Review article
Polycythemia vera: myths, mechanisms, and management
Jerry L. Spivak
Introduction
Polycythemia vera is a clonal disorder arising in a multipotent
hematopoietic progenitor cell that causes the accumulation of
morphologically normal red cells, white cells, platelets, and their
progenitors in the absence of a definable stimulus and to the
exclusion of nonclonal hematopoiesis.1,2 First described in 1892,3
polycythemia vera is not a new disease and while uncommon, with
an incidence of at least 2 per 100 000,4-6 it is not a rare disease. Yet,
after 10 decades of careful clinical and laboratory investigation, the
etiology of polycythemia vera remains unknown and there is no
consensus as to the optimal therapy for the disorder.7 There is,
however, no reason for this to be so. Although the molecular basis
of polycythemia vera remains elusive, it is the central thesis of this
review that the pathophysiology of polycythemia vera is suffi-
ciently well defined for the provision of a rational treatment
program that prolongs life, alleviates the specific morbidities
associated with the disease, and avoids complications related to the
consequences of the underlying molecular defect. However, for
such an approach to be successful, it is first necessary to recognize
the contradictions between what is actually known about this
disease and how that knowledge has been interpreted and applied
clinically, and that is the purpose of this review.
The pathogenesis of polycythemia vera:
polycythemia vera is a myeloaccumulative
disorder not a myeloproliferative disorder
Erythropoiesis and growth factor hypersensitivity
Because it involves a multipotent hematopoietic progenitor cell, the
hallmark of polycythemia vera is trilineage hematopoietic cell
hyperplasia. However, erythrocytosis is its most prominent clinical
manifestation, the cause of its most serious complications, and the
“sine qua non” for its diagnosis. Therefore, most investigations of
the pathogenesis of polycythemia vera have focused on erythropoi-
esis but with paradoxical results. Red cell life span is not prolonged
in polycythemia vera8 and the erythroid progenitor cell pool is not
expanded at the expense of the myeloid progenitor cell pool.9 At the
same time, neither hyperoxia10 nor renal failure11 suppress erythro-
poiesis in polycythemia vera patients, phlebotomy does not stimu-
late it,12,13 and serum erythropoietin levels are lower than in any
other disease14 (Figure 1).
These paradoxical results are due to the ability of polycythemia vera
erythroid progenitor cells to proliferate in vitro in the absence of
erythropoietin.15 This unusual behavior, however, does not define the
limits of the abnormal clone since not all polycythemia vera erythroid
progenitor cells exhibit erythropoietin-independence in vitro.16,17 Impor-
From the Division of Hematology, Department of Medicine, Johns Hopkins
University School of Medicine, Baltimore, MD.
Submitted 12/28/2001; accepted July 15, 2002. Prepublished online as Blood
First Edition Paper, August 8, 2002; DOI 10.1182/blood-2001-12-0349.
4272
tantly, primitive polycythemia vera erythroid progenitor cells exhibiting
either erythropoietin-dependence or -independence could give rise to
both erythropoietin-dependent and -independent progeny, a characteris-
tic that appeared fixed given that it remained constant over time when
these progenitor cells were cultured in vitro. It is also worth noting that
the in vitro proliferation of polycythemia vera erythroid progenitor cells
in the absence of erythropoietin was not robust.17 This may be a
consequence of the tendency of these cells to differentiate faster in vitro
than normal erythroid progenitor cells in the absence of erythropoietin.18
Thus, the dominance exerted by the polycythemia vera erythroid clone
over polyclonal erythroid precursors2 could be due in part to its ability
to complete its differentiation more efficiently in a low erythro-
poietin milieu.
This dominance may also involve transforming growth factors
produced by polycythemia vera mononuclear cells19 and the
hypersensitivity of polycythemia erythroid progenitor cells to
interleukin 3 (IL-3), granulocyte macrophage–colony-stimulating
factor (GM-CSF),20 stem cell factor (SCF),21 and insulinlike
growth factor (IGF-1).22 Despite claims to the contrary,23,24 this
hypersensitivity does not appear to be the consequence of an
abnormality in the negative regulatory hematopoietic phosphatase,
SHP-1.25,26 Indeed, evidence has been obtained for increased
activity of a membrane-associated protein tyrosine phosphatase in
polycythemia vera erythroid progenitor cells27 and although
overexpression of INK4a and ARF has also been documented in
these cells28 and constitutive phosphorylation of STAT3 has been
observed in the granulocytes in a minority of patients,29 no
consistent abnormality of signal transduction or cell cycle regula-
tion has been identified to date in polycythemia vera nor have
mutations been identified in p53 or Ras during the chronic phase of
the illness.30 There is evidence for both gain31,32 and loss33,34
of suppressor genes in polycythemia vera but exactly which genes
and how they might affect erythroid progenitor cell behavior
remain unknown.
Erythropoietin receptor function
Given the ability of polycythemia vera erythroid progenitor cells to
survive in vitro in the absence of erythropoietin as well as their
hypersensitivity to erythropoietin in particular and hematopoietic
growth factors in general, there has been substantial interest in
growth factor receptor function in this disease. c-Kit expression,
ligand affinity, and internalization were normal in polycythemia
vera erythroid progenitor cells35 but the development of erythropoi-
etin hypersensitivity or independence as a consequence of gain in
function mutations in the ligand-binding and cytoplasmic domains
of the erythropoietin receptor36 raised the possibility that this
receptor was involved in the pathogenesis of the disease. However,
Reprints: Jerry L. Spivak, Traylor 924, Johns Hopkins University School of
Medicine, 720 Rutland Ave, Baltimore, MD 21205; e-mail: jlspivak@jhmi.edu.
© 2002 by The American Society of Hematology
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
Figure 1. Relationship between serum erythropoietin and hemoglobin in
patients with polycythemia vera (E), secondary erythrocytosis (F) or relative
erythrocytosis (x). Adapted from Handin et al369 with permission of the publisher,
Lippincott, Williams, and Wilkins.
erythropoietin receptor expression and ligand binding were not
different in polycythemia vera erythroid progenitor cells compared
with normal erythroid progenitor cells.37,38 Furthermore, no eryth-
ropoietin receptor gene amplification, rearrangements, or func-
tional mutations have been identified in polycythemia vera pa-
tients.39 This is not surprising because forced expression of the
erythropoietin receptor in primitive hematopoietic stem cells did
not induce autonomous proliferation, enhance progenitor cell
renewal, or stimulate granulopoiesis,40 all of which are features of
polycythemia vera. Furthermore, although expression of a constitu-
tively-active erythropoietin receptor caused both erythrocytosis
and thrombocytosis in vivo,41 it did not cause trilineage hematopoi-
etic progenitor cell hyperplasia.
Alternatively spliced forms of the erythropoietin receptor have been
identified, one of which has a truncated cytoplasmic domain and was
expressed at high levels in immature erythroid progenitor cells in
contrast to the full-length receptor, expression of which increased with
progenitor cell maturation.42 The function of the truncated receptor
splice variant has been a matter of controversy.43,44 It was incapable of
transmitting a signal but interfered with the proliferative activity of the
full-length erythropoietin receptor44 while promoting differentiation.45
The truncated erythropoietin receptor splice variant was either not
expressed well or at all in various erythroleukemia cell lines42,46 and its
expression was also decreased or absent in polycythemia vera mono-
nuclear cells.46 Since polycythemia vera erythroid progenitor cells
differentiate more quickly than their normal counterparts,18 the signifi-
cance of these observations with respect to the pathophysiology of the
disease remains to be established.
Programmed cell death
The diverse and often conflicting observations concerning the
behavior of polycythemia vera erythroid progenitor cells can be
reconciled by the recent recognition that polycythemia vera
erythroid progenitors overexpressed the antiapoptotic protein Bcl-xl
and were resistant to apoptosis in the absence of erythropoietin.47
Under normal circumstances, early erythroid progenitor cells are
largely dormant and require erythropoietin as a mitogen to initiate
their entry into cell cycle,48 while late erythroid progenitor cells
which are largely cycling require only erythropoietin as a survival
factor to allow completion of terminal differentiation.49 Erythropoi-
etin deprivation results in cell cycle arrest in G0/G1,50 and
POLYCYTHEMIA VERA: AN ANALYTICAL REVIEW 4273
down-regulation of expression of the antiapoptotic proteins Bcl-2
and Bcl-xl followed by programmed cell death.51 By contrast,
overexpression of Bcl-2 or Bcl-xl allowed erythroid progenitor
cells to maintain their viability while undergoing terminal differen-
tiation in the absence of erythropoietin.51
This behavior is not unique to erythroid progenitor cells, since
multipotent hematopoietic progenitor cells overexpressing Bcl-2
not only remained viable in the absence of both growth factors and
serum but were also able to undergo unrestricted lineage-specific
commitment and terminal differentiation under these conditions as
well.52 A significant feature of Bcl-2 overexpression was prolonga-
tion of the G1 phase of the cell cycle.52 Importantly in this regard, in
vitro, the duration of G1 in erythroid progenitor cells appeared to be
erythropoietin dependent; low concentrations of erythropoietin
were associated with G1 prolongation and initiation of differentia-
tion while high concentrations were associated with G1 shortening
and cell proliferation.53 Thus, Bcl-xl overexpression could explain
the accelerated differentiation of polycythemia vera erythroid
progenitor cells in vitro in the absence of erythropoietin in contrast
to their normal counterparts, as well as their survival advantage in
vivo where erythropoietin production is suppressed, since both
conditions promote G1 arrest and terminal differentiation. There-
fore, the excess of erythroid cells that defines this disorder is more
likely a consequence of cell accumulation than cell proliferation.
This type of behavior is also consistent with and explains the
incremental nature of the erythrocytosis in polycythemia vera
(Figure 2) since only a fraction (5%-25%) of the erythroid
progenitor cell population exhibited this behavior and its expres-
sion appeared to be random.17 Whether resistance to apoptosis in
the absence of growth factors is a feature of myelopoiesis or
thrombopoiesis in this disorder remains to be determined. One
caveat with respect to this mechanism is that Bcl-xl expression is
normally up-regulated with terminal erythroid differentiation54 and
whether accelerated terminal erythroid differentiation in polycythe-
mia vera was the cause of increased Bcl-xl expression or its
consequence, and thus, whether another antiapoptotic mechanism
might be involved, has not been established.
