a manuscript submitted in partial fulfillment of

The Evaluation of Polycythemia and the Diagnosis of Polycythemia Vera

By

Kerri Lantz Petersen

A manuscript submitted in partial fulfillment of the requirements for the degree of

MASTER OF NURSING

WASIDNGTON STATE UNIVERSITY College of Nursing Education

May 2001

..

To the faculty of Washington State University:

The members of the committee appointed to examine the College ofNursing

Education Research requirements and manuscript of Kerri Lantz Petersen

find it satisfactory and recommend that it be accepted.

~lrq~ C air: Dr. Lorna Schumann

Dr. Billie Severtsen

~/V~~t:=-. Naomi Lungst1'OlIlRN, MN

ii

TABLE OF CONTENTS

page

ABSTRACT vi

LIST OFTABLES iv

LIST OFFIGURES v

rnTRODUCTION -1

EPIDEMIOLOGY 1

ETIOLOGy 2

PATHOPHYSIOLOGY 2

CLOOCAL COURSE 3

CLrnICAL PRESENTATION 4

LABORATORY FEATURES 6

DIFFERENTIAL DIAGNOSIS 7

CLrnICAL DECISION MAKING 10

TREATMENT 14

COMPLICATIONS 17

CONCLUSION 18

REFERENCES 19

iii

LIST OF TABLES

1. The Occurrence of Signs and Symptoms in Patients 30

2. Differential Diagnosis of Polycythemia Vera 31

3. Laboratory Differentiation of Polycythemia 32

4. PVSG Criteria for the Diagnosis of Polycythemia Vera 33

5. The Rotterdam Criteria of Polycythemia Vera 34

6. Proposed Modified Criteria for the Diagnosis of Polycythemia Vera 35

7. Laboratory and Diagnostic Tests for Polycythemia Vera 36

8. Patient Education Resources 42

iv

LIST OF FIGURES

1. Diagnostic Approach to "Suspected Polycythemia Vera" 43

2. Diagnostic Approach to an Elevated Hematocrit 44

v


Abstract

By Kerri Lantz Petersen Washington State University

May,2001

Chair: Dr. Lorna Schumann

Polycythemia vera (PV) is a rare clonal blood disorder marked by an elevated hematocrit,

hemoglobin, and red cell mass. Although the etiology is unknown, PV is characterized by the

proliferation of hematopoietic progenitor cells which creates an increased red cell mass

accompanied by an expanded blood volume. Red blood cell production continues independent of

increased blood viscosity. Onset is insidious and the patient may present without symptoms or

complain of headache, dizziness, or pruritus. Physical examination typically reveals

splenomegaly, plethora, and retinal vein engorgement. Laboratory features include leukocytosis,

thrombocytosis, and erythrocytosis. Serum erythropoietin levels are low or absent. PV must be

distinguished from relative and secondary polycythemia. Relative polycythemia causes a

moderate increase in hematocrit frequently secondary to fluid contraction. The red cell mass,

although not truly increased, reflects hemoconcentration. Secondary polycythemia is suspected,

if an elevated hematocrit occurs without leukocytosis, thrombocytosis, and splenomegaly. The

red cell mass measurement and serum erythropoietin level will be increased. Tests used in the

differential diagnosis of PV include red cell mass determination, erythropoietin assays, arterial

oxygen saturation, and renal ultrasounds. Regular phlebotomy is the safest treatment for PV.

vi

Myelosuppressive agents may be given in addition to phlebotomy therapy. The median survival

time for patients with PV is 11 to 15 years with appropriate medical treatment.

vii


Polycythemia vera (PV) is a relatively rare clonal blood disorder often discovered

incidentally through routine blood testing (Wasserman, 1954; Adamson, Fialkow, Murphy,

Prchal, & Steinmann, 1976; Talarico, 1998). The complete blood count characteristically shows

an elevated hematocrit and hemoglobin with an increased red cell count (Peterson & Wasserman,

1995; Ferri, 2001). PV must be distinguished from other causes of polycythemia, including

relative and secondary polycythemia (Spivak, 2001). How does the primary care provider

accurately evaluate an elevated hematocrit and hemoglobin and the polycythemias? It has been

reported that 50% of persons with untreated PV die within the first 18 months after the first signs

or symptoms appear (Chievitz & Thiede, 1962). Diagnosis, careful monitoring, and appropriate

treatment can reduce the risk of complications (Spivak, 2001).

Epidemiology

The reported incidence of PV has varied greatly due to a number of factors including

quality of medical care, diligence of record keeping, and the age, ethnic, and racial distributions

of study populations (Modan, 1995; Michiels et aI., 2000; Chaiter, Brenner, Aghai, & Tatarsky,

1992; Berglund & Zettervall, 1992). Prochazka and Markowe (1986), in their large study of

incidence rates from New Wales and England, found a rate of 5 to 10 cases per million per year

with a male to female ratio of 1:3. Chaiter et aI., (1992) found a slight increase in males as

opposed to females. Increased incidences have occurred among those of Jewish origin with 11.4

cases per one million residents in northern Israel with myeloproliferative disorders in general

occurring with a higher incidence among Ashkenazi Jews specifically (Chaiter et aI., 1992). The

median age at onset is 56.9 years (Modan & Lilienfeld, 1965). Rare cases have occurred during

2

childhood (Marlowe & Fairbanks, 1960; Aggeler, Pollycove, Hoag, Donald, & Lawrence, 1961).

Exposure to radiation has been associated with an increased incidence of PV (Caldwell, Kelley,

Heath, & Zack, 1984).

Etiology

Although the etiology is unknown, this disorder is marked by an autonomous clonal

proliferation of bone marrow progenitors, such as erythroid, granulocytic, and megakaryocytic

cells representing a neoplastic process (Adamson et aI., 1976). Stem cell cloning and

proliferation of red blood cells (RBCs) in patients with PV occurs independent of erythropoietin

production as demonstrated by bone marrow and peripheral blood in vitro culture studies

(Zanjani & Lutton, 1977; Prchal, Adamson, Murphy, Steimann, & Fialkow, 1978). Recent

studies to explain the erythropoietin- independent proliferation of red blood cells have not shown

a functional or structural abnormality in the erythropoietin receptor (Hess et aI., 1994;

Asimakopoulos et aI., 1997). Recently, Silva and colleagues (1998) examined the role of a Bcl-2

gene, an apoptosis-inhibiting oncoprotein, and its possible relationship to the erythropoietin

independent proliferation of red blood cells (RBCs). Molitemo, Hankins, and Spivak (1998)

found that the thrombopoietin receptor, Mpl, on platelets and megakaryocytes was absent or

greatly reduced in their patients with PV. Studies suggest a defect in programmed cell death and

proliferation independent from growth factors (Silva et aI., 1998; Molitemo et aI., 1998).

