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Polycythemia
Victor Politi, M.D., FACP
Medical Director, SVCMC, School of
Allied Health Professions, Physician
Assistant Program
Introduction
Polycythemia vera is a chronic
myeloproliferative disorder characterized
by increased red blood cell mass (RCM),
or erythrocytosis
 The resultant hyperviscosity of the blood
predisposes such patients to thrombosis

Introduction

Increased RCM is accompanied by
increased white blood cell (myeloid) and
platelet (megakaryocytic) production,
which is due to an abnormal clone of the
hematopoietic stem cells with increased
sensitivity to the different growth factors
for maturation.
Introduction

Its etiology is not fully established, but
hypersensitivity to interleukin-3 may play a
role in the sustained erythrocytosis
observed in this disease.
Introduction

Polycythemia vera should be suspected in
patients with elevated hemoglobin or
hematocrit levels, splenomegaly, or portal
venous thrombosis.
Introduction

Secondary causes of increased red blood
cell mass (e.g., heavy smoking, chronic
pulmonary disease, renal disease) are
more common than polycythemia vera and
must be excluded
Introduction


Patients may present with complaints of pruritus
after bathing, burning pains in the distal
extremities (erythromelalgia), gastrointestinal
disturbances, or nonspecific complaints such as
weakness, headaches, or dizziness.
Other patients are diagnosed after an incidental
finding of an elevated hemoglobin and/or
hematocrit level on a complete blood count.
Introduction

Diagnosis is made using criteria
developed by the Polycythemia Vera
Study Group; major criteria include
elevated red blood cell mass, normal
oxygen saturation, and palpable
splenomegaly.
Introduction

Untreated patients may survive for six to
18 months, whereas adequate treatment
may extend life expectancy to more than
10 years.
Introduction
Treatment includes phlebotomy with the
possible addition of myelosuppressive
agents based on a risk-stratified approach.
 Agents under investigation include
interferon alfa-2b, anagrelide, and aspirin.
Consultation with a hematologist is
recommended.

Introduction
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Alternative Names:
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Primary polycythemia
Polycythemia rubra vera
Myeloproliferative disorder
Erythremia
Splenomegalic polycythemia
Vaquez's disease
Osler's disease
Polycythemia with chronic cyanosis
Myelopathic polycythemia
Erythrocytosis megalosplenica
Cryptogenic polycythemia
Pathophysiology
Normal stem cells are present in the bone
marrow of patients with PV.
 Also present are abnormal clonal stem
cells that interfere with or suppress normal
stem cell growth and maturation.
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Pathophysiology
Evidence indicates that the etiology of
panmyelosis is unregulated neoplastic
proliferation.
 The origin of the stem cell transformation
remains unknown
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Polycythemia vera
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Bone marrow film at 100X magnification
demonstrating hypercellularity and
increased number of megakaryocytes
Pathophysiology

Thromboses and bleeding are frequent in
persons with PV and myeloproliferative
disease (MPD), and they result from the
disruption of hemostatic mechanisms
because of
an increased level of red blood cells
 an elevation of the platelet count

Pathophysiology

Tissue factor is also synthesized by blood
leukocytes, the level of which is increased
in persons with MPD, which can contribute
to thrombosis.
Pathophysiology

Hyperhomocystinemia is a risk factor for
thrombosis and is also widely prevalent in
patients with MPD (35% in controls, 56%
in persons with PV).
Statistics
Polycythemia vera is a rare disease
 The peak incidence of PV is age 50-70
years
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However, it occurs in persons of all age
groups, including those in early adulthood and
childhood, albeit rarely.
The disease is slightly more common in
males than in females.
History
The disease usually develops slowly
 Symptoms are often insidious in onset
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They are often related to blood hyperviscosity
secondary to a marked increase in the cellular
elements of blood, which impairs
microcirculation.
History

Symptoms are related to hyperviscosity,
sludging of blood flow, and thromboses,
which lead to poor oxygen delivery and
symptoms that include:
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headache, dizziness, vertigo, tinnitus, visual
disturbances, angina pectoris, or intermittent
claudications
History

Bleeding complications ,, include epistaxis,
gum bleeding, ecchymoses, and GI
bleeding.