IGF-1
Insight into the mechanism for the resistance of polycythemia vera
erythroid progenitor cells to apoptosis was provided by the
observation that in the absence of serum, polycythemia vera
erythroid progenitor cells were not more sensitive to erythropoietin
than their normal counterparts. Rather, they were more sensitive to
Figure 2. Rate of rise of the hematocrit level in a patient with polycythemia vera
who sought treatment for the disease 9 years after the hematocrit level began
to increase. Adapted from Conley368 with permission of the publisher, The McGraw-
Hill Companies.
4274 SPIVAK
the antiapoptotic growth factor IGF-1.22 Furthermore, IGF-1 recep-
tors on polycythemia vera peripheral blood mononuclear cells were
constitutively tyrosine phosphorylated in contrast to those of
normal blood mononuclear cells and also more sensitive to
IGF-1.55 The serum concentration of IGF-1 binding protein-1 was
increased in polycythemia vera patients and this protein was
capable of stimulating erythroid burst formation in vitro.56 Importantly
in this regard, it was recently demonstrated that cells expressing
truncated erythropoietin receptors lacking their negative regulatory
cytoplasmic domain and thought to be hypersensitive to erythropoietin36
were actually hyposensitive to the hormone in the absence of serum and
hypersensitive to IGF-1.57 Thus, growth factor hypersensitivity in
polycythemia vera could be a result of compensation for defective
receptor-mediated signal transduction.
The thrombopoietin receptor, Mpl
Based on studies to date, the erythropoietin receptor cannot be
implicated in such a process but the thrombopoietin receptor, Mpl,
is a candidate. Mpl is expressed not only by megakaryocytes and
platelets but also by pluripotent hematopoietic progenitor cells,58
the survival of which is enhanced by the cognate ligand of Mpl,
thrombopoietin.59 Thrombopoietin also acts synergistically with
SCF and IL-3 to promote the proliferation of pluripotent hematopoi-
etic stem cells,60 while impaired Mpl or thrombopoietin expression
results in a reduction in the number of both multilineage and
committed hematopoietic progenitor cells.61 Thrombopoietin in
conjunction with SCF promotes the production of neutrophils from
CD34⫹ cells62 and in conjunction with erythropoietin, the produc-
tion of erythroid progenitor cells,63 an effect that may be due to
abrogation of apoptosis.64 Thrombopoietin overexpression in mice
caused granulocytosis, thrombocytosis, osteomyelofibrosis with
extramedullary hematopoiesis, and death,65 while ectopic expres-
sion of Mpl caused fatal erythroblastosis.66 Importantly, the
retrovirus, MPLV, which encodes an Mpl gene truncated in its
extracellular domain and fused with a viral envelope protein gene,
induced a syndrome in mice that mimicked polycythemia vera,67
while hematopoietic progenitor cells infected with MPLV were
growth factor–independent in vitro and capable of terminal differ-
entiation in the absence of growth factors.68 Finally, Mpl expres-
sion and, therefore, its responsiveness to thrombopoietin in the
megakaryocytes and platelets of polycythemia vera patients, were
defective due to an as-yet-undefined impairment of its posttranslational
glycosylation that became more profound with disease duration and
extent.69 These observations, taken together with the recent demonstra-
tion that removal of the Mpl distal extracellular cytokine receptor
domain conferred growth factor–independent survival on hematopoietic
cells expressing these truncated receptors,70 support the contentions that
impaired hematopoietic growth factor receptor signaling has a fundamen-
tal role in the pathophysiology of polycythemia vera, that Mpl is a
candidate receptor in this regard, and that polycythemia vera is a
disorder of cell accumulation not cell proliferation.
The diagnosis of polycythemia vera:
Osler’s legacy; polycythemia vera is
a clinical diagnosis
Diagnostic criteria
William Osler was not the first to describe a patient with
polycythemia vera.3 He was, however, the first to emphasize that
phenotypic mimicry could confound the diagnostic process and to
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
propose clinical criteria to distinguish polycythemia vera from
other disorders causing erythrocytosis71 (Table 1). Remarkably, the
Osler diagnostic criteria omit leukocytosis or thrombocytosis, an
omission that may have diagnostic connotations as discussed
below, but are otherwise similar to the major diagnostic criteria
proposed by the Polycythemia Vera Study Group (PVSG) 6
decades later72 (Table 1). These diagnostic criteria are as important
for what they do not specify as for what they do. First, bone marrow
examination is not part of the diagnostic criteria. This is appropriate
because bone marrow abnormalities, such as an increase in
megakaryocytes and cellular hyperplasia with a loss of the fat
spaces, while characteristic, can never alone be diagnostic for
polycythemia vera,73 and if the other major PVSG diagnostic
criteria are met, bone marrow examination is unnecessary. Further-
more, while nonrandom cytogenetic abnormalities and myelofibro-
sis have diagnostic implications, neither has prognostic implica-
tions74,75 and their frequency is too low to make bone marrow
examination cost-effective. Even if bone marrow examination were
diagnostic, that would still not abrogate the need for red cell mass
and plasma volume determinations, tests that are justifiably cost-
effective. Consequently, marrow examination is useful only when
there is a change in the clinical course of the disease, for research
purposes or for clinical trials. Yet, bone marrow aspiration and
biopsy are frequently performed in the initial evaluation for
polycythemia vera.7 This only confirms or generates an unex-
pressed fear of leukemia on the part of patients; a fear often
validated by their physicians with respect to prognosis when in
fact, with appropriate management, such an occurrence is only a
remote possibility. Second, assays for erythropoietin and erythroid
colony-forming cells are not part of the PVSG diagnostic criteria.
While it can be argued that 30 years ago these tests were either
insensitive or unavailable, it is equally easy to argue for the latter
test that availability is still restricted clinically and that for both,
specificity and sensitivity are unsatisfactory.
Serum erythropoietin
The development of a sensitive and specific assay for circulating
erythropoietin for the purpose of distinguishing autonomous from
secondary erythrocytosis was long a holy grail of hematologists.
Although we now have such an assay, it is an irony that due to the
unique physiology of erythropoietin, measurement of the hormone
in the circulation cannot be relied on to distinguish between
autonomous and erythropoietin-driven erythrocytosis. This is be-
cause as the red cell mass expands, both improved tissue oxygen-
ation and the associated increase in blood viscosity serve to depress
erythropoietin production,76 while the plasma residence of erythro-
poietin is simultaneously reduced through increased catabolism by
the expanded erythroid progenitor cell pool.77 The net result is that
Table 1. The diagnosis of polycythemia vera
1903* 1971†
Erythrocytosis Elevated red cell mass
Cyanosis Normal arterial 02 saturation
Splenomegaly Splenomegaly
Plus any 2 below if no splenomegaly
Leukocytosis greater than 12 000/␮L
Thrombocytosis greater than 400 000/␮L
Leukocyte alkaline phosphatase greater than 100
Serum B12 greater than 900 pg/mL or unbound
B12 binding capacity greater than 2200 pg/mL
*From Osler.71
†From Wasserman.72
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
while the lowest erythropoietin levels occur in polycythemia vera14
(Figure 1), this is not absolute and a “normal” erythropoietin level
is common in hypoxic erythrocytosis unless the hypoxia is
extreme.78 Indeed, given the wide range of normal for serum
erythropoietin (4 mU/mL-26 mU/mL), unless the premorbid serum
erythropoietin level is known, a 6-fold elevation could occur
without exceeding the normal range. Thus, while an elevated serum
erythropoietin level suggests tissue hypoxia as a cause for erythro-
cytosis, a normal serum erythropoietin level does not exclude an
hypoxic cause. Only an arterial oxygen saturation determination, as
stipulated by the PVSG criteria, will suffice for this purpose.
Erythroid progenitor cell assay
Similarly, although erythropoietin-independent erythroid colony
formation in vitro is characteristic of polycythemia vera15 and has
been widely embraced as a diagnostic test for the disease, it cannot
be recommended for this purpose. The reasons are many and
cogent. Erythropoietin-independent erythroid colony formation is
not specific for polycythemia vera. Although it is most obvious in
this disorder, it can be seen in nonclonal causes of erythrocyto-
sis79,80 and in healthy controls79,81 as well as in essential thrombocy-
tosis.81-84 Furthermore, endogenous erythroid colony formation has
been absent in some patients who meet the PVSG criteria for
polycythemia vera.85 Part of the problem may be methodologic
since the greatest specificity and sensitivity has been observed
when bone marrow was used as the source for erythroid progenitor
cells as opposed to peripheral blood and when erythroid colony-
forming units (CFU-Es) were analyzed as opposed to erythroid
burst-forming units (BFU-Es).86 The in vitro clonal assay for
erythroid progenitor cells is also neither standardized nor widely
available. For these reasons and because this assay does not
establish clonality, it cannot be recommended as a routine clinical
diagnostic test for polycythemia vera.
PVSG minor criteria
In an effort to improve diagnostic accuracy, particularly in the
absence of splenomegaly, the PVSG added additional criteria such
as the presence of leukocytosis and thrombocytosis. Approximately
60% of patients will not have both of these abnormalities ini-
tially4,87,88 nor will leukocyte alkaline phosphatase expression,
serum vitamin B12, and unbound serum vitamin B12 binding
capacity be uniformly elevated.88,89
Impaired platelet Mpl expression
A number of other phenotypic abnormalities of the red cells (eg,
microcytic erythrocytosis,90 increased hemoglobin F synthesis18),
white cells (eg, increased surface expression of IgG receptors,91
impaired responsiveness to chemotactants92), and platelets (eg,
reduced PGD2 receptor expression,93 impaired lipoxygenase genera-
tion94,95) have been observed in polycythemia vera but none of
these abnormalities are either specific for the disease or suitable
clinically for diagnostic use. Recently, impaired expression of the
thrombopoietin receptor, Mpl, by the platelets of polycythemia
vera and idiopathic myelofibrosis patients was documented96 and
the severity of this defect correlated with the duration and extent of
disease.69 A similar abnormality was not present in secondary
erythrocytosis or chronic myelogenous leukemia (CML) but was
present in some patients with essential thrombocytosis.97 Interest-
ingly, recently the development of polycythemia vera or idiopathic
myelofibrosis was observed in 3 of 4 essential thrombocytosis
patients with reduced platelet Mpl expression,98 suggesting that the
POLYCYTHEMIA VERA: AN ANALYTICAL REVIEW 4275
abnormality could have prognostic significance in this disorder.