Pathophysiology

Polycythemia is defined as an increase in packed cell volume (hematocrit). The increased

hematocrit may occur with an increased red cell mass (secondary polycythemia and PV) or a

normal red cell mass (RCM) (Pearson & Messinezy, 1996). The increased RCM can be due to a

physiologic appropriate or inappropriate erythropoietin response. Erythropoietin, produced

3

mainly by the kidneys in adults, normally regulates erythropoiesis (proliferation and maturation

of erythryoid progenitor cells). Erythropoietin is a potent glycoprotein carefully controlled by the

body to maintain stability. Hypoxia can stimulate the production of erythropoietin, producing red

blood cells to maintain tissue oxygenation by increasing the number of oxygen carrying cells in

the blood. The plasma erythropoietin level (EPa) reflects tissue oxygenation. Tumors capable

of causing inappropriate erythropoietin production can elevate EPa levels in spite of normal

tissue oxygenation (Waldmann, Rosse, & Swarm, 1968; Balcerak & Bromberg, 1975). PV is

characterized by neoplastic progenitor growth and erythroid colony forming units (CFU-E),

although EPa production and concentration are decreased and arterial oxygen saturation is

normal. The proliferation of RBCs continues independently of exogenous erythropoietin

stimulation. CFU-E have been shown to form in marrow cell culture without the addition of

exogenous erythropoietin in patients with PV (Weinberg et aI., 1989; Prchal & Axelrad, 1974;

Zanjani, Lutton, Hoffman, & Wasserman, 1977; Eaves & Eaves, 1978). London, Shemin, West,

and Rittenberg (1949) demonstrated a two and one-half fold increase in red cell production by

the hyperplastic marrow of PV patients. The elevated RCM (equal to or greater than 36 mUkg

for males, equal to or greater than 32 mUkg for females) that results from this proliferation

causes increased whole-blood viscosity (Wasserman, 1954; Shien & Gallik, 1995).

Clinical Course

PV is characterized by: the preerythrocytic phase; the erythrocytic phase; the proliferative

phase, and the "spent" or postpolycythemic phase. During the preerythrocytic phase, which can

last many years, the patient frequently remains asymptomatic. The RBC mass slightly increases

and the patient may complain of pruritus after bathing. The only sign noted during the physical

exam may be splenomegaly. The erythrocytic phase presents with ischemic events due to

4

increased blood viscosity and RCM. Bleeding episodes, cyanosis, plethora, and an elevated

platelet count can occur. Treatment may prolong the erythrocytic phase for 5 to 20 years. The

proliferative phase is characterized by bruising, hemorrhage, leukocytosis, and progressive

splenomegaly. Ten years may pass between phases 3 and 4. Approximately 20% of patients

reach the "spent" phase and may experience severe anemia with progression to leukemia or bone

marrow fibrosis (David, 1995). Transfusions may be required during this phase (Beutler, 2001).

Mortality is high once the patient reaches the fourth phase (David, 1995).

Wasserman and Peterson (1995) describe the asymptomatic developmental phase of PV

as insidious and possibly accompanied by hepatosplenomegaly, thrombocytosis, or an elevated

hemoglobin without an increase in the red cell mass. The next phase, the erythrocytic phase,

may last from 5 to 20 years. Laboratory results show an increased red cell mass, with an

expanded blood volume and the proliferation of all the elements of the bone marrow,

panmyelosis. The following phase, known as the "spent" or "stable" phase, is characterized by

postpolycythemic myeloid metaplasia. This phase of thrombocytopenia, leukopenia, and anemia

is accompanied by a stabilization of the red cell mass and blood volume. The bone marrow may

become fibrotic and patients may succumb or progress to acute leukemia (Wasserman, 1954;

Peterson & Wasserman, 1995; Silverstein, Brown, & Linman, 1973; Silverstein, 1974).

Clinical Presentation

The onset of PV is insidious and its course progressive. The patient may be

asymptomatic or experience signs and symptoms related to increased blood viscosity and

expanded blood volume (Peterson & Wasserman, 1995; Berk, 1975). Initial presentation varies

from patient to patient. Family members may have expressed concerned about the patients ruddy

comple.xion and hypertension may have been found during the physical examination (Berlin,

5

1975, 1995). Initial signs and symptoms may include headache, peptic ulcer, tinnitus,

thrombosis, dizziness, paresthesias, gastrointestinal bleeding, intermittent claudication, gout, or

pruritus (Berlin, 1975, 1995; Peterson & Wasserman, 1995; Beutler, 2001). Generalized pruritus

is intense and exacerbated by warm baths and showers. The cellular release of histamine from

increased basophils may be responsible for the intense itching although antihistamines are

usually ineffective (Krajink & Zylicz, 2001). Other symptoms include visual disturbances and

abdominal discomfort (Berlin, 1975; Hocking, 1995). Weight loss may be apparent (Wasserman,

1954; Berlin, 1975; Talarico, 1998).

Physical examination often reveals cyanosis, plethora, splenomegaly, congestion of oral

mucosa, and retinal vein engorgement (Berlin, 1975; Talarico, 1998; Ferri, 2001). Episodes of

epistaxis, bruising, and gingival bleeding can occur. Small vessel insufficiency may result in

cyanosis and even frank gangrene of the toes and fingers (Talarico, 1998). Erythromelalgia,

redness and burning pain in the extremities, may be a presenting symptom of PV (Michiels et aI.,

1985). Transient ischemic attacks, cerebrovascular accidents, pulmonary emboli, arterial

thrombosis, or deep vein thrombosis can also be present initially or during the course of the

disease (Peterson & Wasserman, 1995). The Gruppo Italiano Studio Policitemia (1995)

conducted a retrospective study that revealed 140/0 of PV patients had a thrombotic event prior to

diagnosis. Hyperviscosity of the blood with an elevated hematocrit is responsible for many of

the features of PV especially those related to the brain, lungs, and retina (Peterson & Wasserman,

1995; Chien & Gallick, 1995). Table 1 lists signs and symptoms characteristic of PV.

