in
PV147 and in other CMPDs.148,149 In ET, the decreased
surface expression of c-MPL has been associated with
reduced c-mpl transcription.146,150 In PV, the particular de-
fect was traced to a posttranslational hypoglycosylation
of the c-mpl protein with derailment of membrane local-
ization.151 Although markedly decreased megakaryocyte
c-mpl expression may complement morphologic diagno-
sis in PV and ET, its pathogenetic relevance remains
unclear.152,153
Polycythemia Rubra Vera-1 Gene
The polycythemia rubra vera-1 (PRV-1) gene was re-
cently described as a novel gene that is highly expressed in
granulocytes of patients with PV but not in granulocytes of
normal controls or of patients with secondary erythrocyto-
sis.154 Examination of the open reading frame of the
complementary DNA that is synthesized from the PRV-1
transcript suggested that that particular gene encodes for a
cell surface receptor with homology to the Ly-6 gene fam-
ily that includes the urokinase-type plasminogen activator
receptor and reactive inhibitor of lysis receptor (CD59).
Subsequently, it was shown that the PRV-1 gene was
highly homologous to that of human neutrophil antigen-2
(CD117), suggesting that the two may not be separate
genes but alleles of the same gene.155 PRV-1 expression has
also been shown in normal bone marrow, granulocyte
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Polycythemia Vera 177
colony-stimulating factor stimulated granulocytes, and
granulocytes of some patients with ET or MMM.154 Obvi-
ously, more studies are needed to decipher the pathogenetic
relevance of PRV-1 in PV.
Pathogenetic Mechanisms of Thrombosis and
Bleeding in PV
During the pre-phlebotomy era, thrombosis was the ma-
jor cause of death in patients with PV, and the median life
expectancy was less than 2 years.156 The marked improve-
ment in median survival (≥10 years) with aggressive phle-
botomy established the primary role of increased hemat-
ocrit in PV-associated thrombosis. How does increased
hematocrit enhance thrombus formation in PV?
In vitro, hematocrit has been shown to be the major
determinant of whole blood viscosity, especially at low
shear rates.157 However, in vitro observations do not neces-
sarily reflect in vivo events because of several confounding
variables including the different flow dynamics in blood
vessels and the strong relationship between hematocrit and
oxygen transport. As a result, the effect of hematocrit on in
vivo blood viscosity is lower than that suggested by in vitro
studies.157 For example, in vivo, increased hematocrit is
associated with a decreased cerebral blood flow rate,158 not
because of the change in viscosity but because of the
change in arterial oxygen content.159 Furthermore, although
venesection in patients with PV may reduce whole blood
viscosity, it does not necessarily result in improved tissue
oxygenation.160 Therefore, the relationship between throm-
bosis and high hematocrit in patients with PV represents a
more complex scenario with multiple physical and chemi-
cal factors.
At low shear rates, which are comparable to flow rates
in large veins, the endothelial displacement of platelets and
leukocytes and other proteins from the axial migration of
red blood cells might enhance thrombogenic interaction
between endothelial cells and platelets.161 A different
mechanism that involves platelets, leukocytes, and red
blood cell–derived platelet aggregates such as adenosine
diphosphate (ADP) might contribute to thrombosis at high-
shear-rate conditions, which are comparable to flow in
arterioles and other small vessels. Such aberrations com-
bined with decreased flow rates induced by high hematocrit
values might explain the beneficial effect of phlebotomy in
patients with PV.161,162
Phlebotomy substantially reduces but does not abolish
the risk of thrombosis in patients with PV. Therefore, fac-
tors other than hematocrit (platelets, leukocytes, endothe-
lial cells, coagulation proteins) might contribute to throm-
bosis risk in these patients. Although about half of patients
with PV display either thrombocytosis or leukocytosis, the
risk of thrombosis in such patients has not been correlated
178 Polycythemia Vera
with either platelet or white blood cell count.163 In con-
trast, various potentially thrombogenic, qualitative cell de-
fects have been described and include a diminished re-
sponse of platelet adenylate cyclase to prostaglandin D2
(a physiological inhibitor of platelet aggregation),164 an
increased baseline platelet production of thromboxane A2
(a platelet aggregate),165,166 and abnormal in vivo activation
of leukocytes,167 endothelial cells,167,168 and platelets.166,168
Furthermore, previous reports of widespread activation in
coagulation proteins,167 reduced levels of physiologic an-
ticoagulants (antithrombin III, proteins C and S),169,170 and
decreased fibrinolytic activity171 that in part may be sec-
ondary to increased plasma levels of plasminogen activa-
tor inhibitor 1172 suggest a baseline pro-thrombotic state in
PV.
