Running head: POLYCYTHEMIA
Polycythemia: A Review of Recent Literature
Liane Chlus and Christina Riggall
State University of New York Institute of Technology
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Polycythemia
Polycythemia is a chronic condition that occurs when the body produces too many red blood
cells, this in turn causes the blood to become thicker resulting in complications over time
(National Heart, Lung and Blood Institute [NHLBI], 2011). There are two types of
polycythemia, primary (polycythemia vera) and secondary. Polycythemia vera (PV) is caused by
a genetic mutation of the JAK2 V617F gene; secondary is caused by chronic low levels of
oxygen (NHLBI, 2011). Treatment of PV is continuing to be studied. Current treatment
modalities for primary polycythemia include therapeutic phlebotomy, medications, radiation, and
symptomatic treatments. Treatment of secondary polycythemia is based upon managing the
underlying cause or lifestyle modifications (Antle, 2010). The focus of this literature review is to
explore what the hematocrit goal should be; the current treatments to reach this goal, how to
reduce the risk of complications from polycythemia vera and future treatment options.
The goal of treatment for polycythemia is to reduce the risk of complications. Complications
from polycythemia vera include thrombosis, splenomegaly, puritis, peptic ulcers, or progression
to other diseases such as acute leukemia, myelofibrosis or myelodysplastic syndrome (Mayo
Clinic Staff, 2014). The family practitioner may initially obtain a complete blood count that may
have an elevated hematocrit, hemoglobin, red blood cells or platelet levels. Passamonti (2012a)
recommends performing an erythropoietin (EPO) level to differentiate between secondary
polycythemia and primary polycythemia vera. In polycythemia vera, the EPO level will be low
and in secondary the level will be high (Passamonti, 2012a). Referral to a Hematologist should
be ordered for possible bone marrow aspiration and treatment recommendations (Mayo Clinic
Staff, 2014).
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Methods
The State University of New York Institute of Technology's library database was used to find
articles for this literature review. Databases included CINHAL Plus, MEDLINE Plus and Health
Source: Nursing/Academic Edition. The Google search engine was used for general internet
resources. Search terms included: Polycythemia vera, therapeutic phlebotomy, target hematocrit
for polycythemia, treatments for polycythemia, thrombosis, management of polycythemia and
JAK2 inhibitors. Through the internet source, national organizations were searched to obtain
reputable information on the topic and similar search terms were used. The search was limited to
peer-reviewed articles published within the last five years. This literature review included ten
articles focused on treatment goals and therapies for polycythemia. Many of the large-scale
studies that were found on the topic were over five years old. Several of the studies or articles
that were included in our review mention these earlier studies on polycythemia vera. Secondary
polycythemia was excluded from our literature review because the treatment is based upon
treating the underlying cause.
Results
One of the main research questions studied was: What the target hematocrit (Hct) should be to
reduce the risk of complications? The New England Journal of Medicine published an article by
Marchioli et al. (2013) that studied JAK2 positive patients with polycythemia vera and their
intensity of treatment. 365 adults were split into two group, a high hematocrit group (45-50%)
and a low hematocrit group (<45%) (Marchioli, et al., 2013). The patients were treated with
phlebotomy and/or hydroxyurea (HU) to maintain their hematocrit at these levels over time. All
patients were treated with low dose aspirin unless contraindicated. The results from this study
were that the patients in the high Hct group had a four times higher rate of death from
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cardiovascular problems than the low Hct group (Marchioli, et al., 2013). The number of
participants was a limitation of this study. The researchers had initially set up to recruit around
1,000 patients but due to time constraints and lack of participation the study size was reduced
(Marchioli, et al, 2013). According to a review by Barbui, Finazzi and Finazzi (2012), the
recommended hematocrit for males should be less than 45% and for women less than 42%.
Barbui et al. (2012) states that there are no controlled studies to date that adequately confirm
higher hematocrit levels lead to more thrombotic events. The current recommendations from the
American Society of Hematology are based upon the study from Marchiolo, et al. (2013) to aim
treatment to maintain the hematocrit less than 45% (American Society of Hematology, 2013).