Thrombotic complications ,, include
venous thrombosis or thromboembolism
and an increased prevalence of stroke and
other arterial thromboses.
History

Abdominal pain due to peptic ulcer
disease is present because PV is
associated with increased histamine levels
and gastric acidity or possible Budd-Chiari
syndrome (hepatic portal vein thrombosis)
or mesenteric vein thrombosis.
History
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Splenomegaly, when present, can cause
early satiety because of
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gastric filling being impaired by the enlarged
spleen or, rarely, symptoms of splenic
infarction.
Weight loss may result from early satiety
or from the increased myeloproliferative
activity of the abnormal clone.
History
Pruritus results from increased histamine
levels released from increased basophils
and mast cells and can be exacerbated by
a warm bath or shower.
 This occurs in up to 40% of patients.
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Physical

The following symptoms are due to the
manifestations of myeloproliferative
disorders with extramedullary
hematopoiesis:
Splenomegaly - Present in 75% of patients at
the time of diagnosis
 Hepatomegaly - Present in approximately
30% of patients with PV
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Physical

Hypertension is common in patients with
PV. The red blood cell mass should
differentiate PV from Gaisbock syndrome,
which is hypertension and
pseudopolycythemia (ie, high hemoglobin
levels due to low plasma volume).
Physical
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Polycythemia is characterized by
increased cell counts in all cell lines in the
myeloid series (ie, red blood cells, white
blood cells [preferentially granulocytes],
and platelets).
Physical
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However, if red blood cell levels are increased,
several conditions must be excluded, including:
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conditions that increase red blood cells secondary to
systemic hypoxic conditions or an artificial condition
stimulating Epo secretion in the kidneys
granulocytosis from infections or mobilization by
secondary causes, as in leukemoid reactions
thrombocytosis from bleeding and iron deficiency.
Secondary Causes of Increased
Red Cell Mass (Erythrocytosis)
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Chronic pulmonary or cardiac disease
Decreased 2,3-diphosphoglycerate
High oxygen affinity hemoglobinopathy
Increased carboxyhemoglobin (in smokers) and
methemoglobin
Residence at high altitude
Adrenal cortical hypersecretion
Hydronephrosis
Tumors producing erythropoietin or anabolic steroids
Relative (stress)
Disorders associated with decreased plasma volume
(e.g., diarrhea, emesis, renal diseases)
Diagnosis
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PV should be suspected when hemoglobin
and/or hematocrit levels are elevated
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(> than 18 g per dL [180 g per L] in white men
and > than 16 g per dL [160 g per L] in blacks
and women)
hematocrit level greater than 52 percent
(0.52) in white men and 47 percent (0.47)
in blacks and women
Diagnosis

PV also should be suspected in patients
with portal venous thrombosis and
splenomegaly with or without
thrombocytosis and leukocytosis.
Diagnosis: Other Signs and Symptoms of
Polycythemia Vera
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More Common
Hematocrit level >52 percent
(0.52) in white men, >47
percent (0.47) in blacks and
women
Hemoglobin level >18 g per dL
(180 g per L) in white men,
>16 g per dL (160 g per L) in
blacks and women)
Plethora
Pruritus after bathing
Splenomegaly
Weight loss
Weakness
Sweating
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Less Common
Bruising/epistaxis
Budd-Chiari syndrome
Erythromelalgia
Gout
Hemorrhagic events
Hepatomegaly
Ischemic digits
Thrombotic events
Transient neurologic
complaints (headache, tinnitus,
dizziness, blurred vision,
paresthesias)
Atypical chest pain
Diagnosis
In making the diagnosis of PV, once a
secondary cause is ruled out, the
diagnosis of PV is made using a
combination of major and minor criteria
defined by the Polycythemia Vera Study
Group (PVSG).
 Although new diagnostic modalities have
been developed, these criteria remain the
standard method to diagnose PV
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A diagnosis of polycythemia vera is made when a patent fulfills
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Or
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all three of the major criteria
any two major and any two minor criteria
Major Criteria
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total RBC vol
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Men > or = to 36 mL/kg
Women > or = to 32 mL/kg
arterial 02 saturation > or = to 92%
Splenomegaly
Minor Criteria
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Thrombocytosis with platelet count > 400,000/mL
Leukocytosis with WBC > 12,000/mL
Increased leukocyte alkaline phosphatase LAP > 100U/L (no infection)
Serum B12 > 900 pg/mL or binding capacity UB12 BC > 2200 pg/mL
Serum Epo assay