In a recent study of patients with PV, the presence of the
PIA2 allele of platelet glycoprotein (GP) IIIa was associated
with an increased risk of arterial thrombosis, whereas al-
tered polymorphisms in either other platelet GPs (GP Ib,
GP Ia) or coagulation proteins (factors II [prothrombin]
and V [proaccelerin]) were not detected.173 It was interest-
ing but not easily explained to note a statistically signifi-
cant correlation in that study between the occurrence of the
factor II G20210A mutation and the presence of microvas-
cular disturbances in patients with either ET or PV. These
events, which include erythromelalgia (see “Microvascular
Disturbances Including Erythromelalgia” section), previ-
ously have been associated with both platelet-mediated
arteriolar inflammation174,175 and increased thromboxane
production.176
Pro-hemorrhagic platelet defects in PV include poor
platelet aggregation in response to various platelet agonists
including thrombin, ADP, epinephrine, collagen, throm-
boxane A2, and platelet-activating factor177-180; abnormally
low intraplatelet levels of adenine nucleotides and seroto-
nin181; reduced platelet factor X–activating activity182; de-
fective platelet lipid peroxidation183; impaired binding to
fibrinogen as a result of decreased GP IIb/IIIa expres-
sion184; and acquired von Willebrand disease.185 Acquired
von Willebrand disease occurs in more than a third of
patients with PV and has been associated with a bleeding
diathesis.186,187 Acquired von Willebrand disease in myelo-
proliferative disorders is associated with decreased large
von Willebrand factor multimers and increased cleavage
products of the same, which suggests removal by proteoly-
sis.185 Furthermore, because the particular abnormality is
characteristically associated with extreme thrombocyto-
sis188,189 and corrects with platelet count normalization,189 it
is believed that the pathogenesis involves abnormal ad-
sorption of the large von Willebrand proteins to clonal
platelets, which effectively exposes protein cleavage sites
and enhances proteolysis.190
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Mayo Clin Proc, February 2003, Vol 78
DIAGNOSIS
Definitions
In conventional terminology, polycythemia refers to ei-
ther a real (true polycythemia) or spurious (apparent poly-
cythemia) increase in erythrocyte volume, ie, red blood cell
mass (RCM). True polycythemia may represent either a
clonal myeloproliferative disorder (PV) or a nonclonal in-
crease in RCM that is often, but not always, mediated by
EPO (SP). Apparent polycythemia may result from either a
reduction in plasma volume (relative polycythemia) or an
inaccurate perception of an elevated hemoglobin/hemat-
ocrit value that results from not appreciating extreme nor-
mal values that exceed the 95th percentile range of refer-
ence intervals (Figure 2).191,192 Inapparent polycythemia
vera is the converse of apparent polycythemia and indi-
cates a true increase in RCM that is masked by a normal
hemoglobin/hematocrit value secondary to a concomitant
increase in plasma volume (Figure 2).193
Distinguishing Apparent From True Polycythemia
Obviously, familiarity with sex- and race-adjusted nor-
mal values as well as the realization that hemoglobin/
hematocrit values in some individuals may fall outside the
2 SD range for normal values should prevent unnecessary
testing, including RCM measurements, in many suspected
cases.192 Similarly, most factors that cause plasma volume
depletion (ie, relative polycythemia) are clinically obvious
(severe dehydration, diarrhea, vomiting, diuretics use, cap-
illary leak syndrome, severe burns, etc) and do not require
specialized tests for diagnostic confirmation of the relative
polycythemia. Again, it is inappropriate to perform RCM
measurements in such instances.
The existence of both a chronic and a subtle state of
contracted plasma volume is controversial.194 In this regard,
both Gaisböck syndrome (relative polycythemia associated
with hypertension and nephropathy)195 and stress poly-
cythemia (relative polycythemia associated with emotional
stress)196 are poorly understood, and the general concept
has little foundation. In a series of 109 consecutive RCM
and plasma volume measurements performed at the Mayo
Clinic in Rochester, Minn, no patients with relative poly-
cythemia were identified.197 In contrast, smoker’s poly-
cythemia is real and is secondary to chronic exposure to
carbon monoxide, and the polycythemia resolves with dis-
continuation of the habit.198 Again, the use of RCM mea-
surements in the aforementioned instances may be unnec-
essary in light of the availability of modern diagnostic tests
for differentiating apparent polycythemia from PV.
Secondary Polycythemia
Secondary polycythemia may or may not be EPO medi-
ated (Table 1115,198-224). Erythropoietin-mediated SP may be
Mayo Clin Proc, February 2003, Vol 78
Figure 2. The relationship of red blood cell mass and plasma volume in the varieties of poly-
cythemias. Hct = hematocrit.
classified into a hypoxia-driven or hypoxia-independent
process (Table 1). In hypoxia-driven SP (Table 1), the
serum EPO level often is increased initially but may return
to within the normal reference range once the hemoglobin
level has stabilized at a higher level.200,201,225 Hypoxia-inde-
pendent EPO production stems from either malignant or
benign tumor tissue (renal cancer, uterine leiomyoma,
pheochromocytoma, meningioma, etc)209,212,214,215 or a con-
genital process that is believed to result from either an
abnormally elevated set point for EPO production216,226,227
or abnormal oxygen homeostasis (Chuvash polycy-
themia).217 Often, serum EPO levels are increased in these
hypoxia-independent processes. Chuvash polycythemia is
endemic in Russia,228 and the disease gene has been as-
signed to chromosome 11 by one group229 and chromosome
3 by another.217 The latter study suggests the presence of a
mutation in the von Hippel-Lindau gene in Chuvash poly-
cythemia; interestingly, other patients with germline muta-
tions of the von Hippel-Lindau tumor-suppressor gene
have experienced SP after treatment with antiangiogenic
therapy.230
Other cases of SP may be EPOR mediated,218,231 second-
ary to exogenous administration of erythropoietic drugs
(EPO, androgen preparation)219,220,232 or related to as yet un-
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Polycythemia Vera 179
explained mechanisms (some cases of congenital polycy-
themia, post–renal transplant erythrocytosis [PRTE]).221,223,228
Some, but not most, patients221 with autosomal-dominant
congenital polycythemia carry an activating mutation of
the EPOR gene that results in a C-terminal–truncated re-
ceptor that is more efficient in signal transduction, possibly
because of defective recruitment of regulatory phospha-
tases.113,115,116,218 The serum EPO level is usually low in such
patients. However, mutations of the EPOR are not found in
most patients with autosomal-dominant congenital poly-
