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Blood First Edition Paper


prepublished online August 8, 2002; DOI 10.1182/blood-2001-
12-0349
Blood, 15
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2001-12-0349v1

Polycythemia vera: myths, mechanisms, and


management
Jerry L. Spivak

From the Division of Hematology, Department of Medicine, Johns


Hopkins University School of Medicine, Baltimore, MD.

Introduction
Top
Polycythemia vera is a clonal
Introduction
disorder arising in a multipotent The pathogenesis of...
hematopoietic progenitor cell that The diagnosis of polycythemia...
The diagnosis of polycythemia...
causes the accumulation of Anecdote as paradigm: the...
Survival with polycythemia...
morphologically normal red cells, Phlebotomy and polycythemia...
white cells, platelets, and their Thrombocytosis and polycythemia...
progenitors in the absence of a The management of polycythemia...
References
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 sufficiently 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
Top
Erythropoiesis and growth factor
Introduction
hypersensitivity The pathogenesis of...
The diagnosis of polycythemia...
Because it involves a multipotent Anecdote as paradigm: the...
hematopoietic progenitor cell, the Survival with polycythemia...
hallmark of polycythemia vera is Phlebotomy and polycythemia...
Thrombocytosis and polycythemia...
trilineage hematopoietic cell The management of polycythemia...
hyperplasia. However, References
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
erythropoiesis 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
erythropoiesis in polycythemia vera patients, phlebotomy does not
stimulate it,12,13 and serum erythropoietin levels are lower than in any
other disease 14 (Figure 1).

Figure 1. Relationship
between serum erythropoietin
and hemoglobin in patients
with polycythemia vera
( ), secondary
erythrocytosis ( ) or
relative erythrocytosis (x).
Adapted from Handin et al369
with permission of the
View larger version (11K):
publisher, Lippincott, Williams,
[in this window]
and Wilkins.
[in a new window]

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
Importantly, primitive polycythemia vera erythroid progenitor cells
exhibiting either erythropoietin-dependence or -independence could give
rise to both erythropoietin-dependent and -independent progeny, a
characteristic 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
erythropoietin milieu.
This dominance may also involve transforming growth factors produced
by polycythemia vera mononuclear cells 19 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 cells 27
and although overexpression of INK4a and ARF has also been
documented in these cells 28 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 regulation 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
cells 35 but the development of erythropoietin hypersensitivity or
independence as a consequence of gain in function mutations in the
ligand-binding and cytoplasmic domains of the erythropoietin receptor 36
raised the possibility that this receptor was involved in the pathogenesis
of the disease. However, 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 erythropoietin receptor gene amplification, rearrangements, or
functional mutations have been identified in polycythemia vera
patients.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 constitutively-active
erythropoietin receptor caused both erythrocytosis and thrombocytosis in
vivo, 41 it did not cause trilineage hematopoietic 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 receptor 44 while promoting differentiation. 45
The truncated erythropoietin receptor splice variant was either not
expressed well or at all in various erythroleukemia cell lines 42,46 and its
expression was also decreased or absent in polycythemia vera
mononuclear cells. 46 Since polycythemia vera erythroid progenitor cells
differentiate more quickly than their normal counterparts, 18 the
significance 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 Erythropoietin deprivation results in cell cycle
arrest in G0 /G1 ,50 and 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 differentiation 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 prolongation 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 differentiation 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. Therefore, 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 expression 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
differentiation 54 and whether accelerated terminal erythroid
differentiation in polycythemia 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.

Figure 2. Rate of rise of the


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
View larger version (15K): Conley 368 with permission of
[in this window] the publisher, The McGraw-
[in a new window] Hill Companies.

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 the antiapoptotic
growth factor IGF-1.22 Furthermore, IGF-1 receptors 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 hematopoietic 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 + cells 62 and in conjunction with
erythropoietin, the production 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 expression 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
differentiation in the absence of growth factors.68 Finally, Mpl
expression 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
demonstration 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 fundamental 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
Top
Diagnostic criteria Introduction
The pathogenesis of...
William Osler was not the first to The diagnosis of polycythemia...
describe a patient with Anecdote as paradigm: the...
polycythemia vera.3 He was, Survival with polycythemia...
Phlebotomy and polycythemia...
however, the first to emphasize that Thrombocytosis and polycythemia...
phenotypic mimicry could The management of polycythemia...
confound the diagnostic process References
and to 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 later 72 (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. Furthermore, while nonrandom
cytogenetic abnormalities and myelofibrosis have diagnostic
implications, neither has prognostic implications 74,75 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 unexpressed 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.

