[1]

Polycythemia
Definition:
Polycythemia (also known as polycythaemia or polyglobulia) is a disease
state in which the proportion of blood volume that is occupied by red blood
cells increases. Blood volume proportions can be measured as hematocrit
level. It can be due to an increase in the number of red blood cells ("absolute
polycythemia") or to a decrease in the volume of plasma ("relative
polycythemia"). Polycythemia is sometimes called erythrocytosis, but the
terms are not synonymous because polycythemia refers to any increase in
red blood cells, whereas erythrocytosis only refers to a documented increase
of red cell mass.
The emergency treatment of polycythemia (e.g., in hyperviscosity or
thrombosis) is by venesection, the removal of blood from the circulation.
Depending on the underlying cause, venesection may also be used on a
regular basis to reduce the red blood cell count. Cytostatics (busulfan,
hydroxyurea)

are

sometimes

used

if

venesection

is

ineffective

or

contraindicated.
Polycythemia is a condition that results in an increased level of circulating
red blood cells in the bloodstream. People with polycythemia have an
increase in hematocrit, hemoglobin, or red blood cell count above the
normal limits.
Polycythemia is normally reported in terms of increased hematocrit or
hemoglobin.

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Hematocrit (HCT): Polycythemia is considered when the hematocrit is

greater than 48% in women and 52% in men.
Hemoglobin (HGB): Polycythemia is considered when a hemoglobin
level of greater than 16.5g/dL in women or hemoglobin level greater
than18.5 g/dL in men.
Categories of Polycythemia:
Polycythemia can be divided into two categories;
Primary Polycythemia
Secondary Polycythemia
Primary Polycythemia (Polycythemia vera):
Primary polycythemias are due to factors intrinsic to red cell precursors.
Polycythemia vera (PCV), polycythemia rubra vera (PRV), or erythremia,
occurs when excess red blood cells are produced as a result of an
abnormality of the bone marrow. Often, excess white blood cells and
platelets

are

also

produced.

Polycythemia

vera

is

classified

as

myeloproliferative disease. Symptoms include headaches and vertigo, and

signs on physical examination include an abnormally enlarged spleen
and/or liver. In some cases, affected individuals may have associated
conditions including high blood pressure or formation of blood clots.
Transformation to acute leukemia is rare. Phlebotomy is the mainstay of
treatment. A hallmark of polycythemia is an elevated hematocrit, with Hct >
55% seen in 83% of cases. A somatic (non-hereditary) mutation (V617F) in
the JAK2 gene is found in 95% of cases, though also present in other
myeloproliferative disorders.

[3]

Primary familial polycythemia, also known as primary familial and

congenital polycythemia (PFCP), exists as a benign hereditary condition, in
contrast with the myeloproliferative changes associated with acquired
polycythemia vera. In many families, PFCP is due to an autosomal dominant
mutation in the EPOR erythropoietin receptor gene. PFCP can cause an
increase of up to 50% in the oxygen-carrying capacity of the blood; skier
Eero Mntyranta had PFCP, which is considered to have given him a large
advantage in endurance events.
Secondary Polycythemia:
Secondary polycythemia is caused by either natural or artificial increases in
the production of erythropoietin, hence an increased production of
erythrocytes. In secondary polycythemia, there may be 6 to 8 million and
occasionally 9 million erythrocytes per cubic millimeter of blood. Secondary
polycythemia resolves when the underlying cause is treated.
Secondary polycythemia in which the production of erythropoietin increases
appropriately is called physiologic polycythemia.
Conditions which may result in a physiologically appropriate polycythemia
include:
Altitude related - This physiologic polycythemia is a normal adaptation
to living at high altitudes (see altitude sickness). Many athletes train
at high altitude to take advantage of this effect a legal form of blood
doping. Some individuals believe athletes with primary polycythemia
may have a competitive advantage due to greater stamina. However,
this has yet to be proven due to the multifaceted complications
associated with this condition.