cythemia.221 Serum EPO levels may be either elevated or
normal in PRTE. The pathogenesis of PRTE may involve
EPO hypersensitivity of erythroid progenitor cells224 that
may or may not be related to the increase in IGF-1 and its
binding proteins in these patients.233
Diagnosing PV
In 1975, the PVSG published a set of diagnostic criteria
to ensure that patients with SP or apparent polycythemia
are excluded from treatment protocols.234 These criteria
required the demonstration of increased RCM by blood
volume measurement using labeled erythrocytes and the
demonstration of normal hemoglobin oxygen saturation. It
is therefore immediately apparent that some patients with
180 Polycythemia Vera Mayo Clin Proc, February 2003, Vol 78

Table 1. Classification of Polycythemia* nostic criteria (splenomegaly, leukocytosis, thrombocyto-

Apparent polycythemia sis, elevated leukocyte alkaline phosphatase, and increased
Relative polycythemia serum vitamin B12 level or unbound vitamin B12 binding
Extreme “high-normal” values capacity) lack both sensitivity and specificity. Subsequent
True polycythemia
Polycythemia vera identification and clinical application of PV-specific bio-
Secondary polycythemia logical parameters have allowed further refinements in the
EPO mediated original PVSG diagnostic criteria. Such revised PVSG cri-
Hypoxia driven
Central hypoxic process teria have increased diagnostic accuracy but have added
Chronic lung disease199 complexity to the diagnostic process.235-237
Right-to-left cardiopulmonary vascular shunts200 In the absence of a disease-specific positive marker,
High-altitude habitat201
Carbon monoxide poisoning202 such as with CML, it is reasonable to use disease-character-
Smoker’s polycythemia (long-term carbon monoxide istic biological and histological features to formulate a
exposure)198 working diagnosis of PV. Two such tests that are widely
Hypoventilation syndromes including sleep apnea203
Peripheral hypoxic process available to routine clinical practice include the determina-
Localized tion of serum EPO and the examination of bone marrow
Renal artery stenosis204 histology. With use of these 2 tests, a diagnostic algorithm
Diffuse
High oxygen-affinity hemoglobinopathy (Figure 3), rather than a set of diagnostic criteria, can be
(congenital; autosomal-dominant)205 followed to make a working diagnosis of PV. In the pro-
2,3-Diphosphoglycerate mutase deficiency cess, the information from RCM determination is seldom
(congenital; autosomal-recessive)206
Hypoxia independent (pathologic EPO production) required. Regarding RCM measurement, it is once again
Malignant tumors underscored that (1) a normal-range RCM reading does not
Hepatocellular carcinoma207,208 rule out the possibility of PV since it misses the PV popula-
Renal cell cancer209
Cerebellar hemangioblastoma210 tion that is distributed at the left extreme tail of the
Parathyroid carcinoma211 Gaussian distribution of RCM values for PV patients; (2)
Nonmalignant conditions the measurement of RCM in the presence of a hematocrit
Uterine leiomyomas212
Renal cysts (polycystic kidney disease)213 level higher than 60% and in the absence of a clinically
Pheochromocytoma214 obvious hemoconcentration is a costly redundancy since
Meningioma215 RCM is almost always increased in such cases; and (3) the
Abnormally elevated set point for EPO production
(congenital)216 likelihood of an otherwise isolated hematocrit level less
Chuvash polycythemia (congenital; abnormal oxygen than 60% to be secondary to PV, in the absence of other
homeostasis?)217 PV-related features, is extremely low and can be addressed
EPOR mediated
Activating mutation of the EPOR by more practical and cost-effective biological tests such as
Some cases of autosomal-dominant congenital serum EPO level (described subsequently). In contrast, if
polycythemia115,218 an upper-normal hematocrit value is associated with a PV-
Drug associated
EPO doping219 related feature, the diagnosis of PV should be pursued with
Treatment with androgen preparations220 more sensitive biological tests, including in some patients a
Unknown mechanisms bone marrow examination, regardless of the measured
Most cases of autosomal-dominant congenital polycythemia221
Some forms of autosomal-recessive congenital polycythemia222 RCM value.
Post–renal transplant erythrocytosis223,224 The first step in the diagnostic evaluation of PV is to
*EPO = erythropoietin; EPOR = EPO receptor. determine whether this diagnosis should be suspected. The
diagnostic possibility of PV may be entertained only if (1)
the hemoglobin/hematocrit level is higher than the 95th
PV may not fulfill these “study requirements” because (1) percentile of the normal distribution adjusted for sex and
their measured RCM value lies at the extreme left tail of the race, (2) there is a documented increase in the hemoglobin/
Gaussian distribution of RCM values for PV and overlaps hematocrit level above the baseline for an individual pa-
the upper normal values of the reference range; (2) the tient, regardless of where the specific hematocrit level lies
pathologic baseline RCM value of a specific PV patient within the reference range, or (3) a PV-related feature
may be lowered to within the normal reference range by a (thrombocytosis, leukocytosis, microcytosis from iron de-
superimposed iron deficiency or bleeding; or (3) a patient ficiency, splenomegaly, aquagenic pruritus, unusual throm-
with PV may also have an unrelated comorbid condition bosis including Budd-Chiari syndrome, erythromelalgia)
that causes hypoxia (eg, a patient can have both PV and accompanies a borderline-high hematocrit value. Other-
chronic lung disease). Furthermore, the other PVSG diag- wise, a repeated blood test in 3 months should suffice.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, February 2003, Vol 78 Polycythemia Vera 181

In the presence of one of the aforementioned three sce-

narios, it is reasonable to start the diagnostic work-up by Serum erythropoietin
determining the serum EPO level (Figure 3). In general,
serum EPO levels are low in PV, even in the presence of
treatment with phlebotomy (Figure 4).238-241 However, se- Low Normal High
rum EPO levels also can be low in other CMPDs including
ET241-243 and rare cases of congenital polycythemia with
activating mutation of the EPOR.115 Therefore, a low serum PV diagnosis PV diagnosis Evaluate for
EPO level is highly suggestive but not diagnostic of PV probable possible secondary
(estimated specificity of >90%).244 In contrast, the serum polycythemia
EPO level may lie within the reference range in patients
with a definite diagnosis of PV (a sensitivity of a low serum
EPO level for PV is estimated to be <70%) (Figure 4).244,245 Bone marrow
However, PV is unlikely to be associated with an increased biopsy
serum EPO level.244 Therefore, PV remains a diagnostic
consideration in the presence of either a low or normal
serum EPO level. Histology
The next step is bone marrow examination with cytoge- characteristic
for PV?