Table 1. The diagnosis of polycythemia vera


View this table:
[in this window]
[in a new window]

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 because as the red cell mass
expands, both improved tissue oxygenation and the associated increase
in blood viscosity serve to depress erythropoietin production, 76 while the
plasma residence of erythropoietin is simultaneously reduced through
increased catabolism by the expanded erythroid progenitor cell pool. 77
The net result is that 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
erythrocytosis, 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 erythrocytosis79,80 and in healthy
controls79,81 as well as in essential thrombocytosis.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 initially4,87,88 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 chemotactants 92), and platelets (eg, reduced PGD 2
receptor expression, 93 impaired lipoxygenase generation 94,95) 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
documented 96 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
Interestingly, 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
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 myelofibrosis and essential
thrombocytosis. Nonrandom chromosome abnormalities 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 cytogenetic 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 However, 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 consequences
of transformation of a multipotent hematopoietic progenitor cell, there is
currently no way to establish clonality in the majority of patients
considered to have the disease. While this is 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
nonclonal 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 polycythemia 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 particular 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 hyperbole 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, erythropoietin 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 tension 116 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
transfusion 119 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 polycythemia vera where erythropoiesis
is autonomous and erythropoietin production is suppressed, as the red
cell mass increases the plasma volume may be unchanged or increase 121
until the hematocrit level is more than 60%. 122

Unfortunately, the hematocrit level, whether directly determined 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 independent 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 vessels. 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
differently, 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 repeatedly


confirmed125,126,137,138 that only by independently measuring the red
cell mass (currently with 51chromium) and the plasma volume (with
125 I-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. Consequently, 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
hematocrit 141 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 problem. 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 determination
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.

Table 2. Examples of the diagnostic value of


View this table: red cell mass (RCM) and plasma volume
[in this window] (PV) determinations
[in a new window]

Anecdote as paradigm: the natural history


of polycythemia vera has not yet been
defined
Top
The description of the natural Introduction
history of polycythemia vera in The pathogenesis of...
current hematology textbooks The diagnosis of polycythemia...
disguises the fact that little more is Anecdote as paradigm: the...
Survival with polycythemia...
known today about its clinical Phlebotomy and polycythemia...
course than was known 80 years Thrombocytosis and polycythemia...
ago. Attempts to define the natural The management of polycythemia...
References
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 physicians
from seeing more than a few of these patients or even following them for
a sufficient duration to encounter the full scope 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 description 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 manifestations 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 disorders are interrelated152
when in fact proof is lacking that they are.153

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 disease 155 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
uncommon.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 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 polycythemia


vera, myeloid metaplasia and myelofibrosis. Since splenomegaly in
polycythemia vera is initially due to red cell congestion, 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 organomegaly, 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
survival.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 mechanisms for myelofibrosis are
poorly understood 170-172 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
substantiated scientifically. Indeed, some investigators have considered
the development of myeloid metaplasia and myelofibrosis in
polycythemia vera as indicating the onset of a "transitional
myeloproliferative 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 another erroneous
assumption.75,150,156,174,177

Because there is no widely accepted standard for the quantitation of


marrow reticulin 158 nor a universally acknowledged definition 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"
phase 75,134,135,155,158,181-183 and can be modified to a certain extent by
therapy,75 particularly with busulfan. 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 exposed 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 diagnosis, 73,181,194,195 a finding that appeared to
have no prognostic significance. 75,150,167 This is in contrast to
development of myelofibrosis in CML, which is generally associated
with disease acceleration. 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 "postpolycythemic 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 polycythemia
vera in the absence of exposure to mutagenic therapy.197 Of
83 published cases, only 30 had unequivocal evidence of polycythemia
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
frequency. By contrast, the advocates of 32P therapy thought that the
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 spondylitis 202 and thymic enlargement 203 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 hematologic 205 and nonhematologic neoplasms.206
Importantly, from a biologic perspective, the leukemogenic effect of
irradiation or alkylating agents in polycythemia vera was neither
qualitatively nor quantitatively 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
suggesting 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 observed 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 reports 215-217 and an additional
11 patients identified by questionnaire 215 in whom acute leukemia
complicated polycythemia 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 60.5 years, in contrast to those developing acute
leukemia following 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 splenectomy 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 erythrocytosis 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 state 222-225 have all
been considered to have a role. In some instances, the development of
myelodysplasia or acute leukemia could even be considered a
paraneoplastic syndrome 226,227 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
polycythemic 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 myelofibrosis223 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 metaplasia, 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
polycythemia vera is uncommon and certainly not inevitable, and our
patients deserve to know this.

Survival with polycythemia vera:


hematology's second amendment privilege
Top
Probably no myth has been more Introduction
pernicious with respect to the well The pathogenesis of...
being of polycythemia vera The diagnosis of polycythemia...
patients than the myth of survival Anecdote as paradigm: the...
which exists in 2 versions. It is Survival with polycythemia...
Phlebotomy and polycythemia...
difficult to understand how this Thrombocytosis and polycythemia...
myth attained credibility since The management of polycythemia...
there were both anecdotal References
reports 185,234,235 and
observational series 146,147,149,236 that firmly established the prolonged
survival of polycythemia vera patients in an era when the mainstays of
therapy were phlebotomy, phenylhydrazine, 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 implementation 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 polycythemia vera