6

Laboratory Features

The hallmarks of PV include erythrocytosis, thrombocytosis, and leukocytosis. The

platelet count is often above 400 x 109/L and the white cell count can exceed 12 x 109/L

(Wasserman, 1954; Berlin, 1966, 1975, 1995). Mild basophilia may be present (Berlin, 1966,

1995). The hematocrit will be elevated, and may be above 60%, although microcytosis with iron

deficiency can result in a moderately increased hematocrit (Fairbanks & Tefferi, 2000;

Silverstein & Tefferi, 2000). Erythrocytosis occurs in other forms of polycythemia. The RCM,

in PV patients will be more than 25% above what is predicted for the patient's height and weight

(Messinezy & Pearson, 1999). The RCM increase contributes to an increase in blood viscosity.

The erythrocytosis and increased RCM occurs without a normal erythropoietin response. The

serum EPO level is decreased or undetectable (Napier & Wieczorek, 1981; Erslev, Caro, Kansu,

Miller, & Cobbs, 1979; de Klerk et aI., 1981). Occasionally the EPO level will remain normal

(Cotes et aI., 1986). Elevated EPO levels raise the suspicion of secondary polycythemia due to

hypoxemia (Tefferi, 1999; Messinezy & Pearson, 1999).

Arterial oxygen saturation is usually above 92% unless the patient has superimposed lung

disease such as chronic bronchitis or emphysema. The Polycythemia Vera Study Group (PVSG)

found that 10% of their patients demonstrated blood saturation levels between 88 and 92% and a

smaller number had unexplained levels below 880/0 (Berlin, 1966, 1975, 1995).

Nonspecific laboratory results include an elevated leukocyte alkaline phosphorus (LAP)

above 100 units, an elevated reticulocyte count above 1.5%, hyperuricemia, and an increased

serum vitamin B12 or B12-binding capacity (Berlin, 1966, 1975, 1995; Wasserman, 1954;

Tefferi, 1998). Coagulation tests are usually normal (Murphy, Davis, Walsh, and Gardner, 1978;

HoclGng, 1995).

7

Bone marrow biopsies from patients with PV have been studied extensively since 1967

by the Polycythemia Vera Study Group (PVSG). They found that the marrow of untreated PV

patients demonstrated panhyperplasia, with wide individual variation. Reticulin fibrosis has also

been found after treatment and during the spent phase of PV. The marrow cavity may become

"obliterated" by fibroblastic or osteoblastic proliferation and the extraosseous marrow production

of blood cells occurs (myeloid metaplasia) (Wasserman, 1954; Peterson & Ellis, 1995).

Differential Diagnosis

The cause of an elevated hematocrit can, in most cases, be determined by the patient's

history, a thorough family history, physical examination, complete blood count, and chest x-ray

(Landaw, 1996). Previous laboratory results should be made available for comparison to recent

laboratory findings. Polycythemia vera must be distinguished from secondary polycythemia, and

relative, or "spurious" polycythemia since all three cause an elevated hematocrit and hemoglobin

(Copelan & Balcerzak, 1995; Weinreb, 1995; Spivak, 2001). Table 2 lists the various causes of

polycythemia.

Types of Polycythemia

The actual incidence of relative polycythemia, also referred to as "spurious", "stress", or

Gaisbock's polycythemia, remains unknown (Weinreb, 1995). Patients with relative

polycythemia are generally younger than those found to have PV (Weinreb & Shih, 1975).

Relative polycythemia is not a true erythrocytosis. It is characterized by a moderate increase in

the hematocrit (Berlin, 1966). The hematocrit ranges consistently above 49% and the erythrocyte

count is elevated. The red cell mass remains normal, but may be in the upper normal range.

Plasma volume may be normal or reduced (Weinreb, 1995). The platelet, white blood cell, and

reticulocyte counts are usually normal (Berlin, 1966; Weinreb & Shih, 1975). Symptoms include

8

epigastric discomfort, lethargy, fatigue, sweating, palpitations, lightheadedness, headache,

dyspnea, and dizziness. Pruritus and weight loss are uncommon. Physical examination may

reveal plethora and conjunctival suffusion without palpable splenomegaly. Hypertension and

obesity are common findings (Burge, Johnson, & Prankerd, 1975; Weinreb & Shih, 1975). The

patient's history may reveal common causes of dehydration such as febrile illness, vomiting, or

diarrhea (Lopez, 1996). The medication history may include diuretics, excessive caffeine intake,

and cardiac medications such as calcium channel blockers and beta-blockers (Burge, Johnson, &

Prankerd, 1975; Landaw, 1996).

Weinreb (1995) classifies relative polycythemia as acute or transient and chronic or

sustained polycythemia. Transient polycythemia most commoflly occurs with a contracted fluid

volume caused by dehydration. The dehydration may be caused by vomiting, diarrhea, or

insensible fluid losses, but is usually corrected with medical treatment. Chronic relative

polycythemia can occur in the context of a normal or low-normal plasma volume with a high

normal RCM (normovolemic relative polycythemia) or a normal RCM with hemoconcentration

secondary to a reduced plasma volume (hypovolemic relative polycythemia). A normal or low

nonnal plasma volume with a high-normal RCM may be idiopathic or due to intermittent

hypoxemia. Smoking, sleep apnea, and postural hypoxemia have been linked to elevated

hematocrits (Smith & Landaw, 1978; Watts & Lewis, 1983; Weinreb, 1995). Idiopathic cases of

nonnovolemic polycythemia can be viewed as normal variants (Brown, Gilbert, & Krauss, and

Wasserman, 1971). Both hypovolemic and normovolemic polycythemias may be associated with

obesity, smoking, hypertension, and/or sleep apnea (Weinreb, 1995). Table 3 lists typical

laboratory findings in the differential diagnosis of polycythemia.

9

Secondary polycythemia (a nonclonal disorder) should be suspected when the hematocrit,

hemoglobin, and RBC count are elevated. Thrombocytosis, leukocytosis, and panhyperplasia of

the bone marrow are found less often as opposed to PV (Balcerak & Bromberg, 1975). The

ReM will be increased (Balcerak & Bromberg, 1975; Copelan & Balcerak, 1995). Patients

characteristically present without splenomegaly unless metastatic neoplasms occur

simultaneously (Ferri, 2001). Arterial oxygen saturation is reduced if a chronic hypoxic

condition is present (Balcerak & Bromberg, 1975). The EPO concentration will be increased

representing a physiologically appropriate or inappropriate response (Copelan & Balcerak, 1995).