netic studies (Figure 3). Bone marrow histology, to the
experienced hematopathologist, often reveals characteris- Yes No
tic changes that include hypercellularity, increased number
of megakaryocytes including cluster formation, the pres- PV Specialized
testing*
ence of giant megakaryocytes and pleomorphism in mega-
karyocyte morphology, mild reticulin fibrosis (in 12% of
patients), and decreased bone marrow iron stores.246 In
Consistent Not
contrast, cytogenetic studies disclose abnormalities (triso- with consistent
mies of chromosomes 9 and 8 and deletions of the long arms PV with PV
of chromosomes 13 and 20) in only 13% to 18% of patients
at diagnosis and hence have limited diagnostic value.74-76
In equivocal cases, which should constitute no more PV Reevaluate
than 10% of the patients seen in routine clinical practice, in 3 mo
additional specialized tests may be necessary to confirm
the working diagnosis of PV. Combined with a bone
marrow morphologic assessment, the demonstration of Figure 3. A practical algorithm for the diagnosis of polycythemia
markedly decreased megakaryocyte expression of the TPO vera (PV). Specialized testing includes bone marrow immunohis-
tochemistry for the thrombopoietin receptor (c-mpl), reverse tran-
receptor (c-mpl) supports the diagnosis of PV.147,152 Simi- scriptase-polymerase chain reaction for neutrophil expression of
larly, a recent study has suggested the possibility of using a the polycythemia rubra vera-1 gene, and spontaneous erythroid
peripheral blood neutrophil assay for PRV-1 expression to colony assay. *Note that most PV can be diagnosed by clinical
distinguish PV (high expression) from SP (not detect- and bone marrow histological parameters and does not require
able).154 Finally, although their value in distinguishing PV specialized testing. Furthermore, none of the 3 specialized tests can
differentiate PV from other myeloproliferative disorders, and their
from SP has been shown in both prospective247 and retro- sensitivity and specificity in distinguishing PV from secondary or
spective248 studies, I rarely use spontaneous (endogenous) apparent polycythemia have not been tested rigorously in an ad-
erythroid colony assays for the diagnosis of PV because of equate number of prospective, well-designed studies that include
their limited availability and the need for considerable enough patients to make statistically valid conclusions. A limited
expertise. Furthermore, as is the case with c-mpl immuno- number of such studies support the usefulness of these specialized
tests in complementing, but not substituting for, other diagnostic
histochemistry, a negative test result does not necessarily procedures.
exclude a diagnosis of PV.248

MANAGEMENT increased hematocrit, vascular events, and clonal evolution

Disease manifestations in PV that require treatment fall into MMM and acute leukemia. Non–life-threatening com-
into 2 major categories, life threatening and non–life plications of PV include constitutional symptoms, mi-
threatening. Life-threatening manifestations of PV include crovascular disturbances, and aquagenic pruritus.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
182 Polycythemia Vera
20
EPO (mU/mL)
18
<2.9
16 2.9-15.1
>15.1
14
No. of patients
12
10
8 1967 and 1978, the EORTC randomized 293 patients to
6
4
2 phlebotomy alone with a median survival of 12.6 years
0 compared with 10.9 and 9.1 years for treatment with 32P
10.1-12.0 12.1-14.0 14.1-16.0
Hemoglobin (g/dL)
Figure 4. Serum erythropoietin levels in 42 unselected patients
with polycythemia vera. EPO = erythropoietin. Reprinted with
permission from Blackwell Publishing.244
Prevention and Treatment of Life-Threatening
Complications in PV
Aggressive phlebotomy and modern supportive care are
primarily responsible for the currently observed marked
improvement in the median survival of patients (>10 years)
initially treated with phlebotomy alone.51 Earlier reports
suggested a median survival of less than 2 years in
nonphlebotomized patients with PV.12,156,249 Furthermore,
in a cohort of 250 patients seen between 1933 and 1961, a
median survival of less than 4 years was documented in
patients treated with nonaggressive venesection, and the
cause of death in most of these patients was thrombotic
complications.156 Aggressive phlebotomy defined as main-
taining the hematocrit level at lower than 45% was sug-
gested on the basis of a retrospective study of PV that
showed a progressive increase in the incidence of vascular
occlusive episodes at hematocrit levels higher than 44%.250
This contention is supported by other studies that showed
suboptimal cerebral blood flow in ranges of hematocrit
values between 46% and 52%.158 Because of the physi-
ological difference in hematocrit values between the sexes
as well as among different races,251-253 it is reasonable,
although not evidence based, to target an even lower he-
matocrit level (42%) in women and African Americans.