Whether impaired platelet Mpl expression will prove clinically
useful for distinguishing polycythemia vera from other types of
erythrocytosis or to identify polycythemia vera in the absence of
erythrocytosis remains to be established. However, the consistency
with which impaired platelet and megakaryocyte Mpl expression
was observed in polycythemia vera patients96,99 suggests that it
may be useful diagnostically.
PRV-1 expression
Recently, overexpression of the mRNA of a novel member of the
uPAR receptor superfamily, designated PRV-1, was identified in
polycythemia vera granulocytes by subtractive hybridization.89
This GPI-linked surface membrane receptor was detected only in
normal granulocytes after exposure to granulocyte–colony-
stimulating factor (G-CSF), was not expressed in the mononuclear
cells from patients with secondary erythrocytosis, CML, or acute
myelogenous leukemia (AML) and did not correlate with the
expression of leukocyte alkaline phosphatase, another GPI-linked
protein.89 Interestingly, like impaired Mpl expression, PRV-1
expression has also been detected in certain patients with essential
thrombocytosis who also demonstrated in vitro erythropoietin-
independent colony formation.100 Quantitation of PRV-1 mRNA
expression may also prove useful diagnostically in distinguishing
polycythemia vera from other disorders causing erythrocytosis.
Clonality assays
The most important omission from the PVSG diagnostic criteria for
polycythemia vera was a requirement for the establishment of
clonality. Unfortunately, however, in contrast to CML, there has
been no clinically applicable clonal assay for polycythemia vera or
its companion myeloproliferative disorders, idiopathic myelofibro-
sis and essential thrombocytosis. Nonrandom chromosome abnor-
malities are not uncommon in these disorders and in polycythemia
vera the most frequent are trisomies of 1q, 8, 9 or 9p, del13q,
del20q, or interstitial deletions of 13 or 20; occasionally multiple
defects are present.31,74,101,102 However, there is no consistent or
unique cytogenetic abnormality associated with any of these
disorders and at the time of diagnosis, using conventional cytoge-
netic techniques, less than 20% of polycythemia vera patients
exhibit a cytogenetic abnormality and many patients never develop
one.74 In this regard, the use of interphase fluorescence in situ
hybridization (FISH) may increase the diagnostic yield.32 How-
ever, bone marrow aspiration is still required for cytogenetic
analysis unless there are numerous primitive cells in the circulation.
In the absence of a specific and consistent cytogenetic marker,
clonality assays in the chronic myeloproliferative disorders other
than CML have been limited to genes on the X chromosome whose
expression in women is subject to random inactivation. It was on
this basis that the clonality of polycythemia vera was first
established.1 However, this type of clonal analysis is limited to
women who are informative with respect to the expression of
G-6PD isoenzymes or specific DNA polymorphisms. Expression of
the former is restricted while the latter analysis is not informative in
up to 30% of female patients103 and its utility is further limited by
nonrandom, age-associated X-linked gene inactivation.104-106 Thus,
although it has been clearly established as a general principle that
polycythemia vera is a clonal disorder and represents the conse-
quences of transformation of a multipotent hematopoietic progeni-
tor cell, there is currently no way to establish clonality in the
majority of patients considered to have the disease. While this is
4276 SPIVAK
not an issue in patients exhibiting trilineage hematopoietic cell
hyperplasia and extramedullary hematopoiesis, it is a critical issue
in patients with erythrocytosis alone since in the absence of proof
of clonality, it is difficult to justify the use of mutagenic drugs.
Osler was well aware of the phenotypic mimicry that complicated
the diagnosis of polycythemia vera71 and given the well-
documented existence of unidentified and newly recognized non-
clonal forms of erythrocytosis107,108 we would do well to follow
his lead.
Measurement of the red cell mass and plasma volume
With respect to what the PVSG diagnostic criteria do stipulate, the
most important is elevation of the red cell mass. Admittedly, this
criterion does not establish clonality or even distinguish polycythe-
mia vera from other disorders that cause erythrocytosis. However,
it makes a vitally important point with respect to the evaluation of a
high hematocrit level in general and polycythemia vera in particu-
lar—that only direct measurement of the red cell mass and plasma
volume will suffice to distinguish absolute erythrocytosis from
so-called spurious or relative erythrocytosis due to plasma volume
contraction or red cell redistribution.109-111 Indeed, it is not hyper-
bole to state that failure to appreciate this basic concept has been
responsible for more diagnostic and therapeutic failures in patients
with polycythemia vera than any other single factor. The reason
appears to be a lack of understanding of the pathophysiology of the
red mass and plasma volume in disorders causing erythrocytosis.
Normally, the hematocrit or hemoglobin is maintained at a
constant level that is characteristic for each individual but varies
between individuals of the same sex by as much as 15% and
between sexes by approximately 10%. As a corollary, erythropoi-
etin production as represented by the serum erythropoietin level
also remains constant.112 With tissue hypoxia, regardless of cause,
as the red cell mass increases there is usually a concomitant
reduction in plasma volume. Given the other factors involved in
plasma volume regulation as well as in its measurement, the
magnitude of plasma volume reduction reported with hypoxic
erythrocytosis due to right-to-left cardiac shunts,113 impaired
pulmonary gas exchange,114 carbon monoxide poisoning,115 and
low ambient oxygen tension116 varies but the downward trend is
unmistakable. It should not be surprising, therefore, that therapy
with recombinant erythropoietin,117 androgenic steroids,118 and
even blood transfusion119 also leads to a reduction in plasma
volume; the mechanisms involved are unknown but may in part be
protective since increasing whole blood viscosity suppresses
endogenous erythropoietin production.76,120 By contrast, in polycy-
themia vera where erythropoiesis is autonomous and erythropoietin
production is suppressed, as the red cell mass increases the plasma
volume may be unchanged or increase121 until the hematocrit level
is more than 60%.122
Unfortunately, the hematocrit level, whether directly deter-
mined by centrifugation or calculated from the mean corpuscular
volume (MCV) and the red cell count, will not reflect these changes
because even under normal circumstances, the distribution of red
cells and plasma is not uniform throughout the circulatory system.123-125
Rather, as demonstrated by independent determinations of the red
cell mass and plasma volume, the ratio of red cells to plasma is
higher in the peripheral vessels, venous or arterial, than it is in the
body as a whole (ie, whole body hematocrit derived from indepen-
dent measurements of red cell mass and plasma volume/peripheral
venous hematocrit ⫽ 0.92).126,127 This is a consequence of both the
slower flow of the peripherally displaced plasma compared with
the axial red cells and plasma skimming in the smaller ves-
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
sels.123,125,128,129 With disease, changes occur in the plasma volume
and red cell mass or in their distribution, particularly if there is
splenomegaly121,130-132 that will not be evident by hematocrit level
determination alone.109,133-136 Indeed, the assumption that the
hematocrit accurately reflects the red cell mass or, stated differ-
ently, that the red cell mass:plasma volume ratio is constant in
health and disease or even for all parts of the circulation, is simply
incorrect and nowhere more so than when erythrocytosis is
present.114,127,134,136
Remarkably, although it was established in 1921123 and repeat-
edly confirmed125,126,137,138 that only by independently measuring
the red cell mass (currently with 51chromium) and the plasma
volume (with 125I-albumin) could an accurate assessment of each as
well as the total blood volume be obtained, there is still resistance
to this standard of practice. The reasons for this are several. First,
the range of normal for such measurements, not unlike the range of
the hematocrit, is wide, which affects their sensitivity. Conse-
quently, only values more than 2 standard deviations (25%) above
the mean are considered abnormal.139 Second, since adipose tissue
has a low vascularity, red cell mass correlates better with lean body
mass than body weight127 but, unfortunately, there is no simple
method for clinically assessing lean body mass.111 Therefore, if
body weight in mL/kg is used as standard, the red cell mass will be
underestimated in the obese,140 requiring correction factors based
on weight.139 For these reasons and because of the need to use 2
radioisotopes, it has been variously advocated that the red cell mass
be calculated from the plasma volume and the hematocrit141 by a
mathematical formula based on the regression of the red cell mass
on the hematocrit,142 or dispensed with altogether on the grounds
that the diagnosis of polycythemia vera is usually clinically
apparent on the basis of other findings.143 None of these approaches
are either physiologically sound or clinically acceptable because
they rely on assumptions about the red cell mass:plasma volume
ratio derived from measurements in healthy individuals that are not
valid in disease.109,127 Simply stated, in disease, the red cell mass
and plasma volume can vary independently of each other and it is
no more possible to assess the red cell mass from the hematocrit
than it is to determine total body sodium from the serum sodium
concentration. Splenomegaly, of course, just compounds the prob-
lem.130-132,144 Stated differently, it is the author’s opinion that
whenever the diagnosis of polycythemia vera is considered, due to
the potential of plasma volume expansion, a “normal” hematocrit
value can never be considered normal and an independent determi-
nation of both the red cell mass and plasma volume by isotope
dilution is mandatory for diagnostic and therapeutic purposes.
Examples of the usefulness of red cell mass and plasma volume
measurements in the evaluation of the cause of a high hematocrit
level are shown in Table 2.
Anecdote as paradigm: the natural history of
polycythemia vera has not yet been defined
The description of the natural history of polycythemia vera in
current hematology textbooks disguises the fact that little more is
known today about its clinical course than was known 80 years ago.
Attempts to define the natural history of polycythemia vera then as
now have been frustrated not only by the low incidence of the
disorder but also its chronic nature which precludes most physi-
cians from seeing more than a few of these patients or even
following them for a sufficient duration to encounter the full scope
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
Table 2. Examples of the diagnostic value of red cell mass (RCM) and plasma volume (PV) determinations
Disease Pulmonary A-V shunt with hypoxemia
Age, y/sex, M/F 50/M
S 1.85
Hematocrit, % 58.4
Expected* and observed values
RCM, mL 1924, 3982
PV, mL 2919, 2499
TBV, mL 4843, 6481
*The “expected” values were derived using the formulas from Pearson et al.139 These 4 examples illustrate that it is not possible to predict the red cell mass from the
hematocrit alone and that in polycythemia vera a normal hematocrit value does not ensure that the red cell mass is normal. In hypoxic erythrocytosis, the red cell mass expands
at the expense of the plasma volume; with androgen therapy, there is often a reduction in the plasma volume which gives the false impression that erythrocytosis is present. In
polycythemia vera, expansion of the plasma volume can mask expansion of the red cell mass; in the case of the 49-year-old woman, splenomegaly masked the elevated red
cell mass and for at least 8 years she was thought to have idiopathic myelofibrosis.