Secondary polycythemia caused by tissue hypoxia, such as chronic pulmonary disease,

cardiovascular shunts, and high altitudes, can be noted from the history, physical examination,

and laboratory tests (Berlin, 1966; Balcerak & Bromberg, 1975; Copelan & Balcerak, 1995;

Lopez, 1996). Rare hemoglobinopathies associated with high oxygen affinity occasionally cause

secondary polycythemia reflected by abnormal oxyhemoglobin dissociation curves. Ectopic

production of erythropoietin can occur with renal carcinoma, uterine tumors, or hepatoma, and

the erythropoietin level will be elevated with a normal arterial oxygen saturation. Renal lesions

can also cause secondary polycythemia with increased erythropoietin production (Berlin, 1975,

1995; Copelan & Balcerak, 1995; Waldmann et aI., 1968).

Secondary polycythemia due to carbon monoxide also results in an elevated hematocrit

from an increased circulating carboxyhemoglobin level. It is important to question the patient

about possible chronic exposure to carbon monoxide from faulty heating systems or automobile

exhaust. Patients should be questioned about cigar, cigarette, and marijuana use (Landaw, 1998).

Inhaled carbon monoxide affects the release of oxygen from hemoglobin, leads to the formation

of carboxyhemoglobin, and stimulates erythropoietin production (Copelan & Balcerak, 1995).

10

The serum EPO level rises while plasma volume decreases. Carboxyhemoglobin measurements

should be timed to coincide with peak levels. For example, blood should be drawn in the early

morning, if a faulty home heating system is suspected (Landaw, 1996).

Clinical Decision Making

No single diagnostic marker exists to diagnose PV. Historically the PVSG diagnostic

criteria have been used to diagnose PV (Berk, 1997). Major and minor criteria are presented in

Table 4. RCM measurement with chromium-51 tagged RBCs has been recommended for the

initial evaluation of polycythemia to distinguish relative polycythemia from secondary

polycythemia and PV (Najean, Dresch, Rain, & Chomienne, 1995; Peereboom, 1996). RCM

determination helps confirm the diagnosis of PV, but does not distinguish between secondary

polycythemia and PV (Beutler, 2001; Lamy et aI., 1997). Differentiating secondary polycythemia

from PV has, until recently, relied on demonstrating pancytopenia in the peripheral blood,

increased RCM, palpable splenomegaly, arterial oxygen saturation, serum B12 binding capacity,

hemoglobin electrophoresis, and other tests to rule out causes of inappropriate erythropoietin

production (Modan & Lilienfeld, 1965; Berlin, 1975). The expense and inaccurate

interpretations of RCM determination coupled with the availability of more accurate tests has led

to various proposals to modify the original criteria designed by the PVSG (Michiels et aI., 1999;

Michiels & Juvonen, 1997; Tefferi, Solberg, & Silverstein, 2000; Messinezy & Pearson, 1999).

The Thrombocythemia Vera Study Group (TVSG) from The Netherlands has proposed a

revision of the PVSG criteria (See Table 5). The TVSG recommends replacing palpable

splenomegaly with bone marrow biopsy histopathology to improve the present PVSG criteria.

Michiels and Juvonen (1997) cite Kumick and colleagues' (1972) study of 90 bone marrow

specimens. Kumick et aI., found that 900/0 of PV patients had increased megakaryocytes and/or

11

eosinophils compared with 25% from the secondary polycythemia group. They concluded that

bone marrow sections should be included as a major criterion for PV diagnosis. Those patients

with anemia and hemorrhagic PV and those with splenomegaly secondary to an erythropoietin

producing tumor would be more accurately diagnosed, if bone marrow histopathology were

included in the criteria. The proposed criteria would aid the diagnosis of patients with secondary

polycythemia or early stage PV. Michiels and Juvonen (1997) propose using ultrasound or

computer tomography to assess more accurately spleen size, as opposed to only palpation of the

spleen. The Rotterdam criteria include erythroid colony formation in the absence of

erythropoietin. This occurs almost exclusively in PV (Michiels & Juvonen, 1997).

Pearson and Messinezy (1999) reevaluated the PVSG criteria with the newer diagnostic

tests available. See table 6 for Pearson and Messinezy's proposed diagnostic criteria. They

recommend eliminating the RCM measurement expressed as mL per kilogram, replacing it with

the more accurate recommendations from the International Council for Standardization

Hematology based on height and weight (Pearson, 2001; Pearson, 1995; Pearson & Messinezy,

1999). Pearson & Messinezy (1999) do not include bone marrow histopathology among their

proposed criteria due to the lack of "objective, quantitative methods of describing appearances"

to reduce sampling error histology. Clonality marker and palpable splenomegaly remain major

criterion (Pearson, 2001). Pearson (2001) recommends erythropoietin level and endogenous

erythroid colonies (EEC) remain minor criterion. He cites the expense of demonstrating

endogenous erythroid colony growth (EEC) and its low specificity for PV to justify this

recommendation.

Tefferi (1999) has suggested the use of serum EPO level and EEC assay as an alternative

approach to the diagnosis of PV (Figure 1). The presence or absence of PV-related features with

12

a normal serum EPO helps determine the diagnostic pathway. PV-related features are persistent

leukocytosis, persistent thrombocytosis, microcytosis, splenomegaly, generalized pruritus after

bathing, unusual thrombosis, and erythromelalgia (acral dysesthesia and erythema). Tefferi

claims that RCM measurement is expensive and may not identify cases of early PV or PV with

iron deficiency. Tefferi suggests the "narrow" reference range for RCM may result in a segment

of the normal population mistakenly diagnosed with PV. Cameskog et aI., (1999) have also

demonstrated the value of plasma EPO measurement in patients with elevated hematocrits.

Fairbanks and Tefferi (2000) conducted an extensive investigation of normal ranges for

hematocrit and hemoglobin. They analyzed all the published data they could find including

medical textbooks and data from government surveys and hematology laboratories. They found

that when the ranges for anemia are set too low, cases may not be diagnosed and ranges set too

high may result in the misdiagnosis of PV in normal patients. Testing for polycythemia may

mistakenly be undertaken, subsequently diagnosed, and treated in patients with normal values.