The second research consideration identified was: How to maintain the hematocrit below
45% in patients with polycythemia vera? A review by Harrison (2010) suggested that the
treatment should be based upon the cardiovascular risk group of the patient. According to
Harrison (2010), high risk patients includes anyone over age 60, history of previous thrombosis,
platelet count over 1000 x109/L, diabetes or hypertension requiring pharmacological
management and significant or symptomatic splenomegaly. Significant splenomegaly was
defined as the spleen being palpated 5cm below the costal margin (Harrison, 2010).
Symptomatic splenomegaly was defined as early satiety or pain (Harrison, 2010). According to
Harrison (2010), all patients with polycythemia vera should be treated with low-dose aspirin
unless contraindicated. This article did not discuss phlebotomy as an option for maintaining
hematocrit levels for low or high risk patients. High risk patients should be placed on either
hydroxyurea (if over age 60), or Interferon (less than age 60) for first line treatment (Harrison,
2010).
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The third consideration for patients with PV was: What treatment regime is best for
prevention of complications? In an article published in Blood Reviews, Barbui, et al. (2012) seem
to take a less aggressive pharmacological management approach for treating polycythemia vera.
Their first approach consideration is to educate the person on the disease and what modifying
factors the patient can make in their lifestyle. For example, smoking was found to increase the
risk of arterial thrombosis and therefore smoking cessation should be highly encouraged in
patients with polycythemia vera (Barbui et al., 2012). In this article, Barbui et al. (2012) suggest
the first treatment for high hematocrit associated with PV should be phlebotomy. This rapidly
reduces the viscosity of the blood, thereby reducing the risk of thrombosis. Recommendations
are to complete phlebotomy every other day until the goal hematocrit is reached (Barbui et al.,
2012). This article also suggested that a low dose aspirin be given daily to prevent thrombosis
(Barbui et al., 2012). For low risk patients, aspirin and phlebotomy were considered the first line
treatments (Barbui et al., 2012). For high risk patients, hydroxyurea and interferon-alpha (INFa) were considered first-line drugs of choice to prevent thrombosis (Barbui et al., 2012). HU was
also shown to reduce the incidence of myelofibrosis (Barbui et al., 2012). Effects of INF-a were
a reduced need for phlebotomy (maintaining lower Hct levels), decrease in spleen size and
decreased puritis (Barbui et al., 2012). Reikvam and Tiu (2012) also recommend modifying
lifestyle factors to reduce the risk of arterial and venous thrombosis. Reikvam and Tiu (2012)
recommended treatment of hyperlipidemia, exercise, smoking cessation, weight reduction, and
treatment of hypertension to prevent thrombosis. Similarly to Barbui et al. (2012), Reikvam and
Tiu (2012) suggest a low dose aspirin daily for all patients with polycythemia vera and
hydroxyurea for patients with a history of thrombosis. One of the research gaps that this article
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mentioned was whether a history of venous thrombosis should be treated differently than a
history of arterial thrombosis (Reikvam & Tiu, 2012).
Individual hematologists may have their own recommendations for treating polycythemia
vera. Passamonti (2012a) recommends a combination of lifestyle modification, antiplatelet
therapy, cytoreduction and phlebotomy. Passamonti (2012a) discussed the research obtained
from the Polycythemia Vera Study Group (PVSG) in 1997, a study that compared complications
with phlebotomy versus hydroxyurea. The study found no significant differences in thrombotic
events between the two groups. The hydroxyurea treated group developed more acute myeloid
leukemia (AML) and the phlebotomy group developed more myelofibrosis (MF) (Passamonti,
2012a). Passamonti (2012a) argues that other studies have not shown the same results, and his
recommendation is to discuss the possible risks associated with each of the treatments with the
patient, so they are aware of the potential adverse effects. Similarly to the other
recommendations, Passamonti (2012b) treats all of his patients diagnosed with PV a low dose
aspirin unless contraindicated and prescribes hydroxyurea for patients with more than one risk
factor for thrombosis.