Epo levels in patients with PV are often
below the lower limit of normal compared
with patients with secondary erythrocytosis
and pseudoerythrocytosis
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but the levels for PV and secondary
erythrocytosis or pseudoerythrocytosis
overlap and are nonspecific for differentiating
these conditions.
Bone marrow morphology and
histology
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Overall hypercellularity with expansion of all cell
lines with megakaryocytic proliferation and the
presence of myelofibrosis can help diagnose PV
and MPD
PV patients may have normal bone marrow
findings
These results are nonspecific and may be
observed in the other Philadelphia
chromosome–negative MPDs.
Bone marrow findings for
Polycythemia vera include
Moderate to marked hypercellularity
 trilineage hyperplasia
 megakaryocytes increased;
hyperlobulated
 dilated sinusoids with intravascular
hematopoiesis
 decreased or absent iron stores
 increased reticulin (only in a minority of
patients)
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Labs
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Peripheral blood findings
Increased hemoglobin & hematocrit
 Normal red blood cell morphology, unless iron
deficient or spent phase
 Normoblasts may be present
 Mild to moderate leukocytosis
 Mild neutrophilia and/or basophilia
 Thrombocytosis
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Labs
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This disease may also alter the results of the
following tests:
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Lactate dehydrogenase
u/a
Serum uric acid
T- wbc
RBC count
Platelet aggregation test
Leukocyte alkaline phosphatase
Hemoglobin
ESR
Erythropoietin
Labs
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Automated red blood cell counts and hematocrit values
(including hemoglobin levels) may be deceptive with
regard to the total red blood cell mass.
Direct measurement of the red blood cell mass should
show an increase with a normal or slightly decreased
plasma volume.
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This is a nuclear medicine test that uses radiochromium-labeled
red blood cells to measure actual red blood cell and plasma
volume.
However, patients with hemoglobin concentrations of at
least 20 g/dL or hematocrit values of at least 60% in
males and 56% in females always have an elevated red
blood cell mass.
Labs
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The red blood cells in patients with PV are
usually normochromic normocytic unless
the patient has been bleeding from
underlying peptic ulcer disease or
phlebotomy treatment (wherein the cells
may be hypochromic and microcytic,
reflecting low iron stores).
Labs
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An elevated white blood cell count (>12,000/µL)
occurs in approximately 60% of patients. It is
mainly composed of neutrophils with a left shift
and a few immature cells.
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Mild basophilia occurs in 60% of patients.
The leukocyte alkaline phosphatase score is elevated
(>100 U/L) in 70% of patients.
This technique is only semiquantitative and is
susceptible to laboratory errors unless it can be
performed by flow cytometry, which is not routinely
available
Labs
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The platelet count is elevated to 400,000800,000/mL in approximately 50% of
patients.
Labs
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The release of potassium into the serum
caused by the increased number of
platelets during in vitro coagulation may
cause a pseudohyperkalemia in the
serum, while the true plasma potassium
level in vivo is actually within the reference
range, as shown by measuring plasma
levels and the lack of ECG changes.
Labs
Abnormal platelet function (as measured
by platelet aggregation tests with
epinephrine, adenosine diphosphate, or
collagen) may be demonstrated, but
bleeding time may be normal.
 Some patients' platelet-rich plasma
aggregates spontaneously without the
addition of any of the above substances.
 This indicates a propensity for thromboses
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Labs
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Bone marrow studies are not necessary to
establish the diagnosis but the findings of:
hypercellularity
 hyperplasia of the erythroid, granulocytic and
megakaryocytic cell lines
 myelofibrosis
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support the diagnosis of a
myeloproliferative process.
Labs
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Iron stores are decreased or absent
because of the increased red blood cell
mass, and macrophages may be masked
in the myeloid hyperplasia that is present.
Labs
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Fibrosis is increased and detected early by
silver stains for reticulin
Labs
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Cytogenetics of the bone marrow cells
show a clonal abnormality in
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30% of patients who are not treated and in
50% of patients who are treated with
alkylating or myelosuppressive agents.
 These
chromosomal abnormalities include
deletions of the long arm of chromosome 5 or 20
(5q-, 20q-) and trisomy 8 (+8) or 9 (+9).
 Leukemic transformation is usually associated with
multiple or complex abnormalities.
Labs
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Hyperuricemia occurs in 40% of patients
and reflects the high turnover rate of bone
marrow cells releasing DNA metabolites.
Imaging Studies
An enlarged spleen is often palpable and
does not require any imaging studies.
 In some patients with posteriorly enlarged
spleens or in those who are obese,
ultrasonography or CT scanning may be
able to detect an enlargement missed
during the physical examination.
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Other Tests
The serum Epo level should be decreased
in nearly all patients with PV and no recent
hemorrhage.
 This distinguishes polycythemia from
secondary causes of polycythemia in
which the serum Epo level is generally
within the reference range or is elevated.
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Each lab has its own reference range for
serum Epo level
Treatment
The objective of treatment is to reduce the
high blood viscosity (thickness of the
blood) due to the increased red blood cell
mass and to prevent hemorrhage and
thrombosis.
 No single treatment is available for PV.
 Thrombosis accounts for the majority of
morbidity and mortality. The major goal of
treatment is to prevent thrombotic events.
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Treatment
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Examples of thrombotic events include
arterial and venous thrombosis,
cerebrovascular accident, deep venous
thrombosis, myocardial infarction,
peripheral arterial occlusion, and
pulmonary infarct
Treatment
The mainstay of treatment for PV is
phlebotomy, which is aimed at reducing
hyperviscosity by decreasing the venous
hematocrit level to less than 45 percent
(0.45) in white men and 42 percent (0.42)
in blacks and women.
 The PVSG reported the best median
survival, 12.6 years, for this type of
treatment.
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Phlebotomy is a simple procedure without
many risks, except for the eventual
development of iron deficiency
Treatment
Patients with hematocrit values of less
than 70% may be bled twice a week to
reduce the hematocrit to the range of 40%.
 Patients with severe plethora who have
altered mentation or associated vascular
compromise can be bled more vigorously,
with daily removal of 500 mL of whole
blood
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Treatment
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Elderly patients with some cardiovascular
compromise or cerebral vascular
complications should have the volume
replaced with saline solution after each
procedure to avoid postural hypotension
Treatment
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Because phlebotomy is the most efficient
method of lowering the hemoglobin and
hematocrit levels to the reference range, all new
patients are initially phlebotomized to decrease
the risk of complications.
The presence of elevated platelet counts that
may be exacerbated by the phlebotomy is an
indication to use myelosuppressive agents to
avoid thrombotic or hemorrhagic complications
Treatment
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Once the patient's hemoglobin and
hematocrit values are reduced to within
the reference range (ie, <45%), implement
a maintenance program either by inducing
iron deficiency by continuous
phlebotomies (frequency of the procedure
depends on the rate of reaccumulation of
red blood cells) or using a
myelosuppressive agent.
Treatment
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The use of myelosuppressive agents such as radioactive
phosphorus (32P), chlorambucil (Leukeran), busulfan
(Myleran), pipobroman (Vercyte), and hydroxyurea
(Hydrea) in conjunction with phlebotomy has been
studied.
Chlorambucil, busulfan, and pipobroman, all alkylating
agents, have fallen out of favor because of concerns
about rates of iatrogenic leukemia.
The agent 32P remains in use with supplemental
phlebotomy and has a reported median survival similar
to that of phlebotomy alone-10.9 years according to
PVSG data.
Treatment