Nevertheless, phlebotomy in any patient, and especially in
those with cardiovascular disease, should be performed un-
der careful conditions with appropriate and monitored fluid
replacement to avoid both hypotension and fluid overload.254
Observations From Randomized Studies.—The first
2 randomized studies of PV were run concurrently by the
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, February 2003, Vol 78
PVSG26,163,255 and the European Organisation for Research
and Treatment of Cancer (EORTC).256-258 Between 1967
and 1974, the PVSG study randomized 431 patients with
actively proliferating PV to treatment with either phle-
botomy alone or phlebotomy supplemented with either oral
chlorambucil (10 mg/d for 6 weeks followed by a 30-day
rest and similar daily treatment every other month) or
intravenous 32P (2.3 mCi/m2) (ie, a 3-arm study). Between
treatment with either 32P (0.5-1.0 mCi/10 kg body weight)
or oral busulfan (4-6 mg/d for 4-6 weeks).
The results from the PVSG study favored treatment with
16.1-18.0 >18.0
and chlorambucil, respectively (P=.008). The difference in
survival was attributed to an increased incidence of acute
leukemia in patients treated with chlorambucil or 32P com-
pared with those treated with phlebotomy alone (13.2% vs
9.6% vs 1.5% for 13-19 years).163,259 Furthermore, 3.5% of
the patients treated with chlorambucil developed large cell
lymphoma, and incidences of gastrointestinal and skin can-
cers increased in patients treated with either chlorambucil
or 32P.260
Additional observations from the PVSG study included
the following: (1) a significantly higher incidence of
thrombotic events in the first 3 years in patients treated
with phlebotomy alone, (2) a lack of correlation between
thrombosis and either platelet count or hematocrit value,
and (3) a significant association between thrombosis risk
and patients either older than 70 years or with a history of
thrombosis. In addition, in patients treated with phle-
botomy alone, thrombosis risk was associated with an in-
creased frequency of phlebotomy (maintenance phle-
botomy of more than once every 3 months).
The results from the EORTC study favored busulfan to
32
P for both first remission duration (median, 4 years vs 2
years) and overall survival (10-year survival rates of 70%
vs 55%; P=.02). At a median follow-up of 8 years, there
were no significant differences in the risks of leukemic
transformation (2% vs 1.4%), nonhematologic malignancy
(2.8% vs 5%), vascular complications (27% vs 37%), or
transformation into MMM (4.8% vs 4.1%) between the
busulfan and 32P arms, respectively.257
In an effort to reduce the risk of thrombosis associated
with treatment by phlebotomy alone, the PVSG initiated
another randomized study in 1977 in which treatment with
intravenous 32P (2.7 mCi/m2) plus phlebotomy was com-
pared with treatment with phlebotomy plus high-dose aspi-
rin (900 mg/d) in combination with dipyridamole (225 mg/
d).261 Results showed that the addition of antiplatelet
agents, at the specific doses used, had no benefit in terms of
thrombosis prevention but increased the risk of gastrointes-
Mayo Clin Proc, February 2003, Vol 78
tinal bleeding. However, a more recent randomized study
of PV (112 patients) using a much lower dose of aspirin (40
mg/d) showed no increased bleeding diathesis.262 Further-
more, the results of the PVSG aspirin study may have been
influenced by the fact that 27% of the patients randomized
to the phlebotomy-aspirin-dipyridamole arm had a history
of thrombosis compared with 13% in the other arm. It is
hoped that an ongoing European Collaboration on Low-
dose Aspirin in Polycythemia Vera (ECLAP) study will
further clarify the role of low-dose aspirin in the treatment
of PV.
Other randomized studies of PV have compared hy-
droxyurea with pipobroman (a significant difference favor-
ing pipobroman in the incidence of transformation into
MMM but no difference in survival, incidence of thrombo-
sis, or the rate of leukemic conversion)263 and compared 32P
alone with 32P plus hydroxyurea (no difference in survival,
incidence of thrombosis, or risk of transformation into
MMM, but 32P alone was associated with significantly fewer
incidences of both acute leukemia and other cancers).264
The findings from these randomized studies indicate
that chlorambucil and 32P significantly shorten the survival
of patients with PV.255,257 The findings also suggest that
other cytoreductive agents including hydroxyurea, busul-
fan, and pipobroman may not have similar detrimental
effects on survival and maintain the apparently nonspe-
cific, antithrombotic benefit of myelosuppressive ther-
apy.257,263,265 Whether hydroxyurea, busulfan, and pipobro-
man increase the underlying risk of acute leukemia in PV
when used alone with phlebotomy is currently unknown,
and this issue can be addressed definitively only in the
setting of a controlled, randomized study. However, these
agents might contribute to leukemogenicity if used with
other leukemogenic drugs.264,266
Observations From Nonrandomized Studies.—Al-
though the use of chlorambucil or 32P was associated with
inferior survival, it resulted in a significantly reduced rate
of early thrombotic complications compared with that in
patients treated with phlebotomy alone.255 This led to the
exploration of presumably less leukemogenic drugs to re-
duce the risk of thrombosis. In a nonrandomized study by
the PVSG, treatment with hydroxyurea was associated with
a lower incidence of early thrombosis compared with a
historical cohort treated with phlebotomy alone (6.6% vs
14% at 2 years).265,267 Similarly, the incidence of acute
leukemia compared with a historical control treated with
either chlorambucil or 32P was significantly lower (5.9% vs
10.6% vs 8.3%, respectively, in the first 11 years of treat-
ment).163,268 A limited survey of other clinical trials that used
single-agent hydroxyurea in PV revealed leukemic conver-
sion rates of 1% (100 patients treated for 3-216 months)269
and 5.6% (71 patients treated for 1.5-15 years).270
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Polycythemia Vera 183
Many studies have reported the use of pipobroman as a
single agent in PV.266,271-273 In one of these studies involving
163 patients, the drug was effective in more than 90% of
the patients, and median survival exceeded 17 years.271 In
the first 10 years, the incidences of thrombotic events,
acute leukemia, MMM, and other malignancies were 16%,
5%, 4%, and 8%, respectively. In this group, female sex
and age older than 65 years were significantly associated
with thrombosis.