Clinical trials are being conducted on JAK-2 inhibitors in their efficacy in treating
polycythemia vera and other myeloproliferative neoplasms. In the clinical trials that have been
initiated, benefits from these medications include a reduction in spleen size, improved fatigue
and a reduction in puritis (Apostolidou, Kantarjian, & Verstovsek, 2009). Side effects that have
been reported are gastrointestinal disturbances, myelosuppression and neurotoxicity
(Apostolidou et al., 2009). In 2011, the first JAK2 inhibitor was approved for use in the United
States for treatment of myelofibrosis, which can be an evolution of polycythemia vera (McCall,
2013). An article by Hensley, Geyer, and Mesa (2013) suggests that JAK-2 inhibitors may
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actually slow the progression of the disease and recommends that further research be completed
to test these new agents in comparison to the effects of hydroxyurea or interferon.
Conclusion
Multiple treatment modalities for polycythemia exist, and treatments need to be
individualized for the patient's specific situation. Family Nurse Practitioners may collaborate
with the Hematologist/Oncologist to manage the treatment regimen for these patients. The goal
of treatment is to reduce the risk of thrombosis, reduce the risk of other complications and slow
the progression of the disease. The literature that was reviewed recommended lifestyle
modification and low dose aspirin for all patients with polycythemia, unless contraindicated. For
secondary polycythemia treatment was geared towards the underlying cause of the disease.
Primary treatments for polycythemia vera included aspirin, hydroxyurea, interferon-alpha and
phlebotomy. Clinical trials are being completed to inhibit the JAK2 gene to reduce the risk of
progression to myelofibrosis or acute leukemia. Current treatment modalities are effective at
reducing the risk of thrombosis and mortality associated with this, but more studies need to be
conducted to determine which treatments are the most successful.
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References
American Society of Hematology. (2013). In polycythemia vera, 45 is the number. The
Hematologist. Retrieved from http://www.hematology.org/Publications/
Hematologist/2013/9946.aspx
Antle, E. (2010). Who Needs a Therapeutic Phlebotomy?. Clinical Journal Of Oncology
Nursing, 14(6), 694-696. doi:10.1188/10.CJON.694-696
Apostolidou, E., Kantarjian, H., & Verstovsek, S. (2009). JAK2 inhibitors: A reality? A hope?.
Clinical Lymphoma & Myeloma, 9S340-5. doi:10.3816/CLM.2009.s.033
Barbui, T., Finazzi, M., & Finazzi, G. (2012). Front-line therapy in polycythemia vera and
essential thrombocythemia. Blood Reviews, 26(5), 205-211.
doi:10.1016/j.blre.2012.06.002
Harrison, C. (2010). Rethinking disease definitions and therapeutic strategies in essential
thrombocythemia and polycythemia vera. Hematology / The Education Program Of The
American Society Of Hematology. American Society Of Hematology. Education
Program, 2010129-134. doi:10.1182/asheducation-2010.1.129
Hensley, B., Geyer, H. & Mesa, R. (2013). Polycythemia vera: Current pharmacotherapy and
future directions. Expert opinion, 14(5), 609-617.
Marchioli, R., Finazzi, G., Specchia, G., Cacciola, R., Cavazzina, R., Cilloni, D., & ... Rapezzi,
D. (2013). Cardiovascular Events and Intensity of Treatment in Polycythemia Vera. New
England Journal Of Medicine, 368(1), 22-33. doi:10.1056/NEJMoa1208500
Mayo Clinic Staff. (2014). Diseases and conditions: Polycythemia vera. Retrieved from
http://www.mayoclinic.org/diseases-conditions/polycythemiavera/basics/complications/con-20031013
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McCall, B. (2013). Second JAK2 Inhibitor for Myelofibrosis shows strong data. Medscape
Medical News. Retrieved from http://www.medscape.com/viewarticle/806394
Moses, S. (2014). Polycythemia rubra vera. Family Practice Notebook. Retrieved from
http://fpnotebook.com/HemeOnc/Marrow/PlycythmRbrVr.htm
National Heart, Lung and Blood Institute. (2011). What is polycythemia vera? Retrieved from
http://www.nhlbi.nih.gov/health/health-topics/topics/poly/
Passamonti, F. (2012a). How I treat polycythemia vera. Blood, 120(2), 275-284.
doi:10.1182/blood-2012-02-366054
Passamonti, F. (2012b). How to manage polycythemia vera. Leukemia (08876924), 26(5), 870874. doi:10.1038/leu.2011.334
Reikvam, H., & Tiu, R. (2012). Venous thromboembolism in patients with essential
thrombocythemia and polycythemia vera. Leukemia (08876924), 26(4), 563-571.
doi:10.1038/leu.2011.314
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Appendix A
#
Study
Focus
Subj
ects
1
American
Society of
Hematology,
(2013).