In patients treated with chlorambucil and
32P the PVSG demonstrated a decreased
survival rate and increased mortality rate
from acute leukemia in the first 5 years,
and a total of 17% of patients had
leukemia after 15 years with.
Treatment
Hydroxyurea has been the mainstay
therapy for PV after the PVSG results
indicated it is an effective agent for
myelosuppression; however, concerns
have been raised regarding long-term
risks for leukemic transformation.
 In the PVSG trial, HU therapy reduced the
risk of thrombosis compared with
phlebotomy alone
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Treatment
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Recombinant interferon alfa-2b reduces
myeloproliferation and splenomegaly, and alleviates the
symptom of pruritus.
It has no established mutagenic potential, and thus may
prove a valuable option for younger patients and those
with significant splenomegaly.
A small case series of 11 patients found that the patients'
red cell indices could be normalized over six to 12
months with interferon therapy alone, and without
evidence of thrombosis.
However, many patients discontinue interferon because
of side effects, and high cost of treatment.
Treatment
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splenectomy in patients with painful
splenomegaly or repeated episodes of
thrombosis causing splenic infarction
Treatment
Occasionally, chemotherapy may be given
to suppress the bone marrow.
 The use of anti-platelet therapy (such as
aspirin) is controversial because it may
cause gastric bleeding.
 Allopurinol is given for hyperuricemia
(gout).
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Treatment
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A risk-stratified approach to the management of
PV is currently recommended
Patients treated with phlebotomy alone benefit
from low rates of malignancy but experience
more thrombosis events during the first few
years of treatment.
Patients treated with myelosuppressive agents
and supplemental phlebotomy avoid this early
thrombotic risk but in turn have significant rates
of malignant transformation after about six years
of therapy
Treatment
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High-risk patients
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those 60 years or older
or those with a history of thrombosis
A myelosuppressive agent with supplemental
phlebotomy is reasonable in this group
This group's generally shorter life expectancy lessens
the threat of eventual iatrogenic malignancy.
Patients in this group stand to gain from the benefit of
lower early thrombosis rates with myelosuppressive
medications.
Treatment
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Indeterminate risk
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< than age 60 and have no history of
thrombocytosis, but do have cardiovascular or
other risk factors
Therapy in this group should be
individualized, possibly with the addition of
agents acting on platelet function or
number.
Treatment
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low risk
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< than 60 years and have no thrombosisrelated risk factors
Phlebotomy alone may be the treatment of
choice with the goal of reducing the
hematocrit level to less than 45 percent
(0.45) or lower based on gender and race
Treatment