Cameskog et aI., (1999) studied 38 patients with apparent polycythemia. They found all patients

had normal RCM measurements with mean hemoglobin levels of 174 gil ± 10 and venous

packed cell volumes (PCV) of 0.53 ±0.03 for males. Fairbanks and Tefferi (2000) concluded

that studies to investigate polycythemia are not usually appropriate for non-iron-deficient adult

Caucasian males with PCV values less than 0.55 (hemoglobin levels less than 180 gIL.) or non

iron-deficient adult Caucasian females with PCV less than 0.50 (hemoglobin concentrations less

than 165 gIL.) (2000). Fairbanks (2000) has reminded clinicians that any adult male with a

hemoglobin of 180gIL and a packed cell volume of 0.54 has approximately a 500 to 1 chance that

he does not have PV. Pearson and Messinezy (1996) recommend at least two blood samples be

drawn before concluding that a patient has an elevated hematocrit. Fluid shifts from fasting

13

states, recumbency, and hydration alter the PCV, blood volume, and hemoglobin level. Blood

drawn in the morning may have vastly different results as opposed to blood drawn from the same

patient in the afternoon (Fairbanks, 2000). See figure 2 algorithm for the evaluation of an

elevated hematocrit.

Pearson et aI., (1995; 1999; 2001) has recommended RCM, measured in relation to body

surface area, for improved accuracy. He proposes RCM measurement in the presence of palpable

splenomegaly when the hematocrit is just below the upper limit of the reference range.

Diagnostic challenges occur when PV exists without splenomegaly or leukocytosis

(Beutler, 2001). Early PV or PV accompanied by iron deficiency may not have an increased

RCM (Tefferi, 1999). Beutler (2001) reveals most cases of PV can be diagnosed without

determining the RCM. Cases of PV with only leukocytosis, thrombocytosis, or splenomegaly

pose a more difficult diagnostic challenge (Beutler, 2001). Lamy et aI., (1997) recommend

RCM measurement for unexplained splenomegaly, thrombocytosis, or hyperleukocytosis and

suggest that the decision to measure RCM not be limited to an elevated hematocrit or

hemoglobin. Table 7 presents tests commonly used to evaluate an elevated hematocrit.

Arterial oxygen saturation can distinguish PV from secondary polycythemia (Berlin,

1975; Beutler, 2001). Arterial oxygen saturation below 92% reveals secondary polycythemia.

Secondary polycythemia due to hypoxia must be evaluated for the underlying cause (Berlin,

1975).

Serum EPO measurement can be useful to differentiate secondary polycythemia from PV

(Napier & Wieczorek, 1981; Silverstein & Tefferi, 2000). A low or absent serum level ofEPO

typically accompanies PV (Adamson & Finch, 1968; Napier & Wieczorek, 1981; de Kleck et aI.,

1981). Secondary polycythemia is usually distinguished by an increased serum EPO (Tefferi,

14

1999). Elevated serum EPa levels due to pathologic production can be caused by cysts in the

liver or kidneys, uterine fibroid tumors, and tumors of the cerebellum, kidneys, or liver. Hypoxic

blood has been has been shown to increase erythropoietin production (Fisher & Langston, 1967).

An elevated serum EPa level without hypoxia raises the suspicion of kidney cysts or tumors

(Taetle, 1998). Tests may be required to confirm the presence of liver or kidney cysts or tumors

in the brain, liver, or kidneys (Talarico, 1998). Sleep studies, abdominal ultrasound,

echocardiogram, liver function tests, and other laboratory tests may be required to investigate

erythrocytosis (Messinezy & Pearson, 1999).

Treatment

Treatment is individualized, based on stage of the disorder, age, sex, clinical

manifestations, and laboratory profile (Hocking, 1995). The risk for thrombohemorrhagic

complications determines whether phlebotomy will be used alone or in combination with

myelosuppressive agents (Tefferi, Solberg, & Silverstein, 2000). Referral to a hematologist for

treatment is recommended. The prevention of thrombotic complications is an important goal of

treatment (Peereboom, 1996). Medications to treat gout, erythromelalgia, and pruritus are often a

necessary part of treatment.

The PVSG data from 1967 to 1987, revealed an increased incidence of thrombosis during

the first 3 years of treatment with phlebotomy alone. They found an increased risk of thrombosis

associated with increasing phlebotomy rates although a causal relationship has not established.

This same subject group had a higher mean survival rate (12.6 years) as opposed to patients

treated more aggressively with medications. The best survival rates have occurred with the use

of phlebotomy alone. The incidence of conversion to acute leukemia was significantly lower

among subjects in the phlebotomy arm of the study. Less than 5% of patients treated with

15

phlebotomy alone experience conversion to acute leukemia (Berk et aI., 1986; Berk, Wasserman,

Fruchtman, & Golclberg, 1995).

Based on the observations by the PVSG all patients with PV should receive phlebotomy

to normalize blood volume (Berk et aI., 1986; Fruchtman & Wasserman, 1995). The goal of

phlebotomy is to keep the hematocrit below 45% in men and below 42% in women (Pearson &

Wetherley-Mein, 1980; Fruchtman & Wasserman, 1995). Pearson and Wetherley (1979) found

that subjects who succumbed to cerebrovascular accidents had venous hematocrits ranging from

0.52 to 0.57. Phlebotomy treatment may initially remove between 250 to 500 cc to reach a

hematocrit between 40 and 45%. Elderly patients and those with cardiovascular disease are less

aggressively phlebotomized. Blood values to determine the frequency of phlebotomy are

monitored every 4 to 8 weeks. Iron deficiency develops with microcytic, hypochromic cells.

Iron supplementation is avoided since it can increase red cell mass and hematocrit (Tefferi et aI.,

2000; Fruchtman & Wasserman, 1995). Phlebotomy does not correct thrombocytosis,

leukocytosis, pruritus, or splenomegaly (Fruchtman & Wasserman, 1995). Elderly patients and

other patients with an increased risk for thrombosis may require additional treatment with

myelosuppressive agents (Fruchtman et aI., 1997).

The myelosuppressive agents frequently used in the United States are interferon alpha,

radioactive phosphorus, and hydroxyurea. Interferon-alpha has been shown to decrease the need

for phlebotomy, and improve splenomegaly, platelet, and hematocrit counts (Taylor et aI., 1996).