Treatment
goals
N/A
2
Antle, E.
(2010).
Therapeutic
phlebotomy
N/A
3
Apostolidou,
E.,
Kantarjian,
H., &
Verstovsek,
S. (2009).
JAK 2
Inhibitors
4
Barbui, et al
(2012)
Current
therapies,
high/low risk
patients
5
Harrison, C.
(2010)
Indications
for
cryoreductive
therapy,
relieving
disease
related
symptoms &
minimizing
risk of
transformatio
n to
Population
Age
Methods
Findings
Pt's with PV
Adults
Reviewed the current
recommendations and
the literate that
brought about the
recommendation.
Pt’s with PV
N/A
The importance of
therapeutic
phlebotomy in
treatment of PV was
discussed.
JAK 2 +
patient's with
myeloprolifera
tive neoplasms
Adults
Several clinical trials
to determine the
effectiveness of these
new medications.
N/A
Pt’s with PV
Lifesp
an
Review of current
literature and
treatment modalities
and effectiveness was
assessed
N/A
Pt's with PV
Adults
Review of current
medications and
future direction in
treating PV.
Discussed the
findings of the
Marchioli, 2013
study with the
low vs. high Hct
groups and the
results from the
study (See
Marchioli et al,
2013).
Phlebotomy can
be used to treat
PV and nurses
should be aware
of the reasoning
behind this and
monitor labs as
needed.
Clinical studies
have shown a
decrease in
spleen size &
puritis with the
new medications.
Side effects
include GI
disturbances &
myelosupression
Low-dose aspirin
& phlebotomy is
safe and effective
at reducing the
risk of
thrombosis as 1st
line tx.
Hydroxyurea can
be added to
maintain Hct less
than 45%.
Treatment based
upon patient's
risk, discussed
potential for
JAK2 Inhibitors,
may reduce
splenomegaly
and symptoms
associated with
PV.
POLYCYTHEMIA
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Hensley,
Geyer &
Mesa,
(2013).
7
Marchioli,
R., et al.
(2013).
8
secondary
myeloid
malignancy
Current
pharmacothre
rapy
11
N/A
Pt's with PV
N/A
Reviewed the current
medications available
for the treatment of
PV and the results of
the studies that had
been completed in the
past.
Determine
which
treatment
intensity had
better
outcomes
N=
365
Pt’s with
JAK2 positive
PCV
Adults
Pts were randomly
assigned to a low or
high Hct group.
Median follow up
was 31 months and
adverse events were
recorded.
Passamonti,
F (2012a)
How he treats
his pt’s with
PV &
problems
encountered
N/A
Pt's with PV
Adults
&
special
popula
tion
Discussed diagnostic
testing for
determining
secondary
polycythemia vs. PV
9
Passamonti,
F (2012b)
Discusses
case
scenarios and
current
recommendat
ions for
treatment of
PV
N/A
Pt's with PV
Case
studies
of
three
patient
s
discuss
ed
Describe
recommendations for
treatment in each
case and why
10
Reikvam,
H., & Tiu,
R. (2012).
Manifestation
s, treatment
modalities
and future
directions
N/A
Patient's with
DVT/PE
related to PV
Adultspecial
popula
tion
discuss
ed
pregna
nt
female
s
Discussed treatment
modalities for
prophylaxis and
treatment of DVT/PE
such as phlebotomy,
hydroxyurea, aspirin,
Coumadin, JAK 2
inhibitors
Current
treatments were
phlebotomy,
aspirin &
hydroxyurea.
INFa and JAK 2
inhibitors still
being studied but
do show benefits.
Those with a Hct
less than 45%
had a lower rate
of CV death and
thrombosis.
*Current
recommendation
from the
American
Society of
Hematology
Explained his
personal
treatment of PV
and reviews the
previous studies
that have been
completed.
Significant
importance
placed on the
serum
erythropoietin
(EPO) level in
aiding the
diagnosis as well
as family history.
Discussed the
pros and cons of
each method.
Recommended
low-dose aspirin
for all PV pt’s
unless
contraindicated.