Adapted from Handin et al369 with permission of the publisher, Lippincott, Williams, and Wilkins.
of the disease. These factors coupled with an initial lack of
appreciation of the effect of radiation or chemotherapy on bone
marrow function led to the acceptance of anecdotal case studies as
representative of the natural history of polycythemia vera.
The natural history hypothesis
In 1954, based on such anecdotal reports, a hypothetical descrip-
tion of the natural history of polycythemia vera was proposed by
Wasserman according to which the disease evolved through a series
of clinical stages beginning with an asymptomatic phase and
proceeding through erythrocytotic, compensated or inactive, and
spent or postpolycythemic myeloid metaplasia phases before
terminating in acute leukemia if death from another cause did not
intervene first.145 Given the similarity of this proposed natural
history to that of CML, it is not surprising that without either
testing or debate, the status of dogma was promptly conferred on
this hypothetical description, and for the past 46 years it has been
reiterated unchanged in greater or lesser detail in virtually every
major hematology textbook when in fact the clinical data from
which it was derived fail to meet the lowest standard of evidence-
based medicine. Indeed, the basis for this concept of the natural
history of polycythemia vera was a 1938 publication by Rosenthal
and Bassen describing 13 patients from a series of 75 who were
thought to be representative of the various hematologic manifesta-
tions of the disease.146 Of the 13 patients. 2 were anemic and
thereby thought to manifest the so-called “spent” phase of the
disorder, a concept first proposed by Minot and Buckman.147 Both,
however, had previously been treated with radiation therapy.
Dameshek had earlier proposed a similar natural history
scheme148 but qualified his proposal as follows: “it is difficult to
state what the ‘normal’ course of the disease would be without the
various therapeutic methods which undoubtedly influence it.”
Unfortunately, this caveat was disregarded and only rarely have
polycythemia vera patients been followed long enough without
exposure to therapeutic interventions such as radiation or 32P that
significantly alter bone marrow function for any meaningful
appreciation of the natural history of the disorder to be obtained.
When this has been achieved, a different picture of the disease
emerges.149,150 Additionally, it is not widely appreciated that the
disease may have different manifestations depending on the age at
onset and the patient’s sex.151 Finally, adding to the confusion has
been the uncritical acceptance or misuse of terms such as “spent
phase” and “postpolycythemic myeloid metaplasia” together with
the assumption that the various chronic myeloproliferative disor-
ders are interrelated152 when in fact proof is lacking that they are.153
POLYCYTHEMIA VERA: AN ANALYTICAL REVIEW 4277
Cases
Androgen therapy Polycythemia vera “Idiopathic myelofibrosis”
52/M 68/F 49/F
2.15 1.64 1.50
56.4 47.0 41.5
2370, 2661 1420, 2217 1284, 2581
3393, 1824 1288, 2500 2095, 3545
5763, 4485 3708, 4717 3379, 6126
The spent phase of polycythemia vera
While it has been clearly established that polycythemia vera can be
complicated by anemia, myelofibrosis, and myeloid metaplasia, the
frequency with which these complications occur and their clinical
significance in the absence of cytotoxic therapy has rarely been
ascertained prospectively. For example, the development of anemia
due to bone marrow exhaustion has been considered an inevitable
event in the natural history of polycythemia vera and possibly a
forerunner of leukemia.145,154 As mentioned above, it was in this
context that the term “spent phase” was initially used.147 However,
in a large series of polycythemia vera patients managed without
radiation therapy, anemia was most often due to chemotherapy,
hemorrhage, deficiency of iron, folic acid or vitamin B12, or another
disease and not to intrinsic marrow failure.149 Importantly, the role
of iron deficiency as a cause for anemia was not recognized in early
descriptions of the disease,147 nor was it appreciated that the plasma
volume expansion associated with splenomegaly could mask the
true red cell mass. Furthermore, in some patients, the “spent phase”
proved to be reversible with therapy.150 When these facts, together
with ferrokinetic studies in patients with advanced disease155 are
taken into account, it is clear that that there is not necessarily an
irreversible exhaustion of erythropoiesis with disease progression
or duration and that while the frequency with which refractory
anemia is a direct consequence of polycythemia vera remains to be
established, from the available data, it appears to be uncom-
mon.156,157 More important than the so-called spent phase is the
peculiar wasting syndrome that can develop late in the course of
polycythemia vera in which intractable weight loss is associated
with extramedullary hematopoiesis and substantial elevation of the
white cell and platelet counts.
Finally, the term “spent phase” as used today also appears to
mean different things to different authors. Initially and still
employed to denote the progression of polycythemia vera to a state
of bone marrow failure and possibly a prelude to leukemia145,146 it
has also been used to describe a phase of polycythemia vera with
splenomegaly without either myelofibrosis or myeloid metaplasia
in which erythrocytosis continues unabated with its extent masked
by plasma volume expansion.136 As indicated above, the former use
of the term has never been authenticated in a scientifically
acceptable fashion and the latter use, of course, is actually
contradictory since in the type of patients described, bone marrow
function was actually robust.155,158 Furthermore, such patients have
also been described by others as being in the “stationary phase” of
the disease,148 a designation that is equally improbable since no
4278 SPIVAK
evidence has been provided that disease activity has changed. All
of this only serves to illustrate the confusion that results when
anecdotal experiences are uncritically elevated to the status of
paradigm and medical jargon is substituted for medical judgment.
In a disease such as polycythemia vera, anecdotal case reports are
invaluable for defining what is possible but only prospective
longitudinal studies of well-defined patient cohorts can establish
what is probable.
Myeloid metaplasia
This conclusion also applies to 2 other complications of polycythe-
mia vera, myeloid metaplasia and myelofibrosis. Since spleno-
megaly in polycythemia vera is initially due to red cell conges-
tion,13,159-161 without a tissue biopsy, the assumption that splenic
enlargement represents extramedullary hematopoiesis could be
erroneous.133,162 It is probably for this reason that estimates of the
frequency of myeloid metaplasia, based on the presence of
immature myeloid and erythroid cells in the circulation or organo-
megaly, have varied from 7% to 14%.75,145,157,163 Furthermore, the
widely used term “postpolycythemic myeloid metaplasia”164 is
more than imprecise; it is an oxymoron since it implies that
myeloid metaplasia is a terminal complication or conversion of
polycythemia vera to another disorder rather than being an integral
component of the disease itself165 that may not shorten sur-
vival.75,166,167 It also implies that bone marrow activity is impaired
when in fact, in the absence of radiation or chemotherapy, there is
no correlation between the extent of extramedullary hematopoiesis
and bone marrow hematopoietic activity in polycythemia vera.168
As originally used, “postpolycythemic myeloid metaplasia”
was a synonym for the spent phase of polycythemia vera in which
the predominant features were myeloid metaplasia, splenomegaly,
myelofibrosis, and anemia.164 However, as indicated above with
respect to anemia, there have been few attempts to analyze the
influence of radiation or chemotherapy on the development of
“postpolycythemic myeloid metaplasia” but when this has been
done, the majority of patients fitting this description have been
exposed to agents toxic to the bone marrow.163,164,169 Thus, a
century after the description of polycythemia vera, judgment must
remain suspended as to the frequency with which bone marrow
failure is a terminal feature of this disease in the absence of an
exogenous cause but published data suggest that it is not high.157
Myelofibrosis
Given the above, it should not be surprising, therefore, that
substantial misconceptions also exist with respect to significance of
myelofibrosis in polycythemia vera. This is because the mecha-
nisms for myelofibrosis are poorly understood170-172 and the means
for quantitating it imprecise due to the patchy nature of the
process.168,173-175 Furthermore, with respect to diagnosis, it has
generally been assumed that polycythemia vera and idiopathic
myelofibrosis are closely related disorders,152 although apart from
phenotypic similarities, this assumption has never been substanti-
ated scientifically. Indeed, some investigators have considered the
development of myeloid metaplasia and myelofibrosis in polycythe-
mia vera as indicating the onset of a “transitional myeloprolifera-
tive disorder”135 rather than part of the natural history of the
disease, while others have considered erythrocytosis to be a
complication of idiopathic myelofibrosis.134 The development of
myelofibrosis per se in the setting of polycythemia vera has also
been considered to have adverse prognostic implications,176 an-
other erroneous assumption.75,150,156,174,177
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
Because there is no widely accepted standard for the quantita-
tion of marrow reticulin158 nor a universally acknowledged defini-
tion for the term “myelofibrosis” outside the setting of the disease,
idiopathic myelofibrosis,178 it is difficult to obtain a precise
frequency for its occurrence in polycythemia vera as well as the
impact of therapy on this. Within the limitations of these data, it
appears that increased marrow reticulin is part of the natural history
of the disease, presumably reflecting in part the increase in marrow
cellularity158,179 and possibly disease duration.180 However, an
increase in marrow reticulin, or even osteosclerosis, is certainly not
synonymous with a “spent” phase75,134,135,155,158,181-183 and can be
modified to a certain extent by therapy,75 particularly with busul-
fan.182,184 Spontaneous regression of myelofibrosis has also been
observed,168,175,182,185,186 although the patchy nature of the process
makes this observation as difficult to substantiate as the contention
that myelofibrosis is a progressive and destructive process.173-175,187
If studies of idiopathic myelofibrosis patients can be used as a
guide, myelofibrosis and osteosclerosis are not usually progressive
processes.168,174,188 There does, however, appear to be a higher
incidence of “myelofibrosis” in polycythemia vera patients ex-
posed to either radiation or chemotherapy than those treated by
phlebotomy alone, 8.4%156,163,164,173,189 versus 4.5%,149,156,163 but
there is not absolute agreement on this point.75,176 As a corollary, in
studies of idiopathic myelofibrosis, polycythemia vera patients
comprised 16% (range, 7%-38%) of the patients and most had been
treated with radiation or chemotherapy.173,175,177,190-193 To the extent
that it has been evaluated, marrow reticulin was increased in 8% to
15% of polycythemia vera patients at the time of diagno-
sis,73,181,194,195 a finding that appeared to have no prognostic
significance.75,150,167 This is in contrast to development of myelofi-
brosis in CML, which is generally associated with disease accelera-
tion.196 Taking everything together, while it is clear that the
hematologic manifestations of polycythemia vera include myeloid
metaplasia and myelofibrosis, it is not yet established that these
processes indicate terminal bone marrow failure or that marrow
failure is an inevitable consequence of the disease in the absence of
cytotoxic therapy. Certainly, given the limitations of the data upon
which the current concept of the natural history of polycythemia
vera is based, it is time to abandon uncritical and unphysiologic
terms such as “stationary,” “spent,” “transitional,” and “postpolycy-
themic myeloid metaplasia” in favor of descriptions based on
quantitative, prospective, and biologically sound observations.