Consultation with a hematologist is
recommended to apply such strategies,
and newer agents may be tailored to
patients on an individualized basis.
Prognosis
Polycythemia vera usually develops
slowly, and most patients treated
appropriately do not experience any
problems related to the disease.
 However, the abnormal bone marrow cells
may begin to grow uncontrollably leading
to acute myelogenous leukemia.
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Prognosis
Patients with polycythemia vera also have
an increased tendency to form blood clots
that can result in strokes or heart attacks.
 Some patients may experience abnormal
bleeding because their platelets are
abnormal.

Prognosis

PV is a chronic disease, and its natural
history of 1.5-3 years of median survival in
the absence of therapy has been extended
to at least 10-20 years because of new
therapeutic tools.
Prognosis

The major causes of morbidity and
mortality are as follows:
Thrombosis
 Hemorrhagic complications
 Peptic ulcer disease
 Myelofibrosis and pancytopenia
 Acute leukemia or a myelodysplastic
syndrome

Thrombosis
reported in 15-60% of patients
 major cause of death in 10-40% of
patients
 Venous and arterial thromboses have
resulted in pulmonary emboli, renal failure
from renal vein or artery thrombosis,
intestinal ischemia from mesenteric vein
thromboses, or peripheral arterial emboli.

Hemorrhagic complications
occur in 15-35% of patients
 lead to death in 6-30% of these patients
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Bleeding is usually the consequence of
vascular compromise resulting from
ischemic changes from thrombosis or
hyperviscosity.
Peptic ulcer disease
Associated with PV at a 3 to 5 fold higher
rate than that of the general population
 This has been attributed to increased
histamine serum levels

Myelofibrosis and pancytopenia
Occur in 3-10% of patients, usually late in
the disease
 In these patients, infections and bleeding
complications may be the most serious
health threats
 red blood cell transfusions may be
required to maintain adequate red blood
cell counts and to improve fatigue and
other anemia-related symptoms.

Acute leukemia or a
myelodysplastic syndrome
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Develops in 1.5% of patients treated with
phlebotomy alone
The transformation risks
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increase to 13.5% within 5 years with treatment using
chlorambucil
And 10.2% within 6-10 years in patients treated with
32P
At 15 years, the transformation risk for HU is
5.9%, which, although not statistically significant,
is a worrisome trend
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Questions