Hydroxyurea is well tolerated, easy to administer, and effective in most patients. Radioactive

phosphorus is often used for elderly patients (Fruchtman et aI., 1997). Median survival rate for

patients treated with radioactive phosphorus was 11.8 years in the PVSG (Fruchtman &

Wasserman, 1995).

16

Historically, busulfan has been used for the treatment of PV. Serious side effects have

limited its use and the PVSG no longer recommends alkylating agents due to the risk of cancer

and leukemia (Fruchtman & Wasserman, 1995). The Gruppo Italiano Studio Policitemia (1995)

found a greater than three-fold increase in cancer mortality for patients receiving alkylating

agents or radiophororus. Pipobroman is an alkylating agent used in Europe, but not approved for

use in the United States. A randomized study by Najean and Rain (1997) found no difference in

survival rates among patients given pipobroman or hydroxyurea. Hydroxyurea demonstrated

less effective hematological control in the same study.

Response to myelosuppressive therapy is carefully monitored with frequent

determinations of hematocrit, leukocyte, and platelet counts. Pearson's (1997) in vivo studies

showed elevated packed cell volumes and platelet counts predispose patients to platelet

activation, aggregation, and adhesion. Evaluations for thrombotic complications and progression

to leukemia should be tested routinely (Peereboom, 1996).

The use of aspirin for its antithrombotic properties was investigated by the Gruppo

Italiano Studio Policitemia (1997). The Gruppo Italiano Studio Policitemia conducted a pilot

study to determine the feasibility of a large trial to examine the use of aspirin in patients with PV

(1997). Forty milligrams of aspirin daily inhibited platelet activity and was well tolerated by

study subjects. The PVSG protocol 05 found no reduction in the incidence of thrombosis and an

increase in hemorrhage when aspirin 300 mg and persantine 75 mg were given three times daily

(Tartaglia, Goldberg, Berk, & Wasserman, 1986). Low-dose aspirin may be effective in the

prevention of thrombotic complications. The European Collaboration on Low-dose Aspirin in

Polycythemia Vera (ECLAP) is currently conducting a large-scale randomized trial to evaluate

the benefits and risks of aspirin prophylaxis for thrombotic complications (1997). Tefferi and

17

others are currently using aspirin for the treatment of vasomotor symptoms (2000). Aspirin is

currently indicated for patients with erythromelalgia, transient ischemic attacks, and those with a

history of arterial thrombosis (van Genderen & Troost, 2000).

The control of severe pruritus is important in the total treatment of PV. It may be

alleviated by the use of hydroxyurea or alpha interferon (Taylor et aI., 1996; Tatarsky & Sharon,

1997). Starch baths in lukewarm water and gentle patting instead of rubbing when drying the

skin is recommended (Fruchtman & Wasserman, 1995). Over-the-counter histamine antagonists

such as diphenhydramine or cimetidine have been used to relieve pruritus (Fruchtman &

Wasserman, 1995; Easton & Galbraith, 1978). Antidepressants such as doxepin or paroxetine

given in low doses have also been prescribed for intractable cases of pruritus. Low-dose aspirin

therapy has been recommended for itching and painful burning in the hands and feet (Tefferi,

1998).

Hyperuricemia with acute gout and nephrolithiasis usually improve with

myelosuppressive therapy. Allopurinol may be given to patients treated with phlebotomy alone.

Anti-inflammatory medications or colchicines have been used (Fruchtman & Wasserman, 1995).

Complications

Thrombotic events comprise about one third of the complications found in PV.

Cerebrovascular accidents represent the most frequent thrombotic event followed by myocardial

infarction, deep vein thrombosis, and pulmonary embolism. Bleeding and bruising occurs in

about one fourth of patients (Berk et aI., 1986). Chievitz and Thiede (1962) found hemorrhage

occurred less frequently than thrombosis. The other frequent causes of death include acute

leukemia, neoplasms, hemorrhage, and the "spent" phase with myelofibrosis and myeloid

18

metaplasia (Berk et aI., 1986; Chievitz & Thiede, 1962). Other complications of PV include

peptic ulcer disease and gastrointestinal bleeding (Talarico, 1998; Tefferi, 1998).

Conclusion

Although no cure exists for PV, treatment can prolong lives and enhance th~ quality-of

life for patients affected by PV. The insidious onset may make diagnosis difficult, but PV should

be suspected when any patient presents with an elevated hematocrit. An abnormally elevated

hematocrit accompanied by symptoms such as thrombocytosis, splenomegaly, and leukocytosis,

strongly suggests PV. Prompt referral to a hematologist for bone marrow aspiration and

treatment is recommended.

19

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30

Table 1

Occurrence of Signs and Symptoms in Patients with Polycythemia Vera

Sign/Symptom

Ruddy cyanosis

Palpable splenomegaly

Palpable hepatomegaly

Generalized pruritus

Headache, dizziness, epigastric distress, fatigue

Thrombotic events

Hemorrhagic events including gastrointestinal bleeding

Increased blood pressure

Thrombocytosis

Leukocytosis

Hyperuricemia

Elevated LAP

Mild basophilia

Percentage

- 700/0

- 70-75%

- 40-50%

- 40-50%

-30%

-20%

- 15-350/0

-30%

- 25-500/0

-60%

-40%

-70%

-6.0%

Note. LAP =leukocyte alkaline phosphatase. From (Silverstein & Tefferi, 1996; Hocking,

1995; Tefferi, 1998)

31

Table 2

Differential Diagnosis of Polycythemia Vera

Type of Polycythemia

Spurious/relative/stress polycythemia

Dehydration

Secondary polycythemia

Chronic pulmonary disease

Right to left cardiovascular shunts

High altitude

Erythropoietin-producing neoplasms

Sleep apnea syndrome

Benign renal lesions

Carbon monoxide intoxication

High oxygen affinity hemoglobinopathy

High serum level of carboxyhemoglobin: smoking

Polycythemia Vera

32

Table 3

Laboratory Differentiation of Polycythemia

Test Relative Polycythemia Secondary Polycythemia Polycythemia Vera

Red cell mass N I I

Leukocyte count N N I

Platelet count N N I

Arterial oxygen N NorD N saturation

Erythropoietin level N I NorD

Leukocyte alkaline N N I phosphatase

Serum vitamin B12 N N I

Bone marrow N Erythroid hyperplasia Hypercellular (panmyelosis)

Note. N, normal; D, decreased; I, increased. The differences listed are not present in all patients.