[4]

Hypoxic disease-associated - for example in cyanotic heart disease

where blood oxygen levels are reduced significantly. May also occur as
a result of hypoxic lung disease such as COPD and as a result of
chronic obstructive sleep apnea.
Iatrogenic - Secondary polycythemia can be induced directly by
phlebotomy (blood letting) to withdraw some blood, concentrate the
erythrocytes, and return them to the body.
Genetic - Heritable causes of secondary polycythemia also exist and
are associated with abnormalities in hemoglobin oxygen release. This
includes patients who have a special form of hemoglobin known as Hb
Chesapeake, which has a greater inherent affinity for oxygen than
normal adult hemoglobin. This reduces oxygen delivery to the kidneys,
causing

increased

erythropoietin

production

and

resultant

polycythemia. Hemoglobin Kempsey also produces a similar clinical

picture. These conditions are relatively uncommon.
Conditions where the secondary polycythemia is not as a result of
physiologic adaptation and occurs irrespective of body needs include:
Neoplasms - Renal-cell carcinoma or liver tumors, von Hippel-Lindau
disease, and endocrine abnormalities including pheochromocytoma
and adrenal adenoma with Cushing's syndrome.
People whose testosterone levels are high because of the use of
anabolic steroids, including athletes who abuse steroids, or people on
testosterone replacement for hypogonadism, as well as people who
take erythropoietin may develop secondary polycythemia.
Causes:
Smoking, which impairs red blood cells' ability to deliver oxygen to body
tissues, can cause secondary polycythemia. So can the following conditions:

[5]

Carbon monoxide poisoning

Chronic heart or lung disease
Hormonal (endocrine) disorders
Exposure to high altitudes
Kidney cysts
Tumors of the brain, liver, or uterus.

Causes of spurious polycythemia include:

Burns
Diarrhea
Hemoconcentration (higher-than-normal concentration of cells and
solids in the blood, usually due to becoming dehydrated or taking
diuretics )
Stress
Weakness, headaches, and fatigue are usually the first symptoms of
secondary polycythemia. Patients may feel lightheaded or experience
shortness of breath.
Visual disturbances associated with this disorder include distorted vision,
blind spots, and flashes of light. The gums and small cuts are likely to bleed,
and the hands and feet may burn. Extensive itching often occurs after
taking a bath or shower.
Pain in the chest or leg muscles is common. The face often becomes ruddy,
then turns blue after exercise or other exertion. Confusion and ringing in
the ears (tinnitus ) may also occur.
Polycythemia vera stems from problems with the bone marrow. Bone
marrow is found in the centre of most bones and normally produces all red
blood cells and platelets and most white blood cells. When this process
breaks down, production of cells is no longer orderly and conditions such as
polycythemia can result. Although the exact cause of polycythemia vera is

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unknown, researchers have found that a specific gene mutation is

associated with almost all people with this condition.
Polycythemia vera is a rare condition usually affecting men in their 60s. It is
more common in men than in women. The condition is rarely seen in people
under age 40, but can also affect babies.
Although the cause of polycythemia vera is unknown, a number of factors
are involved that appear to lead to secondary polycythemia. A high content
of red blood cells builds up in response to low oxygen concentration in the
air. Because there's less oxygen in the blood, the body attempts to overcome
the lack by making more red blood cells. It doesn't stop, however, and keeps
producing them until there are too many. The bone marrow can also be
overstimulated by testosterone replacement therapy.
Living for long periods at high altitudes where there's less oxygen may lead
to polycythemia. It also may occur in people with chronic lung conditions
and certain kidney tumours and cysts. Heavy smoking is associated with an
increase in carbon monoxide in the blood and may also lead to higher red
cell and hemoglobin levels. Low blood oxygen levels (hypoxia) due to
congenital heart disease also appear to be a factor in the development of
polycythemia.
Most people who live at high altitudes don't appear to suffer secondary
polycythemia. In fact, the condition is virtually absent in some mountain
regions. When it does occur, it's thought that other environmental factors,
such as smoking or mining, may contribute.
Polycythemia in babies usually occurs because the baby receives more than
the normal amount of blood from the placenta during birth. It also can