Acute leukemia: relationship to therapy
The relationship between polycythemia vera and acute leukemia
also requires clarification because it is central to the management of
polycythemia vera. In 1950, Schwartz and Ehrlich reviewed the
published evidence that acute leukemia was a feature of polycythe-
mia vera in the absence of exposure to mutagenic therapy.197 Of 83
published cases, only 30 had unequivocal evidence of polycythe-
mia vera preceding the development of acute leukemia and 25 of
these patients had been irradiated. Of the remaining 5 patients, data
supporting the absence of radiation exposure were available for
only one. Since the criteria employed by Schwartz and Ehrlich for
the diagnosis of polycythemia vera and the diagnosis of acute
leukemia were stringent, it is ironic that in the one case of
polycythemia vera that they accepted as spontaneously developing
acute leukemia, the diagnosis was not histologically confirmed.146
They also emphasized the association of the newly introduced 32P
therapy with acute leukemia in polycythemia vera patients and
correctly predicted that this complication would increase in fre-
quency. By contrast, the advocates of 32P therapy thought that the
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
development of acute leukemia was an inevitable consequence of
extended patient survival.133,198
Modan and Lilienfeld’s landmark 1965 paper unequivocally
demonstrated that the leukemogenic effect of irradiation or 32P was
not a consequence of prolonged survival,163 but the impact of their
observations was blunted by the report of Halnan and Russell in
which the incidence of acute leukemia in 32P-treated polycythemia
vera patients was negligible.199 Any doubt about this issue,
however, was eliminated by the PVSG-01 trial which established
that therapy with either 32P or the alkylating agent, chlorambucil,
resulted in an incidence of acute leukemia far exceeding that
observed with phlebotomy alone without prolonging survival.200
The apparent conflict between the Modan and Lilienfeld data and
that of Halnan and Russell was in part due to study design, since the
mean time of onset of 32P-induced acute leukemia is approximately
8.5 years201 while most of Halnan and Russell’s patients were
followed for only 5 years, and in part to differences in radiation
dose. Parenthetically, this episode serves to remind us that the
absence of evidence is not proof of its absence.
Polycythemia vera has the dubious distinction of being the first
hematologic malignancy and only the third disorder temporally—
ankylosing spondylitis202 and thymic enlargement203 being the
other 2—in which an association between acute leukemia and
therapeutic irradiation was identified.197 Unfortunately, acceptance
of the leukemogenicity of irradiation in polycythemia vera was
delayed by the belief that leukemia was an inevitable feature of the
disease.145,154,204 As a consequence, practitioners in this area were
denied an essential paradigm to guide their therapy until similar
observations had been well established for other hematologic205
and nonhematologic neoplasms.206 Importantly, from a biologic
perspective, the leukemogenic effect of irradiation or alkylating
agents in polycythemia vera was neither qualitatively nor quantita-
tively different from that observed for other neoplasms treated in
the same fashion with respect to drug or radiation exposure,
latency, type of leukemia, cytogenetic abnormalities, and response
to treatment.180,207,208 Although data have been presented suggest-
ing that myeloid metaplasia and myelofibrosis predispose to acute
leukemia in polycythemia vera,145,193,209 this contention remains
controversial since the number of patients involved was small and
the observations were not confirmed in other studies.163,167,180
Furthermore, therapy-induced acute leukemia has also been ob-
served in patients with secondary erythrocytosis mistakenly treated
with chemotherapy or radiation.163,210,211 These considerations are
not trivial since they speak to the larger underlying issue of the
spontaneous development of acute leukemia in polycythemia vera.
Spontaneous acute leukemia: Richter syndrome revisited
In contrast to the well-established body of data on treatment-
induced acute leukemia in polycythemia vera,163,180,197,200,207,212-214
few data exist other than anecdotal case reports with respect to the
spontaneous occurrence of acute leukemia. As mentioned above,
up to 1950, Schwartz and Ehrlich accepted as valid only one
published report describing such an event.197 In the same year,
Dameshek reported that one of his 50 patients and 2 of 100 Mayo
Clinic patients treated only by phlebotomy had developed acute
leukemia.148 Since then there have been 12 individually published
case reports215-217 and an additional 11 patients identified by
questionnaire215 in whom acute leukemia complicated polycythe-
mia vera in the absence of irradiation or chemotherapy, while in 4
published series comprising 505 patients, 3 cases of spontaneous
acute leukemia were observed.149,156,163,218 Demographically, these
patients are of interest because 90% were men with a mean age of
POLYCYTHEMIA VERA: AN ANALYTICAL REVIEW 4279
60.5 years, in contrast to those developing acute leukemia follow-
ing alkylating agent therapy, of whom 54% were men with a mean
age of 52.5 years. The interval for the former group between the
onset of polycythemia vera and acute leukemia was 4.8 years
(range, 1-13 years) and in the chemotherapy-treated group 6.7
years (range, 1-20 years), but these latter data are not comparable
because the time of initiation of alkylating agent therapy relative to
the onset of the polycythemia vera was not defined. It is also of
interest that 3 of the 10 patients in the spontaneous leukemia group
for whom the information was available had undergone splenec-
tomy 2 to 8 years before the onset of the leukemia.193,219 Finally, in
contrast to the chemotherapy-treated patients, patients developing
spontaneous acute leukemia could still have concomitant erythrocy-
tosis and only partial bone marrow transformation at the time that
the leukemia was recognized.220
Second cancers occur more often than can be explained by chance in
patients already afflicted by a malignancy221 but with the exception of
exposure to radiation, radiomimetic drugs, or a combination of these, the
mechanisms involved are undefined. With respect to the development of
secondary acute leukemia, age, disease stage, type of cancer,221 and
immunologic status including the postsplenectomy state222-225 have all
been considered to have a role. In some instances, the development of
myelodysplasia or acute leukemia could even be considered a paraneo-
plastic syndrome226,227 since there is precedent for the cytokine-driven
development of acute leukemia.228 With respect to polycythemia vera,
given the increasing incidence of acute leukemia with age,5 the mean
age of polycythemia vera patients, and the restoration of the polycythe-
mic state with successful remission induction therapy,220,229,230 the
possibility of a chance occurrence cannot be excluded particularly with
the simultaneous presence of both disorders.229 At the same time, given
the evidence of clonal evolution or succession in polycythemia vera,74
the possibility of leukemia arising from the malignant clone is also
likely. The role of splenectomy is intriguing since this has been
implicated in the evolution of acute leukemia in idiopathic myelofibro-
sis223 although the observation remains controversial.231
Importantly, the polycythemia vera patients with spontaneous
acute leukemia described to date differ from those with treatment-
induced acute leukemia not only by their male predominance but
also by their age at onset and the short interval between the
diagnosis of polycythemia vera and the development of acute
leukemia, thereby excluding prolonged survival, myeloid metapla-
sia, or myelofibrosis as antecedent factors as claimed.209,218 In fact,
the situation is similar in many respects to Richter syndrome, in
which chronic lymphocytic leukemia is complicated by either the
development of a diffuse large cell lymphoma or transformation to
prolymphocytic leukemia.232 These uncommon events can occur in
untreated patients without regard to disease duration and may arise
from either the original malignant clone or one immunologically
distinct.233 However, regardless of mechanism, the important point
is that the spontaneous development of acute leukemia in polycythe-
mia vera is uncommon and certainly not inevitable, and our
patients deserve to know this.
Survival with polycythemia vera:
hematology’s second amendment privilege
Probably no myth has been more pernicious with respect to the well
being of polycythemia vera patients than the myth of survival
which exists in 2 versions. It is difficult to understand how this
4280 SPIVAK
myth attained credibility since there were both anecdotal re-
ports185,234,235 and observational series146,147,149,236 that firmly estab-
lished the prolonged survival of polycythemia vera patients in an
era when the mainstays of therapy were phlebotomy, phenylhy-
drazine, and sporadic irradiation. Unfortunately, these observations
were ignored in favor of the first version of the myth which arose
from the assumption that leukemia was an inevitable feature of
polycythemia vera.198 This position was stated most emphatically
by Osgood,237 “. . .for any treatment the benefits to be obtained
must be weighed against the risks incurred. Most patients would
rather die at an advanced age with some risk of leukemia than at an
earlier age from some other cause.” However, no patients appear to
have been polled about this contention but it would be more
realistic to conclude that most would rather die at an advanced age
with no risk of leukemia.
The second version derived from an early attempt to study
survival in polycythemia vera in a systematic fashion. In 1962,
Chievitz and Thiede reviewed the causes of death in 250 Danish
polycythemia vera patients. Among their conclusions were the
following: “Out of the untreated patients, 50% had died 18 months
after the onset of the first symptom or sign, and out of patients
treated with venesection half had died 3 1/2 years after this
juncture. Out of patients treated by X-rays half were alive 12 1/2
years after the first sign.”156 This article was one of the first to
report survival data and has been the rationale for the implementa-
tion of various treatments for polycythemia vera without provision
for the inclusion of the appropriate phlebotomy control group.238
And this was true even though 12 years previously, another Danish
physician, Videbaek, reporting on a series of 125 patients, noted a
50% survival of 4.5 years for men and 8.5 years for women treated
with phlebotomy or irradiation but not 32P.239 Indeed, Videbaek
came to the conclusion that “. . .a large proportion of the high
mortality which is known to attend polycythemia vera is not due to
inadequacy of the therapeutic measures, but rather to the fact that
the patients are not followed up as they should be,” a point ignored
not only by Chievitz and Thiede but also by many in the
hematology community.201,240-242
The differences between the experience of Videbaek and that of
Chievitz and Thiede can be explained in part by the fact that more
than twice as many of the patients in the latter series were older
than 65 years and age of onset appears to influence survival.215 At
the same time, Videbaek’s patients undoubtedly had less access to
medical care, which was also likely to have been of a lower
standard, making the differences in survival even more striking.