From (Talarico, 1998; Beutler, 2001; Ansell, 2001)

33

Table 4

PVSG Criteria for the Diagnosis of Polycythemia Vera

AI. Increased RBC mass B1. Thrombocytosis:

Platelet count !A 400,000/yl Male: ~ 36 ml/kg

Female: ~ 32 ml/kg B2. Leukocytosis: !A 12,000/yl (no fever or

A2. Normal arterial infection)

oxygen saturation (~92%)

B3. Increased leukocyte alkaline phosphatase A3. Splenomegaly

(LAP !A 100)

B4. Increased serum BD al binders BD a: (!A 900 pg/ml)

Unbound B D a binding capacity: (!A2200 pg/ml)

Note. PVSG =Polycythemia Vera Study Group; RBC =red blood cells; ml =milliliters; kg =

kilograms; yL =microliter; pg =picogram. Diagnosis of polycythemia vera virtually certain in

the presence of Al + A2 + A3 or Al + A2 + any two from category B. From "Therapeutic

Recommendations in Polycythemia Vera Based on Polycythemia Vera Study Group Protocols,"

by P.D. Berk, J.D. Goldberg, P.B. Donovan, S.M. Fruchtman, N.I. Berlin, and L.R. Wasserman,

1986, Seminars in Hematology, 23, p. 134. Copyright 1997 by W.B. Saunders. Reprinted with

permission.

34

Table 5

The Rotterdam Criteria of Polycythemia Vera Proposed by the Thrombocythemia Vera Study Group

(TVSG)

Al Raised red cell mass: B I Thrombocytosis

male> 36 mL/kg Platelet count> 400 x 109/L

female> 32 mL/kg

A2 Absence of any cause of secondary B2 Granulocytes> 10 x 109/L and/or

erythrocytosis by clinical and laboratory raised neutrophil alkaline phosphatase

investigations score of >100 in the absence of fever

or infection

A3 Histopathology of bone marrow biopsy B3 Splenomegaly on palpation or isotope/

increase of ultrasound scan

a.� Cellularity, panmyelosis B4 Erythroid colony formation

b.� Enlarged megakaryocytes with in absence of Epo: spontaneous EEC

Hyperploid nuclei; clusters of

megakaryocytes

c.� reticulin fibers (optional)

A I+A2+A3 is consistent with early stage PV (so-called "idiopathic erythrocyt<?sis")

AI+A2+A3+ anyone from category B establishes overt PV

A3+B I is consistent with essential thrombocythemia

A3+B3 and/or B4 is consistent with a primary myeloproliferative disorder

Note. Epo =erythropoietin, ml =milliliters, kg =kilogram, EEC =endogenous erythroid colony.

From "Proposal for Revised Diagnostic Criteria of Essential Thrombocythemia and Polycythemia

Vera by the Thrombocythemia Vera Study Group," by J. J. Michiels and E. Juvonen, 1997, Seminars

in Thrombosis and Hemostasis, 23, p. 341. Permission for reprint granted. Thieme Medical

Publishers, Inc.

35

Table 6

Proposed Modified Criteria for the Diagnosis of Polycythemia Vera

Al Raised red cell mass B1 Thrombocytosis

(>25% above mean normal predicted value) (platelet count >400xl09/1)

A2 Absence of cause of secondary erythrocytosis B2 Neutrophil leucocytosis

A3 Palpable splenomegaly (neutrophil count>1Ox109/1)

A4 Clonality marker 3/4 acquired abnormal B3 Splenomegaly demonstrated

marrow karyotype� on isotope/ultrasound scanning

B4 Characteristic BFU-E growth

or reduced serum erythropoietin

Al+A2+A3 or A4 establishes PV

Al+A2+ two of B establishes PV

Note. BFU-E =burst forming units - erythroid; PV =polycythemia vera. From "The

Classification and Diagnostic Criteria of the Erythrocytoses (Polycythaemias)" by T. C.

Pearson and M. Messinezy, 1999, Clinical Laboratory Haematology, 21, p. 313. Copyright

1999, Blackwell Science Limited. Permission for reprint granted.

36

Table 7

Laboratory and Diagnostic Tests for Polycythemia Vera

Test Cost Time to Sensitivity/ Cost Analysis Patient Teaching Results Specificity

CBC $18.55 30 Cost effective Explain to patient test

mins. to screening to evaluates RBCs,

Hematocrit ($10.25 1 hr. 98% identify WBCs, and platelets.

Hemoglobin for 97% erythrocytosis, Requires blood draw

WBC count individual 96% leukocytosis, and lasts 3 mins. No

Platelet tests) (sensitivities) & patient preparation

count $15.65 thrombocytosis required.

Red cell $900.00 1 day Very high Very Explain test measures

mass ($600.00 sensitivity. expensIve. RBCs in the blood. No

(usually for red Does not Effectively patient preparation

done with cell mass distinguish investigates required. Test lasts -2

plasma only) secondary high hrs. Blood is drawn.

volume) from primary hematocrit. RBCs tagged with 51

polycythemia chromium and re

injected. Blood drawn

20-30 mins. later.

37

Table 7 (continued)�

Laboratory and Diagnostic Tests for Polycythemia Vera�

Test Cost Time to Sensitivity/ Cost Analysis Patient Results Specificity Teaching

LAP $71.40 72 hrs. Nonspecific Expensive and Explain test measures

leukocyte test for PV. nonspecific. cellular reaction. No

alkaline patient preparation

phosphatase required. One blood

draw. Best if drawn in

the lab.

Arterial $28.25 Less Highly Cost-effective Test measures oxygen

oxygen than 30 sensitive for test for in the blood. No patient

saturation mIns. hypoxia hypoxia preparation. One blood

induced draw.

secondary

polycythemia

COHb $69.85 30 mins. Specifically Cost-effective Explain test measures

(carboxy to 24 measures approach to carbon monoxide in

hemoglobin) hrs. carbon distinguish the blood. No patient

monoxide secondary preparation. Best to

from any forms of draw before oxygen

source. polycythemia given. Requires one

blood draw.

38



Test Cost Time to Sensitivity/ Cost Analysis Patient Results Specificity Teaching

EPO assay $78.70 2-3 days Sensitivity May help Explain test measures

Erythro -95.5%. determine a protein. No

poietin secondary preparation.

polycythemia.

Serum B 12 $70.10 24-48 Sensitivity Expensive and Explain to patient test

hrs. 950/0 nonspecific for measures level of

Nonspecific PV. vitamin in blood and

test for PV evaluates anemia.