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result from the mother living at a high altitude, or if the baby had a placenta
that was not functioning optimally.
Symptoms:
Polycythemia may not cause any symptoms. It's often discovered only if a
hemoglobin test or a red blood cell count is done. Some people do experience
symptoms that appear gradually. These may include itching following
bathing, dizziness, and a flushing of the face and hands. Weakness,
headaches, visual disturbances, and a sense of "fullness" in the head and in
the left upper abdomen may also be associated with the condition. Some
people may have high blood pressure.
An infant who has polycythemia may be feeding poorly and have low blood
sugar and difficulty breathing. It's very important to note that the problem
isn't a cause for major concern in babies. It often doesn't require treatment,
and it often resolves within a few days. However, these symptoms do warrant
a visit to the doctor. Only very rarely does polycythemia cause serious
problems in babies, such as seizures due to poor circulation to the brain.
Anyone who has polycythemia vera must receive treatment. Without
treatment, the symptoms will become much worse and the risk of death
from stroke, blood clots, or heart attack will increase. With proper
treatment, the average survival of people with polycythemia vera is 7 to 15
years. People will probably feel quite normal and their risk of stroke or heart
attack will be much less than if they didn't seek treatment. Although there's
no cure, most people live for more than 10 years with the disease. Blood
clots are the most common cause of death, followed by complications of
myeloid metaplasia (a progressive disease of the bone marrow), hemorrhage,
and development of acute leukemia.

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Diagnosis:
A

very

important

part

of

diagnosing

secondary

polycythemia

is

differentiating it from primary polycythemia (also called polycythemia rubra

vera

or

Vaquez'

disease).

Unlike

secondary

polycythemia,

primary

polycythemia cannot be traced to an underlying condition such as smoking,

high altitude, or chronic lung disease.
Doctors diagnose polycythemia by measuring oxygen levels in blood drawn
from an artery. A patient whose oxygen level is abnormally low probably has
secondary polycythemia. Erythropoietin may also be measured. Levels of
this hormone, which stimulates the bone marrow to produce red blood cells,
may be normal or elevated in a patient with secondary polycythemia. Red
blood cell mass is also frequently measured in diagnosing the disorder.
Imaging studies are sometimes performed to determine whether the spleen
and liver are enlarged and to detect erythropoietin-producing kidney lesions.
Other diagnostic procedures include chest x rays and an electrocardiogram
(EKG).
To diagnose polycythemia, a doctor will begin by discussing the patient's
health history and doing a physical examination. The doctor will check for
evidence of low brain or lung blood flow by asking about symptoms such as
headache, weakness, tinnitus (ringing or buzzing in the ears), or vision
problems. The doctor will also look for physical signs of increased blood
volume, such as dilated veins and a ruddy complexion. If the skin is flushed
or itchy, particularly after a hot bath, it may indicate a diagnosis of
polycythemia.
The doctor may also check for a history of smoking or alcohol abuse or a
family history of kidney disease. A careful physical examination might also