Furthermore, as stated previously, the literature contains sufficient
other support for the contention that the clinical course of
polycythemia vera, without treatment or treatment mainly by
phlebotomy, was not as dismal as described above.149,150 Therefore,
it is difficult to explain the universally uncritical acceptance of
Chievitz and Thiede’s conclusions except on the grounds that they
either suited the prejudice of those who were enamored of
particular therapies such as 32P204,237 or provided hematologists
with the same type of “constitutional privilege” with respect to the
treatment of polycythemia vera200,201,243,244 that is invoked by those
American citizens who support the right to bear arms without
restriction. Indeed, even today, there are advocates of 32P
therapy,201,245 although it has been widely appreciated for 50 years
that this agent was least effective against the most troublesome
feature of polycythemia vera, extramedullary hematopoiesis.167,189,246
Central to the myth of survival is the assumption that polycythe-
mia vera is a monolithic disease when in fact it is not122,146,246,247
and while no one would advocate withholding treatment once the
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
diagnosis was established, it is important to emphasize that the
disease can develop gradually and be substantially advanced before
it becomes clinically problematic (Figure 2). Presumably, this is a
consequence not only of the slow rate of hematopoietic cell
accumulation but also the concomitant compensatory expansion of
the plasma volume. The occurrence of a preclinical or asymptom-
atic phase was first documented by Rosenthal and Bassen,146
confirmed by Dameshek,148 and calculated to be between 17 and 80
months by Swolin et al based on the rate of accrual of cytogenetic
abnormalities.74 The Gruppo Italiano Studio Policitemia docu-
mented a significant incidence of thrombosis more than 2 years
before the diagnosis of polycythemia vera,244 as did the PVSG,248
and in another study, 11 of 13 patients with an intraabdominal
venous thrombosis had an elevated hematocrit level for 6 or more
months before onset of thrombosis,249 also supporting a significant
latent period even in symptomatic patients. Finally, Rozman et al250
and others251 have presented data suggesting that the life expect-
ancy of polycythemia vera patients in the modern era was not
greatly different from normal. Since both retrospective163 and
prospective controlled clinical trials have established that radiation
or chemotherapy did not prolong life more than phlebotomy,200 and
that the course of polycythemia vera is generally indolent, its
management should be in keeping with its tempo and not with what
we should acknowledge to be historical inaccuracies.
Phlebotomy and polycythemia vera:
women are not small men
Thrombosis and hemorrhage in polycythemia vera
Erythrocytosis not only distinguishes polycythemia vera from its
companion myeloproliferative disorders but is also responsible for
its most frequent and serious complications. Published data indi-
cate that thrombosis was the presenting feature in 12% to 49% of
patients,133,149,156,194,239,244,252,253 occurred in up to 40% during the
course of the illness,194 and was the cause of death in 20% to
40%.145,149,156,239,244,254 Furthermore, in 2 studies, 14% to 15% of
patients had a history of a thrombotic event at least 2 years before
diagnosis.244,248 In general, the central nervous system was the most
frequent site of thrombosis,156,244,253,255 arterial thrombosis was
more common than venous156,244,253-255 and the latter was character-
istically cerebral or intraabdominal and more frequent in
women,151,194,241 possibly in keeping with their higher incidence of
splenomegaly at presentation.239 Indeed, polycythemia vera was
the most common cause of hepatic vein thrombosis in the Western
hemisphere.256 Finally, although not as frequent as thrombosis,
hemorrhage in polycythemia vera was generally considered to be a
consequence of vascular stasis and thrombocytosis133,149,257 and
like thrombotic events, primarily involved the central nervous
system and the gastrointestinal tract, was a presenting manifesta-
tion in 6% to 58% of patients149,156,194,239 and fatal in up to
30.149,156,239,254
Whole blood viscosity
The mechanisms involved in the hypercoagulable state that charac-
terizes polycythemia vera are currently still under scrutiny258 even
though they were apparent to the first clinicians to study the
disease. The hematocrit is the principal determinant of blood
viscosity259-261 and nowhere is this more evident than in polycythe-
mia vera. Perhaps the most cogent observation in this regard was
made by Weber in 1908, “In every case examined after death the
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
distention of the visceral vessels has been very striking, the
mesenteric vessels presenting sometimes the appearance of having
been forcibly injected for purposes of anatomical demonstra-
tion.”262 Brown and Giffin added to that description in 1923 with
their study of nail-fold capillaries, which were elongated and
engorged to capacity due to the formation of red cell aggregates,
leading to diminution of blood flow that was most marked in the
venous limb.263 Since cardiac output was either normal or increased
in polycythemia vera patients due to an increased stroke vol-
ume,264,265 the diminution in capillary flow appeared to represent
the influence of both peripheral vasodilatation and increased blood
viscosity. In this regard, it needs to be emphasized that major vessel
venous thrombosis in polycythemia vera most likely represents the
end stage of a process beginning in very small vessels.266 These
observations are also compatible with the preponderance of
thrombotic events in the brain and the abdomen. In the former, an
increase in hematocrit was associated with a decrease in blood
flow,267-269 while the latter appears to be particularly vulnerable to
disorders conducive to stasis or endothelial damage such as sickle
cell anemia or paroxysmal nocturnal hemoglobinuria.
Although it has been argued that the decrease in cerebral blood
flow associated with a high hematocrit level is a physiologic
response to increased oxygenation not increased viscosity,270 the
data upon which this contention are based either actually support
the latter process270,271 or fail to substantiate the former since the
subjects studied were actually not sufficiently hyperviscous.272,273
On the contrary, there are physiologically sound data indicating
that cerebral blood flow like blood flow elsewhere274 declines
independently of oxygen transport when blood viscosity
increases.275
Blood viscosity is an exponential function of the hematocrit259
and red cell aggregation increases at high hematocrit levels,276
creating the potential for vascular stasis if red cell production is left
checked. While no other mechanism for thrombosis need be
invoked in this circumstance, other mechanisms could contribute.
Thus, increasing the hematocrit at flow rates found in the arterial
circulation enhanced platelet-vessel wall interactions277 and this
mechanism could be involved in the high incidence of arterial
thromboses without requiring an elevation in platelet count.255
Additionally, a high hematocrit level has also been found to
interfere with the vasodilatory effects of nitrous oxide278 which
could account for the hypertension associated with polycythemia
vera133,149,239,279 as well as its thrombotic tendency. Leukocytes can
impede red cell migration in capillaries,280 interact with platelets at
the vessel wall,281 and appear to be activated in polycythemia
vera,282,283 but their role in the thrombotic process remains
undefined because polycythemia vera patients treated with chemo-
therapy did not have a greatly diminished risk of thrombotic
events.200 Finally, although impairment of the fibrinolytic system284
and platelet activation285 have been observed in polycythemia vera
patients, such defects were not limited to this myeloproliferative
disorder. For example, spontaneous platelet aggregation was most
marked in patients with idiopathic myelofibrosis286 who were more
prone to hemorrhage than thrombosis.287 Finally, there is no
evidence that other coagulation defects predisposing to hypercoagu-
lability are more prevalent in polycythemia vera patients than in the
general population, although they are certainly not immune
to them.288,289
Phlebotomy therapy: pros and cons
Not only is there compelling evidence that increased blood
viscosity due to an elevated red cell mass is the principal basis for
POLYCYTHEMIA VERA: AN ANALYTICAL REVIEW 4281
the hypercoagulable state in polycythemia vera, there is equally
strong evidence that phlebotomy, a venerable practice that was well
known in the Hippocratic era, is the most effective remedy.
Unfortunately, it is both an irony and a tragedy that this is one
Hippocratic principle that many hematologists have been reluctant
to embrace wholeheartedly. The reasons are many but none are
clinically tenable or physiologically sound. First, although phle-
botomy was recognized by early clinicians as an effective method
of bringing symptomatic relief to polycythemia vera patients, the
adequate or consistent application of phlebotomy was deterred by
the concern that it would stimulate new blood formation. Thus, in
1928, an authoritative review of the disease stated “One must
conclude that while venesection is an important and useful in relief
in emergency in the treatment of these patients, it cannot be looked
upon in any other light than as a further, and therefore undesirable
stimulant to new blood formation.”159 This contention, reaffirmed
more than once in modern times in the absence of any
data,87,145,148,290 is, of course, erroneous, since bone marrow func-
tion in polycythemia vera, as in the other myeloproliferative
disorders, is autonomous and erythropoiesis can neither be sup-
pressed by hyperoxia10,291 nor substantially stimulated by hypoxia292 or
phlebotomy,12,13,293 and this appears to be true for thrombopoiesis
as well in the absence of anemia.150,182,293-295
Second, it has been contended that phlebotomy provokes
hypercoagulability. As stated by Osgood, “The major risks from
phlebotomy are that it sets in motion all the clotting mechanisms
plus suddenly reducing blood volume and possibly slowing the
blood current and results in increased risk of thromboses and iron
deficiency.”238 All aspects of this contention are indefensible. First,
to the extent that any form of erythrocytosis provokes a hemor-
rhagic diathesis, phlebotomy restores coagulant activity toward
normal by reducing blood viscosity296,297 and thereby improving
blood flow, platelet function,298,299 and the balance between coagu-
lation factor concentration and red cell number, and this is as true in
polycythemia vera133,300 as in the erythrocytosis of cyanotic
congenital heart disease.301 Second, in contrast to 32P therapy,
venesection actually expands the plasma volume and thus results in
a greater reduction in blood viscosity for any reduction in red cell
mass than the former297 (Table 3). Paradoxically, this effect of
venesection is also observed in pseudoerythrocytosis in which the
plasma volume is reduced,302 an effect not always recognized.110
Table 3. Effect of 32P therapy or phlebotomy on the plasma volume and
systemic vascular resistance in polycythemia vera
Therapy
32P Phlebotomy
Measurement Before After Before After
Systemic vascular resistance,
dynes s cm⫺5 1421 1990* 1504 1464
Red cell mass, mL/kg 57.3 28.4* 54.8 39.5*
Plasma volume, mL/kg 37.0 39.3 38.5 48.7*
Total blood volume, mL/kg 94.3 67.6* 93.3 88.2*
Hematocrit, % 64.0 44.0* 63.0 47.0*
Hemoglobin, gm% 19.9 14.9* 19.9 14.9*
In contrast to phlebotomy therapy, 32P not only reduced the red cell mass but also
the plasma volume, resulting in an increase in systemic vascular resistance even
though the red cell mass was reduced to normal. Elevation of the plasma volume by
phlebotomy expanded the total blood volume and reduced systemic vascular
resistance even though phlebotomy therapy in these patients was insufficient to
reduce the red cell mass to normal. Noteworthy for the phlebotomy group is that the
hematocrit and hemoglobin levels were apparently normal even though the red cell
mass was still increased due to masking by the expanded plasma volume. The data
are from Segel and Bishop.297
*Significantly different from before therapy (P ⬍ .01).