Fasting blood

required.

P-50 blood $50.25 Less Helps Can be Explain test measures

gas than 30 differentiate necessary to amount of oxygen in

nuns. cause for rule out hemo the arteries. No patient

increased globinopathies. preparation

EPO assay

39




IVP -$250.00 48 hrs. if High Expensive but Explain to patient test

(intravenous out- sensitivity maybe evaluates kidneys,

pyelogram) patient. for pathology necessary to ureters, and bladder.

Less of kidneys, rule out benign Contrast media is

than 24 ureters, and or malignant injected. Laxative prep

hrs. if bladder. renal may be ordered.

inpatient abnormalities Hydrate well before

when bedtime. NPO after

erythrocytosis midnight.

is unexplained.

Renal -$240.00 48 hrs. if Sensitive May be done to Explain test allows

Ultrasound out- measure for rule out renal visualization of

patient. renal lesions, cysts and kidneys. Noninvasive.

Less cysts. lesions. Test is done with a full

than 24 bladder. Takes less than

hrs. if 45mins.

inpatient

40




Abdominal -$570.00 48 hrs. if Sensitivity Expensive but Explain test evaluates

CT scan to out 85% necessary in organs in the abdomen.

$800.00 patient. absence of NPO 3 hrs. prior if

Liver and 30-60 Specificity hypoxia with contrast used.

spleen scan -$660.00 mins. if 99% normal WBC

inpatient and platelet

count.

CT scan of -$450.00 48 hrs. if Sensitivity Expensive but Explain to patient test

the head to out- 850/0 can be gIves cross

$692.00 patient, Specificity necessary to sectional images of the

30-60 100% rule out brain. NPO 3 hrs. prior

mins. if cerebral to contrast.

inpatient hemangio

blastoma.

Note. CBC =complete blood count; mins. =minutes; hr. =hour; WBC =white blood cells; PV =

polycythemia vera; P50 blood gas = partial pressure of oxygen at which hemoglobin is 50%

saturated; NPO =nothing by mouth; CT =computed tomography. Prices are estimates and may

vary among institutions. Costs and patient instructions from Pathology Associates Medical

41

Laboratory, Inland Imaging, Deaconess Hospital, and Holy Family Hospital, Spokane,

Washington.

42

Table 8�

Patient Education Resources�

National Organization for Rare Disorders, Inc. (NORD)�

Post Office Box 8923�

New Fairfield, CT

Web-Site: http://www.raredisease.orgl�

06812-8923�

Myeloproliferative Disease Research Center, Inc.�

115 East 72nd Street�

New York, NY 10021�

Web Site: http://www.acor.orgl�

Figure 1: Diagnostic Approach To "Suspected Polycythemia Vera" 43

Hb > 18.5 gm/dL, or a borderline elevated Hb with any PV-related feature, Or an interim Hb increase of > 2gm/dL

Check serum EPO Recheck Hb in 3 mo

Elevate serum EPO

Confirm low value Evaluate for secondary erythocytosis

PV-related features

Obtain bone marrow biopsy

Evaluate for secondary erythrocytosis

Obtain EEC Obtain Secondary

assay EEe assay erythrocytosis

Evaluate for PV secondary Repeat Hb in PV

erythrocytosis 3 months

44 Figure 2: Algorithm for the evaluation of an elevated hematocrit

I Elevated hematocrit

Males non-iron-deficit <55% (HbI8.0 gIL) Males non-iron-deficit >55% (> 18 gIL)I[Females non-iron-deficit <50% (Hb 16.5 gIL) Females non-iron-deficit >50% (>16.5 gIL)

I I I I

Asymptomatic Symptomatic, Asymptomatic Splenomegaly No splenomegaly Splenomegaly, Normal WBC Leukocytosis

Normal WBC or microcytosis Normal platelet Thrombocytosis Normal platelets No splenomegaly I INo microcytosis

Measure red cell mass, Spleen scan, CTI Serum EPO level and

Refer to hematologist Refer to hematologist Repeat CBC in 3 months for bone marrow exam

Advise smoking cessation� program if smoker�

I If repeat hematocrit >55% for Measure red

males, >50% for females do red t------------t cell mass cell mass measurement

I I Red cell mass increased I Red cell mass decreased I I

I IRelative Polycythemia Measure Suspect secondary

Assess medications, arterial oxygen polycythemia or PVI Ihabits, hydration, illness saturatIon

Arterial oxygen saturation Arterial oxygen� < 92% suspect secondary saturation�

polycythemia ~92%

I Search for cause of hypoxia, chest�

x-ray, pulmonary function tests�

High EPO above Oxyhemoglobin 30 mU/ml secondary

dissociation curve EPO normal, low, or absent polycythemia

P50 oxygen

IVPlRenal ultrasound, Abdominal CT, CTLeft curve shift and head. Consider: hepatoma, abnormal P50

cerebellar hemangioma, fibroma I

Suspect hemoglobinopathy,� carboxyhemoglobin Carboxyhemoglobin�

level�I Refer to hematologist

Refer to hematologist for bone marrow biopsy. Ifor suspected PV highly likely Determinehemoglobinopathy

Source

45

Figure Caption

Figure 1 Diagnostic Approach to "Suspected Polycythemia Vera." From "Diagnosing

Polycythemia Vera: A Paradigm Shift," by A. Tefferi, 1999, Mayo Clinic Proceedings, 74, p.

161. Copyright 1999 by Mayo Foundation for Medical Education and Research. Permission to

reprint granted. Of note, hemoglobin (Hb) level is for male Caucasians. Hb value for female

Caucasians is 17 gmJdL; for male African-Americans, 17.5 gmJdL; and for female

African=Americans, 16.7 gmJdL. EEC = endogenous erythroid colony; EPO = erythropoietin;

PV = polycythemia vera.

Figure 2 . Algorithm for the evaluation of an elevated hematocrit. Diagnostic approaches to

elevated hematocrits are based on signs, symptoms, and laboratory findings. WBC = white blood

cell; CBC = complete blood count; EPO = erythropoietin; CT = computed tomography; mD =

milliunit; ml = milliliter; IVP = intravenous pyelogram; PV = polycythemia vera; P50 = partial

pressure of oxygen at which hemoglobin is 50% saturated.

a manuscript submitted in partial fulfillment of

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