is a monolithic disease when in fact it is not 122,146,246,247 and while no
one would advocate withholding treatment once the 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 asymptomatic 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 documented 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
others 251 have presented data suggesting that the life expectancy 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
Top
Thrombosis and hemorrhage in Introduction
polycythemia vera The pathogenesis of...
The diagnosis of polycythemia...
Erythrocytosis not only Anecdote as paradigm: the...
distinguishes polycythemia vera Survival with polycythemia...
from its companion Phlebotomy and polycythemia...
Thrombocytosis and polycythemia...
myeloproliferative disorders but is The management of polycythemia...
also responsible for its most References
frequent and serious complications.
Published data indicate 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 venous 156,244,253-255 and the latter was
characteristically 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 manifestation 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 characterizes
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 polycythemia vera. Perhaps the most cogent
observation in this regard was made by Weber in 1908, "In every case
examined after death the 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
demonstration." 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 volume,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 hematocrit 259 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
chemotherapy did not have a greatly diminished risk of thrombotic
events.200 Finally, although impairment of the fibrinolytic system 284 and
platelet activation 285 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 hypercoagulability 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 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
phlebotomy 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 function in polycythemia vera, as in the other myeloproliferative
disorders, is autonomous and erythropoiesis can neither be suppressed 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 hemorrhagic 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 coagulation 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 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

Table 3. Effect of 32P therapy or phlebotomy


View this table:
View this table: on the plasma volume and systemic vascular
[in this window] resistance in polycythemia vera
[in a new window]

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 detected, 310 nor were functional
signs of iron deficiency observed other than the gustatory perversion
pica.311 Iron deficiency-related hyperviscosity is a test tube
artifact 308,309 that also has no physiologic 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
influenced 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 frequently 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 myelofibrosis,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 patients173,175,190,192 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 myelofibrosis 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 thrombotic
events compared with other treatments.200 Unfortunately, the data upon
which this criticism is based were the consequence of a complete
misunderstanding of the pathophysiology 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
hematocrit 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
erythrocytosis132 due to plasma volume expansion that is not only
responsible 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 differences 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

Thrombocytosis and polycythemia vera:


platelets at your finger tips
Top
Fact versus fiction Introduction
The pathogenesis of...
Perhaps no other medical condition The diagnosis of polycythemia...
has caused more otherwise astute Anecdote as paradigm: the...
clinicians to abandon disbelief than Survival with polycythemia...
Phlebotomy and polycythemia...
thrombocytosis, particularly with Thrombocytosis and polycythemia...
respect to its contribution to the The management of polycythemia...
coagulopathy of polycythemia References
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
clinicians 145,154,290 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
thrombosis 332 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 thrombosis 334-338 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 thrombocytosis.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 retrospectively, 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 syndrome 344 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 thrombocytopenia or
thrombotic thrombocytopenic purpura, it becomes 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/µL 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 adsorption to platelets 349 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 constellation of symptoms such as headache or ocular disturbances,
often migrainous in type, amaurosis fugax, vertigo, diplopia, vertigo,
hemiparesis, paresthesias, numbness, dysarthria, aphasia, and
syncope. 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 compromised vascular system could lead
to a stroke, myocardial infarction, or peripheral gangrene.352,355 While
the mechanism for platelet-associated microvascular occlusion is
unknown, it is associated with increased platelet thromboxane B
formation 356 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
Top
From the foregoing it is clear that Introduction
the diagnosis and management of The pathogenesis of...
polycythemia vera continue to The diagnosis of polycythemia...
present formidable problems: Anecdote as paradigm: the...
polycythemia vera is a clonal Survival with polycythemia...
Phlebotomy and polycythemia...
disorder for which there is as yet Thrombocytosis and polycythemia...
no clinically validated clonal The management of polycythemia...
marker; trilineage hyperplasia is References
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 presenting 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
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
determinations 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
chemotherapy nor radiotherapy has proved superior to phlebotomy in
preventing 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 immediately 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, symptomatic
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, represent the
consequences of cell accumulation manifested as organ enlargement,
microvascular occlusive or hemorrhagic phenomenon, 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 progressive, 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.

Table 4. The complications of polycythemia


View this table: vera
[in this window]
[in a new window]

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 complications 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
extramedullary 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
elderly 364 ; 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 conclusive at this time. However, this was
also the situation initially for other cytotoxic agents that subsequently
proved to be leukemogenic in this disease. Therefore, it seems prudent to
employ 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 do no better than to heed the
advice of William Dameshek, a proponent of phlebotomy therapy in
polycythemia vera: "There seems to be a tendency in medical practice
by no means limited to hematologists to treat almost every condition
as vigorously as possible. In hematology, this consists in attempting to
change an abnormal number whether this number is hemoglobin,
hematocrit, WBC, platelet count to normal values whether the patient
needs it or not!" 238

Footnotes
Submitted December 28, 2001; accepted July 15, 2002.

Prepublished online as Blood First Edition Paper, August 8, 2002; DOI


10.1182/blood-2001-12-0349.

Reprints: Jerry L. Spivak, Traylor 924, Johns Hopkins University


School of Medicine, 720 Rutland Ave, Baltimore, MD 21205; e-mail:
jlspivak@jhmi.edu.
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