4282 SPIVAK
Moreover, in addition to a direct reduction in total blood volume,
plasma volume expansion is another relatively immediate effect,303
making phlebotomy at once both corrective and protective. Finally,
the effectiveness of venesection in relieving symptoms due to an
elevated red cell mass has been repeatedly documented in patients
with secondary forms of erythrocytosis.304-307
Iron deficiency and whole blood viscosity
Concerns over the adverse effects of phlebotomy-induced iron
deficiency relate to both its side effects and the potential for
increased blood viscosity.308,309 The former concern was addressed
by exercise studies of chronically iron-deficient polycythemia vera
patients in whom no impairment of aerobic capacity was de-
tected,310 nor were functional signs of iron deficiency observed
other than the gustatory perversion pica.311 Iron deficiency–related
hyperviscosity is a test tube artifact308,309 that also has no physi-
ologic basis.312,313 Although iron-deficient red cell membranes may
be less deformable than normal,314 this abnormality is apparently
offset by their reduced size and internal viscosity since their
hemoglobin content is also reduced.315 Thus, at comparable
hematocrit levels, iron-deficient blood was not more viscous than
normal.312,313 Furthermore, red cell–platelet interactions are influ-
enced by red cell diameter and such interactions are reduced with
small red cells.315 Finally, a state of chronic iron deficiency that
limits erythropoiesis is actually the ultimate goal of phlebotomy
therapy in polycythemia vera, a goal that is unfortunately fre-
quently not achieved judging from published results.156,200,239,244
Phlebotomy and myelofibrosis
A more serious claim has been that the use of phlebotomy therapy
alone in polycythemia vera results in a high incidence of myelofi-
brosis,316 a claim that is difficult to understand except as population
specific since it is contrary to most published experience. For
example, in a series of 207 patients followed for more than 10
years, only 4 patients treated solely by phlebotomy developed
myelofibrosis,149 while in another series of 250 patients, none of the
patients treated solely by phlebotomy developed myelofibrosis.156
Indeed, this experience has been the rule148,156,163 rather than the
exception. As a corollary, the low incidence of polycythemia vera
patients recorded in a published series of myelofibrosis pa-
tients173,175,190,192 as well as the high incidence of myelofibrosis
observed in patients treated with hydroxyurea169 suggest that this
complication is neither frequent nor limited to patients exposed
only to phlebotomy. Furthermore, since myelofibrosis can be a
presenting manifestation of polycythemia vera73,317 and also occurs
in patients exposed to 32P163,189,318 and x-ray therapy,156,163,234 there
are no grounds to implicate venesection as a specific causal factor.
An additional difficulty in this regard, as discussed above, is the
definition of myelofibrosis; a dry tap or increased reticulin is not
sufficient for this purpose.158,179 Finally, implicit in this contention
is the notion that myelofibrosis is deleterious in polycythemia vera,
when in fact it is perfectly compatible with normal bone marrow
function,134,155,181,183 is a reversible process,168,175,184-186 and has not
been shown to impact adversely on survival.150,174,177 Indeed,
failure to recognize polycythemia vera presenting as myelofibrosis
is potentially more deleterious than the development of myelofibro-
sis during the course of the disease.
Phlebotomy and thrombosis
The most serious and damaging criticism of phlebotomy therapy in
polycythemia vera is that it was associated with an excess of
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
thrombotic events compared with other treatments.200 Unfortu-
nately, the data upon which this criticism is based were the
consequence of a complete misunderstanding of the pathophysiol-
ogy of erythrocytosis in polycythemia vera. In contrast to other
forms of erythrocytosis in which expansion of the red cell mass is
typically accompanied by a reduction in plasma volume, expansion
of the plasma volume is common in polycythemia vera.110,132 That
this was not initially appreciated was presumably due to the
practice of measuring only the red cell mass.319 Plasma volume
expansion is associated with a concomitant reduction in peripheral
vascular resistance and an increased cardiac stroke volume for its
accommodation. As a consequence, although peripheral vascular
resistance eventually increases, it does so more slowly than when
erythrocytosis occurs in a normovolemic setting and systemic
oxygen transport is actually increased at any given hematocrit
level.320 However, because of the plasma volume expansion, the
hematocrit is no longer an accurate indicator of the red cell mass in
polycythemia vera patients and this is particularly true when
splenomegaly is present.130-132 Therefore, it is not surprising that
PVSG data indicated that approximately 15% of patients with a
hematocrit level of 50% and up to 40% with hematocrit levels of up
to 55% had an elevated red cell mass88; similar observations have
been made by others.321 More importantly, not only is cerebral
blood flow impaired in polycythemia vera patients when the
hematocrit level is more than 45%,267 but the incidence of
thrombotic events shows a linear increase above the same hemato-
crit level.322 Thus, hematocrit values that are apparently within the
normal range cannot be considered as safe in polycythemia vera
patients and it is this syndrome of masked or inapparent erythrocy-
tosis132 due to plasma volume expansion that is not only respon-
sible for what has been termed a latent,323 “prethrombotic,”244 or
“forme fruste”324 myeloproliferative disorder but also the increased
incidence of thrombotic events in such patients. Since even under
normal circumstances, the hematocrit level in most organs with the
exception of the spleen is much lower than the venous hematocrit
level,124 it is clear that the situation in polycythemia vera is actually
more serious than it appears and that the so-called “prethrombotic
state” of polycythemia vera merely reflects inadequate reduction of
the red cell mass.
The physiology of red cell mass expansion in polycythemia
vera appeared to have been disregarded in the defining PVSG
protocol-01, in which the phlebotomy treatment threshold was
initially set at 50%,72 even though as indicated above, a minimum
of 15% of male patients would be undertreated at this hematocrit
level, as would 100% of women, since no woman normally has a
hematocrit level of 50%. Unfortunately, even when the hematocrit
threshold for phlebotomy was subsequently lowered to 45%,248
women patients were still at risk of undertreatment. Thus, the
therapeutic conundrum of the PVSG, that treatment by phlebotomy
alone resulted in a higher incidence of thrombosis during the first 3
years of therapy while chemotherapy or radiotherapy resulted in a
high incidence of malignancy thereafter,243 was not a conundrum at
all but rather the consequence of inadequate reduction of the red
cell mass to begin with. Furthermore, since in polycythemia vera
red cell production is tightly linked to the iron supply,325 differ-
ences in phlebotomy requirements were not a function of a
difference in disease activity243 but rather in the extent of iron
stores or availability. Unfortunately, based on a recent survey, an
inappropriately high threshold for phlebotomy therapy is still being
employed by many American hematologists.7
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
Thrombocytosis and polycythemia vera:
platelets at your finger tips
Fact versus fiction
Perhaps no other medical condition has caused more otherwise
astute clinicians to abandon disbelief than thrombocytosis, particu-
larly with respect to its contribution to the coagulopathy of
polycythemia vera. The high frequency of vascular occlusion
associated with this disease had been recognized for many years159
but not until 1938, in the absence of any proof, was it suggested that
thrombocytosis was a cause of major vessel thrombosis,146 a
suggestion subsequently accepted by influential clinicians145,154,290
without corroborating evidence. There is a particular irony in this
since when essential thrombocytosis was first recognized, not only
was it called hemorrhagic thrombocythemia326 but many of the
patients described actually had unrecognized polycythemia
vera.327,328 More importantly, no study to date, either prospective or
retrospective, has demonstrated a correlation between platelet
number or function and major vessel thrombosis. For example, in
the PVSG prospective trial involving 431 patients, there was no
correlation between an elevated platelet count and the risk of
thrombosis,243 while a follow-up study employing antiplatelet
agents failed to demonstrate a reduction in thrombotic events.329
This should not have been surprising considering the number of
retrospective studies that failed to identify a correlation between
the platelet count and risk of thrombosis,87,150,255,330,331 the well-
established correlation of thrombosis with an elevated hematocrit
level,322,331 and the failure of the PVSG to ensure adequate
reduction of the red cell mass in their patients.72,200 Furthermore,
even though a large number of platelet function abnormalities have
been identified in polycythemia vera, they did not correlate with the
development of thrombosis332 nor did age in some series.333
Additionally, even when patients with isolated thrombocytosis
were considered, it was difficult to incriminate the platelet count as
a thrombotic risk factor. For example, most patients with familial
thrombocytosis did not have an increased incidence of thrombosis334-338
nor did those with reactive thrombocytosis339 and in the only
prospective, controlled study of essential thrombocytosis to date,
the incidence of thrombosis in untreated patients was not greater
than in the control population.340
Part of the problem with defining the role of thrombocytosis as a
thrombotic risk factor has been the intuition that it must be. This
has led to reportorial bias with the publication and uncritical
acceptance of anecdotal and incompletely studied case reports of
unexpected thrombotic events occurring in association with throm-
bocytosis.242,341-343 These, unfortunately, not only fail to establish a
cause and effect relationship but also merely provide a numerator
without any denominator. As an example, when the factors
associated with hepatic vein thrombosis were evaluated retrospec-
tively, it was found that this event was actually preceded by a high
hematocrit level and followed by thrombocytosis.249 A second issue
has been failure to consider other causes for hypercoagulability
within the population under study such as the antiphospholipid
syndrome344 or cardiovascular risk factors.345,346 In this regard, it is
worth noting that the frequency of coronary artery thrombosis in
the PVSG-01 trial243 was more in keeping with the latter than the
frequency found by others for polycythemia vera patients in the
absence of atherosclerotic disease.253 Indeed, when one considers
the vaso-occlusive havoc initiated by heparin-induced thrombocy-
topenia or thrombotic thrombocytopenic purpura, it becomes
POLYCYTHEMIA VERA: AN ANALYTICAL REVIEW 4283
immediately obvious that platelet number alone is not a critical
determinant of hypercoagulability.