In addition to the information from an aforementioned
randomized study that included a treatment arm with busul-
fan alone,257 other single-arm studies have reported the
therapeutic value of busulfan in PV.274,275 In 65 busulfan-
treated patients with PV monitored between 1962 and
1983, overall median survival was 11.1 years; in patients
whose disease was diagnosed before the patients were age
60 years, overall median survival was 19 years.274 Only 2
patients (3%) treated with busulfan alone developed acute
leukemia.
Most recently, IFN-α276 and anagrelide277 were added to
the therapeutic armamentarium for PV. Interferon α has
been shown to control erythrocytosis in approximately
76% of the patients receiving subcutaneous drugs in doses
ranging from 4.5 to 27 million U per week (usual dosage is
3 million U subcutaneously 3 times a week).276,278,279 A
similar degree of benefit is appreciated in terms of reduc-
tion in spleen size or relief from intractable pruritus.
Anagrelide is an oral imidazoquinazoline derivative that
inhibits platelet aggregation at concentrations higher than
therapeutic drugs but displays a species-specific platelet-
lowering effect in humans at therapeutic concentrations.280
Anagrelide is capable of substantially reducing the platelet
count in more than 80% of patients with PV.281
In summary, the results from single-arm studies support
those from randomized studies and show that pipobroman
and busulfan are valuable treatment agents for PV and
might be considered alternatives to hydroxyurea. Pipobro-
man currently is unavailable in the United States. It is
unclear what value is gained by substituting the aforemen-
tioned traditional cytoreductive agents with the newer
drugs (ie, IFN-α and anagrelide), especially in view of the
newer drugs’ unfavorable toxicity and cost profile (Table
2).282 Furthermore, a recent retrospective study of PV
showed no evidence of a favorable effect in bone marrow
fiber content after treatment with IFN-α.283
Current Treatment Recommendations.—The main-
stay of therapy for all patients with PV is phlebotomy to
keep the hematocrit level below 45% in white men and the
appropriate corresponding values for females and those of
other races.158,250,284,285 In addition to treatment with aggres-
sive phlebotomy, cytoreductive chemotherapy should be
considered in patients who are at high risk for thrombosis
184 Polycythemia Vera Mayo Clin Proc, February 2003, Vol 78

Table 2. Clinical Properties of Drugs Initially Considered for the Treatment of Polycythemia Vera
Hydroxyurea
Drug class Antimetabolite
Mechanism of action Myelosuppressive
Half-life, metabolism ≈4 h, renal excretion
Starting dosage 500 mg twice a day orally
Time before onset of
action (approximate) 3-5 d
Frequent adverse effects Anemia, neutropenia,
oral and skin ulcers,
hyperpigmentation,
nail changes
Infrequent adverse effects Leg ulcers, nausea,
diarrhea, fever, elevated
liver function test results
*Not available in the United States but widely used in Europe.
Interferon α
Biological agent
Myelosuppressive
Kidney metabolized
5 million U 3 times a week
subcutaneously
3 wk
Flulike symptoms, fatigue,
anorexia, weight loss,
alopecia
Confusion, depression,
autoimmunity,
hyperlipidemia
Pipobroman*
Alkylating agent
Myelosuppressive
Insufficient information
1 mg/kg per day orally
28 d
Delayed cytopenia
Nausea, rash,
abdominal cramps,
diarrhea, hemolysis

(Tables 3 and 4).163 In older patients, my current choice of
chemotherapy is hydroxyurea (initial dosage of 500 mg
twice a day) or busulfan (initial dosage of 4 mg/d). Adverse
effects of hydroxyurea that might necessitate the use of an
alternative agent include neutropenia and mucocutaneous
changes (Table 2 and Figure 5). With use of busulfan,
potental toxicity to the lungs (pulmonary fibrosis)286-288 and
to bone marrow (aplasia),289 although infrequent, should be
recognized. Using intermittent treatment with drug holi-
days and withholding treatment of impending cytopenia
are recommended.
In younger but high-risk patients, I sympathize with the
concern over possible drug leukemogenicity associated
with long-term therapy with either hydroxyurea or busul-
fan but inform patients that there is no hard evidence to
support this concern. Regardless, IFN-α (initial dosage of 3
million U subcutaneously 3 times a week) is a reasonable
alternative in this instance (Table 4).278 I also prefer the use
of IFN-α in women of childbearing age because of the
theoretical risk of teratogenicity associated with the other
cytoreductive agents279,290 and in the presence of intractable
pruritus.291
Because 32P-associated leukemia in PV peaks after 7
years of treatment, it is reasonable to advocate the use of 32P
Table 3. Risk Stratification in Polycythemia Vera
Risk category Risk factors
Low risk Age younger than 60 y and no history of
thrombocytosis and platelet count lower than
1500 × 109/L
Indeterminate risk Age younger than 60 y and no history of
thrombocytosis and either platelet count higher
than 1500 × 109/L or the presence of
cardiovascular risk factors
High risk Age 60 y or older or a positive history of
thrombosis
in elderly patients with issues of treatment compliance and
convenience, especially if life expectancy is less than 10
years (intravenous 32P at 2.3 mCi/m2 to be repeated every 3
months if necessary).163
The lack of evidence that correlates thrombocytosis with
thrombosis in PV argues against the potential therapeutic
value of anagrelide in PV. A randomized, controlled study is
necessary to define the role of anagrelide in the treatment of
PV. Similarly, no current evidence suggests that either
anagrelide or IFN-α modifies the risk of disease transforma-
tion into either MMM or leukemia.283 Therefore, I currently
do not recommend the routine use of anagrelide for PV.