Hemorrhage and microvascular thrombosis
However, there is definitely a role for platelets in the coagulopathy
that complicates polycythemia vera. With respect to bleeding, it has
been established that platelet counts of more than 1 000 000/␮L
were associated with a hemorrhagic diathesis regardless of the
cause.347,348 This was thought to be due to a reduction in high-
molecular-weight von Willebrand multimers owing to their adsorp-
tion to platelets349 and was reversible with a reduction in platelet
number350 or treatment with DDAVP.351 Equally important, and
paradoxically, considering its effect on von Willebrand multimers,
thrombocytosis can cause microvascular arteriolar thrombosis.
This is manifest most often in peripheral vessels by the syndrome
of erythromelalgia,352,353 and in the nervous system by a constella-
tion of symptoms such as headache or ocular disturbances, often
migrainous in type, amaurosis fugax, vertigo, diplopia, vertigo,
hemiparesis, paresthesias, numbness, dysarthria, aphasia, and syn-
cope.354 Usually transient and rarely progressive, these symptoms
are distressing to patients and alarming to their physicians. Not
infrequently, they may occur as the presenting manifestation of
polycythemia vera and if superimposed on an already compro-
mised vascular system could lead to a stroke, myocardial infarc-
tion, or peripheral gangrene.352,355 While the mechanism for
platelet-associated microvascular occlusion is unknown, it is
associated with increased platelet thromboxane B formation356 and
increased platelet turnover.357,358 Both can be reversed or prevented
by aspirin-induced platelet inactivation or a reduction in platelet
count, though not necessarily to normal, suggesting that both
platelet activation and platelet number are important. However, as
demonstrated clinically,329 unless the red cell mass is appropriately
reduced, antiplatelet therapy or chemotherapy will be futile, and
this stipulation should be mandatory for any prospective study of
the effect of antiplatelet therapy on large vessel thrombosis in
polycythemia vera.
The management of polycythemia vera:
first, do no harm
From the foregoing it is clear that the diagnosis and management of
polycythemia vera continue to present formidable problems: poly-
cythemia vera is a clonal disorder for which there is as yet no
clinically validated clonal marker; trilineage hyperplasia is the
hallmark of polycythemia vera but clinically the disease can mimic
not only its companion myeloproliferative disorders, idiopathic
myelofibrosis, and essential thrombocytosis, but also nonclonal
causes of erythrocytosis; the disease is uncommon but its present-
ing manifestations are protean, ranging from intractable pruritus to
the Budd-Chiari syndrome. Moreover, due to plasma volume
expansion, splenomegaly, or hemorrhage, erythrocytosis, the one
feature that sets polycythemia vera apart from the other chronic
myeloproliferative disorders, may not be clinically obvious.132
Furthermore, contrary to conventional wisdom, the natural history
of polycythemia vera has not been completely defined and neither
staging criteria nor the factors affecting prognosis have been
established even though it is well documented that the clinical
course of the disorder is variable and that age and sex have an
important influence in this regard.
While the currently accepted diagnostic criteria for polycythemia
vera are useful for protocol studies, they do not define the limits of the
4284 SPIVAK
disease, and a recent poll suggests considerable ambivalence among
hematologists as to the optimal approach to the diagnosis of the disease
as well as to its treatment.7 Remarkably, although erythrocytosis is the
one feature that distinguishes polycythemia vera from its companion
myeloproliferative disorders and the most frequent cause of serious
complications, the utility of red cell mass and plasma volume determina-
tions for diagnosis has been questioned as has the effectiveness of
phlebotomy therapy. Unfortunately, the only prospective, controlled
clinical trial of the disorder to date with respect to phlebotomy therapy,
that of the PVSG, was flawed because the target hematocrit level chosen
for phlebotomy therapy was too high.200 Thus, the therapeutic dilemma
that patients treated initially with phlebotomy had an unacceptably high
incidence of early thromboses while those treated with chemotherapy or
32P later had a high incidence of leukemia, lymphoma, or cancer,243 is
probably more apparent than real, at least with respect to the phlebotomy
group. In the same fashion, given the lack of attention to reducing blood
viscosity in this disorder, it can be seriously questioned whether a prior
history of thrombosis and advanced age are truly risk factors for
thrombosis in polycythemia vera patients.331 Certainly, neither chemo-
therapy nor radiotherapy has proved superior to phlebotomy in prevent-
ing thrombosis but both have proved to be more toxic.244 Furthermore,
since polycythemia vera appears to be a myeloaccumulative disorder
rather than a myeloproliferative one, at least with respect to the
erythrocytosis and a disorder that is often indolent and of long duration,
its treatment should be commensurate with that behavior.
The first issue with respect to management is diagnosis and it should
be obvious that it is not possible to accurately estimate the red cell mass
from the hematocrit level when polycythemia vera is a diagnostic
consideration and the hematocrit level is less than 60% in a man or 50%
in a woman. Measurement of the red cell mass and plasma volume by
isotope dilution should be a standard of care but unfortunately this
standard is more often honored in the breach than in the observance. In
some locales, bogus medical economics have been allowed to dictate the
availability of these procedures, which can only be seen as an abdication
of our professional responsibilities as hematologists. While elevation of
the red cell mass does not establish the diagnosis of polycythemia vera,
the diagnosis cannot be made in its absence. Even if a clonal assay for
polycythemia vera were available, such an assay would not abrogate the
need for red cell mass and plasma volume determinations in this disease
any more than the HFE assay for hemochromatosis has abrogated the
need for serum transferrin saturation measurements as a guide to both
diagnosis and therapy.
Reduction of the red cell mass and maintaining it at a safe level
by phlebotomy (hematocrit level of ⬍ 45% in men and ⬍ 42% in
women and ⬍ 36% during pregnancy) is the first principle of
therapy in polycythemia vera. Venesection is a safe and immedi-
ately effective therapy and its desired side effect, iron deficiency, is
not a liability,310 claims that cannot be made for any of the
surrogate therapies for polycythemia vera that have been proposed
to date. Reduction of the red cell mass and maintaining it at a
physiologic level removes a major source of complications and
may also alleviate systemic hypertension and pruritus359 and reduce
splenomegaly.161,360 For many patients, no other therapy may be
necessary for many years. Aspirin or anticoagulants such as
coumadin are not substitutes for adequate phlebotomy; low doses
of aspirin block urate excretion while titration of the coumadin
dose can be difficult if the red cell mass is not controlled.
Occasionally, with blood loss or overzealous phlebotomy, symptom-
atic anemia can ensue. Judicious iron replacement can accelerate
the recovery process but too much iron will result in an explosive
increase in red cell mass. The other complications of polycythemia
vera (Table 4), with the exception of leukemic transformation,
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
Table 4. The complications of polycythemia vera
Complication Cause
Thrombosis, hypertension Elevated red cell mass
Organomegaly Elevated red cell mass or
extramedullary hematopoiesis
Pruritis, acid-peptic disease Inflammatory mediators or elevated
red cell mass
Hyperuricemia, gout, renal stones Increased cell turnover
Erythromelalgia or ocular migraine Thrombocytosis
Hemorrhage Elevated red cell mass, or acquired
von Willebrand disease due to
thrombocytosis
Myelofibrosis Reaction to the neoplastic clone
Wasting syndrome Disease acceleration
Acute leukemia Therapy-related or clonal evolution
represent the consequences of cell accumulation manifested as
organ enlargement, microvascular occlusive or hemorrhagic phe-
nomenon, hyperuricemia, or cytokine-mediated events such as
pruritus and acid-peptic disease, but their treatment need not
necessarily be genotoxic. For example, aspirin alone353,361 or
anagrelide362 may be sufficient to combat the microvascular
occlusive syndrome associated with thrombocytosis. It is, of
course, important to remember that polycythemia vera patients are
not immune to other illnesses causing thrombosis. Similarly, a
modest leukocytosis requires no correction; however, if progres-
sive, leukocytosis is a harbinger of extramedullary hematopoiesis
or disease acceleration. In which case, the leukocytosis can serve as
a guide to disease control following the institution of therapy.
Because there is currently no clonal marker for polycythemia
vera, it is currently impossible to determine if a particular therapy is
curative or merely palliative. In this regard, the long natural history
of the disorder and the infrequent and unpredictable occurence of
spontaneous leukemic transformation make it difficult to establish
the superiority of any therapy or to recommend a potentially
curative therapy such as allogeneic bone marrow transplantation
that carries an immediate obligate mortality as well as the potential
for substantial chronic morbidity. We are, however, fortunate to
have a variety of symptomatic remedies for the many complica-
tions of polycythemia vera because no single remedy has proved
completely effective for any of them. However, many of these
remedies are not without risk and have their own unique toxicities.
For example, pruritus can prove to be so intractable to phlebotomy,
antihistamines, or psoralen-activated light therapy that resort must
be made to suppression of hematopoiesis with alpha interferon,
hydroxyurea, or even busulphan. Splenomegaly due to extramedul-
lary hematopoiesis can be similarly difficult to manage. Yet
attempts to avoid the complications of cell accumulation by
chemotherapy or irradiation have not been without substantial
toxicity,163,200,244 and while alpha interferon is a promising agent in
this regard,363 it can have substantial side effects, particularly in the
elderly364; it is also unknown whether this agent can alter the
natural history of polycythemia vera. Tolerance to alpha interferon
may be aided by starting with a low dose (500 000 U, 3 times per
week) and escalating slowly; the addition of an antidepressant has
also been found helpful.365 Although alpha interferon is expensive
and its side effects can be debilitating, it has not been demonstrated
to cause permanent marrow damage. The same may not be true for
hydroxyurea,212,214,366 although the evidence is not entirely conclu-
sive at this time. However, this was also the situation initially for
other cytotoxic agents that subsequently proved to be leukemo-
genic in this disease. Therefore, it seems prudent to employ
BLOOD, 15 DECEMBER 2002 䡠 VOLUME 100, NUMBER 13
hydroxyurea only when other remedies have failed and to avoid
long-term exposure whenever possible.
Since few physicians see many of these patients, the concerns
described above emphasize the need to gain greater insight into the
natural history of polycythemia vera and to reinitiate prospective,
controlled multicenter clinical trials using the wisdom gained from
such initiatives as the Cooperative Study of Sickle Cell Disease367
and the PVSG. Until such a time as those goals are realized, we can
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