Under current treatment strategies, the incidences of
transformation into MMM or acute leukemia in the first
decade of disease are estimated at 10% and 5%, respec-
tively.163 The risk beyond the first decade increases
progressively.292
Treatment of Non–Life-Threatening Complications
in PV
Microvascular Disturbances Including Erythromel-
algia.—Microvascular disturbances in PV and related
disorders are believed to represent a transient inflamma-
tion-based occlusive phenomenon that is a result of inter-
action between clonal platelets and the endothelium of
arterioles. The corresponding clinical manifestations in-
clude headache, light-headedness, transient neurologic or
ocular disturbances, tinnitus, atypical chest discomfort,
paresthesias, and erythromelalgia (painful and burning sen-
sation of the feet or hands associated with erythema and
warmth).
Erythromelalgia is an extremely rare disease,293 and
most cases are not associated with myeloproliferative dis-
orders.294,295 Two thirds of patients with erythromelalgia
may have no identifiable comorbid condition (primary
erythromelalgia), whereas the remaining third may have

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Mayo Clin Proc, February 2003, Vol 78
Table 4. Treatment of Polycythemia Vera
Risk category Age <60 y
Low risk Phlebotomy alone ± low-dose
aspirin*
Indeterminate risk Phlebotomy alone†
High risk Phlebotomy + hydroxyurea or
interferon α + low-dose aspirin*
*Not evidence based.
†Use of aspirin is discouraged if the platelet count is >1000 × 109/L but is encouraged otherwise.
associated various clinical conditions or factors (secondary
erythromelalgia) including diabetes, autoimmune diseases
including systemic lupus erythematosus, drugs (calcium
channel blockers, ergot derivatives), and myeloproliferative
disorders.295 In a retrospective series of 168 patients with
erythromelalgia, only 15 had an associated myeloprolifera-
tive disorder (9 with PV, 4 with ET, and 2 with CML).294
The characteristic occurrence of erythromelalgia in PV
has been recognized for several decades, and the estimated
incidence is approximately 3%.296,297 The syndrome is often
associated with thrombocythemia, and the pathogenesis
may involve platelet-mediated endothelial cell injury that
results in inflammation and transient thrombotic occlusion
by platelet aggregates.174,175,298 Some studies have suggested
a pathogenetic role for thromboxane-mediated platelet acti-
vation,176 which is consistent with the efficacy of treatment
with low-dose aspirin (81 mg/d).299 Aspirin produces
prompt (within hours) alleviation of symptoms in most
patients with PV-associated erythromelalgia. However,
normalization of platelet count with cytoreductive therapy
may be necessary in certain patients who do not respond
well to aspirin (A.T., unpublished data).
Management of Pruritus in PV.—Generalized pruri-
tus that is often exacerbated by a hot bath is a characteristic
feature of PV. In a single institutional study of 397 con-
secutive patients with PV, a history of pruritus was docu-
mented in 48% either at diagnosis or at a later stage of the
disease.300 Pruritus may be the most agonizing aspect of PV
and may result in sleep deprivation and interference with
various social and physical activities.301
Information is conflicting regarding the pathogenetic
role of both histamine302-304 and mast cells304,305 in PV-
associated pruritus. Regardless, conventional treatment of-
ten includes antihistamines,306,307 and responses have been
both unpredictable and variable.300
Platelets and their contents have also been implicated in
the pathogenesis of pruritus associated with PV. Accord-
ingly, an early double-blind crossover study had suggested
a benefit for aspirin therapy, and the proposed mechanism
was inhibition of platelet release of pruritogenic amines
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Polycythemia Vera 185
Women of
Age ≥60 y childbearing age
Not applicable Phlebotomy alone ± low-dose
aspirin*
Not applicable Phlebotomy alone†
Phlebotomy + hydroxyurea + Phlebotomy + interferon α +
low-dose aspirin* low-dose aspirin*
including prostaglandins and serotonin.301 Interestingly, a
recent study showed a response rate higher than 80% in
PV-associated pruritus treated with paroxetine, a selective
serotonin reuptake inhibitor.308
A recent study suggested a significant correlation be-
tween active pruritus and low mean corpuscular volume
that implied a potential pathogenetic role for iron defi-
ciency.300 Likewise, previous reports have suggested that
iron deficiency might be pathogenetically contributory and
that iron replacement may benefit some patients with PV-
associated pruritus.309-311 However, iron replacement ther-
apy has not been consistently effective in the treatment of
PV-associated pruritus,304 and its indiscriminate use in this
context is discouraged.
Other treatment modalities that have been used in PV-
associated pruritus include IFN-α,291,312-314 psoralen photo-
chemotherapy,315-317 and cholestyramine.318 The results of
several studies indicate that IFN-α may reduce pruritus in up
to 81% of affected patients. The mechanism of action in
IFN-α–induced alleviation of pruritus is unclear but may be
related partly to the decreased need for phlebotomy, which
results in a lesser degree of iron deficiency.300,313
My current recommendation for treating patients with
PV associated with intractable pruritus is to use IFN-α in
Figure 5. Nail pigmentation as a result of treatment with hydroxy-
urea. Reprinted with permission from Elsevier Science.33
186 Polycythemia Vera
high-risk patients and paroxetine in low-risk patients who
otherwise do not require cytoreductive therapy.
DIAGNOSIS AND TREATMENT OF SP
Although an increased serum EPO level is highly sugges-
tive of SP, a normal level does not exclude the possibil-
ity.244 Therefore, regardless of the serum EPO level, if
family history suggests a congenital cause, it is essential to
measure P50 (oxygen pressure at 50% hemoglobin-oxygen
saturation). A low P50 would be consistent with either a high
oxygen-affinity hemoglobinopathy205 or 2,3-diphospho-
glycerate mutase deficiency.206 Other types of congenital
polycythemia may be inherited in either an autosomal-
dominant or autosomal-recessive fashion and may display
high, normal, or low serum EPO levels.222 If low serum
EPO levels are displayed, the possibility of mutations in
the EPO receptor should be included in the differential
diagnosis.115
In acquired SP, initial laboratory tests should include the
measurement of arterial hemoglobin-oxygen saturation and
the carboxyhemoglobin level, especially in smokers. In the
absence of a central hypoxic state, renal vascular studies
should be performed to rule out the possibility of renal
artery stenosis.204,319,320 Imaging studies of the kidney, liver,
and central nervous system may be considered when either
the aforementioned studies are unrevealing or the patient
has a persistently elevated serum EPO level. Patients
should always be questioned about the use of androgen
preparations: oral, transdermal, or intramuscular.220,321,322
Regarding EPO doping, immunoblotting techniques have
been developed to differentiate endogenous EPO from ex-
ogenously administered recombinant EPO.232
Specific management of SP depends on the underlying
cause and should take into account the balance between the
physiological benefit of an increased hematocrit level and
the possible impairment of oxygen delivery to tissues as a
result of increased whole blood viscosity. In cyanotic con-
genital heart disease, aggressive phlebotomy should be
avoided because of the potential risk of stroke.323-325 A
detrimental effect of overzealous phlebotomy may also be
expected in patients with high oxygen-affinity hemoglo-
binopathy.326 In both of these conditions, judicious phle-
botomy to a hematocrit level of 60% is reasonable, may
alleviate symptoms of hyperviscosity, and may provide
some hemodynamic improvement.327,328 Similarly, graded
phlebotomy in chronic obstructive pulmonary disease
(COPD) to a hematocrit range of 55% to 60% may improve
both exercise tolerance and cardiac function.329-333
Post–renal transplant erythrocytosis is distinctly associ-
ated with an increased risk of thrombosis.223 Fortunately,
both angiotensin-converting enzyme (ACE) and angio-
tensin II receptor inhibitors are effective in lowering he-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, February 2003, Vol 78
matocrit levels in PRTE.334 The mechanism of action is
unknown. Recent data suggest that angiotensin II promotes
erythropoiesis and that ACE inhibition may induce
apoptosis in erythroid precursor cells.335,336 Also, ACE inhi-
bition has been shown to reduce hematocrit levels in
COPD-associated SP.337 In addition, treatment with the-
ophylline has been shown to lower hematocrit levels in
both COPD and PRTE.338,339
CONCLUSIONS
The fundamental pathogenetic processes in PV remain in-
adequately defined. Most investigators agree that PV repre-
sents a clonal stem cell disease and that the resultant clonal
myeloproliferation displays altered behavior in terms of
both sensitivity to a multitude of hematopoietic growth
factors and expression of a variety of cellular and mem-
brane molecules. However, none of the currently discussed
biological processes regarding the pathogenesis of PV are
disease specific and none have been particularly insightful
in further advancing the current state of the science. A
genomic approach that uses global analyses of genes as
well as protein expression may provide an alternative and
more effective method of deciphering the pathogenesis of
PV and related disorders.340
In routine clinical practice, it is more practical to use a
diagnostic algorithm instead of diagnostic criteria to make
a working diagnosis of PV. In this regard, the measurement
of RCM is seldom necessary and can be replaced easily by
an accurate interpretation of the observed hematocrit level
within the context of the clinical presentation as well as the
use of PV-related biological markers. Some PV-related
biological markers, such as serum EPO concentration, are
used to help clinicians decide on further diagnostic work-
up.244 Other biological markers, such as bone marrow ex-
amination, are used to confirm the diagnosis.246 Often, the
diagnosis is made on the basis of clinical and bone marrow
findings, and it is not necessary to perform specialized tests
such as endogenous erythroid colony assays,248 bone mar-
row c-mpl immunostains,152 or determination of granulo-
cyte PRV-1 expression.154 In equivocal cases, any of the 3
specialized tests, depending on test availability, may be
used for further clarification.
It is important to separate non–life-threatening from
life-threatening disease manifestations in PV. The former
include microvascular disturbances that are often con-
trolled with low-dose aspirin, as well as aquagenic pruritus,
which recently was shown to respond to selective serotonin
reuptake inhibitors. Life-threatening complications of PV
include thrombosis and disease transformation into MMM
or acute leukemia. To date, no controlled and reproducible
treatment has been shown to influence disease transforma-
tion in PV. Therefore, it is unwarranted to suggest that any
Mayo Clin Proc, February 2003, Vol 78
one of the currently available treatment agents is of proven
benefit in this regard. Furthermore, it is unnerving to wit-
ness the increasing use of new cytoreductive agents in PV
with no evidence of their superiority over conventional
therapy for thrombosis prevention. High priority should be
given for the development of randomized studies to select
the “best” drug, from the standpoint of both toxicity and
efficacy, among the currently available cytoreductive
agents.
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