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be done to check for high blood pressure, obesity, lack of oxygen (cyanosis),
heart murmurs, or abdominal noises (audible swishing or murmuring
sounds heard over an artery or vascular channel, called bruits). Various
blood tests will likely be done, including a complete blood cell count and
measurement of levels of vitamin B12 and certain other substances. Uric
acid levels may also be increased and should be checked. Your doctor may
also order tests for gene mutations associated with the condition.
Additional tests will then be done to find out whether it is polycythemia vera
or secondary polycythemia. These tests will probably include a history and
physical examination, measurements of oxygen saturation, and a complete
blood count. For some people, the doctor may suggest a bone marrow test. A
blood test to look for a mutation in a protein called Jak-2 may be performed.
Treatment:
Treatment will vary according to the person's age, gender, medical status,
symptoms, and blood test results.
To reduce the risk of blood clots, treatment with low-dose acetylsalicylic
acid* (ASA) is recommended for most people with polycythemia (unless there
is a reason they should not take it). Phlebotomy (removal of small amounts of
blood) used to be the most common type of therapy for polycythemia vera.
When phlebotomy is used, blood will be withdrawn in amounts of 300 mL to
500 mL every few days at first, then every few weeks, and then every few
months. The treatment goal will be to keep the blood hemoglobin level
within the low-to-normal range. Often, the process of blood withdrawal can
be stopped for months at a time if the hemoglobin level stays in the required
range. For seniors or for people with heart or brain blood vessel disease, less
blood is usually taken (i.e., only 200 mL to 300 mL twice a week). Once a

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person's hemoglobin levels are normal, he or she will probably have monthly
doctor's appointments.
If the blood has high white blood cell and platelet counts in addition to a
high content of red blood cells, the physician may prescribe a medication
that cuts down blood cell production by the bone marrow (e.g., radioactive
phosphorus). This medication has a success rate of 80% to 90%. Remissions
may last from 6 months to several years. This medication has few side
effects. Its main advantage is that people need fewer follow-up visits when
the disease is controlled. In fact, just one treatment a year may be enough to
control the disease. A disadvantage of radioactive phosphorus therapy is
that it may turn normal white cells into leukemia cells. For this reason, it is
rarely used.
Other medications may be used on a daily basis to lower both the white
blood cell count and the platelet count. For example, hydroxyurea is
commonly used.
Complications such as high uric acid blood levels and itchy skin may be
treated with allopurinol or antihistamines, respectively.
In rare cases, the spleen can become extremely enlarged. The physician may
recommend its surgical removal (splenectomy). Anyone who has had a
splenectomy must get vaccinations to prevent future infections.
If the disorder seems to be causing considerable problems in an infant, up
to several ounces of blood can be removed and replaced with intravenous
fluid. This procedure usually dilutes the circulating red blood cells until they
return to a normal level.

[11]

Unfortunately, there's no way to prevent polycythemia vera. However, you

may reduce your risk of secondary polycythemia by not smoking and by not
spending long periods of time at high altitudes.
Secondary polycythemia is treated primarily by treating the underlying
condition causing the disorder. For example, patients with Gaisbock's
syndrome are often taken off diuretics and encouraged to lose weight. Lung
disorders, such as chronic obstructive pulmonary disease (COPD), may
cause secondary polycythemia; treating the lung disorder generally improves
the polycythemia.
Some medications may also be taken to treat symptoms caused by
polycythemia. For example, antihistamines can alleviate itching, and aspirin
can soothe burning sensations and bone pain.
Until the underlying condition is controlled, doctors use bloodletting
(phlebotomy ) to reduce the number of red blood cells in the patient's body.
In most instances, a pint of blood is drained from the patient as needed and
tolerated, until the hematocrit (the proportion of red cells in the blood)
reaches an acceptable level. Chemotherapy is not used to treat secondary
polycythemia; however, it may be used to treat the primary form.

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Drugs To Treat Polycythemia (Generic Name):

Hydroxyurea:
Hydroxyurea

or Hydroxycarbamide

is an antineoplastic drug, first

synthesized in 1869, used in myeloproliferative disorders, specifically

polycythemia vera and essential thrombocythemia. It is also used to reduce
the rate of painful attacks in sickle-cell disease and has antiretroviral
properties in diseases such as AIDS.
It is on the World Health Organization's List of Essential Medicines, a list of
the most important medication needed in a basic health system.
Mechanism of Action:
Hydroxycarbamide decreases the production of deoxyribonucleotides via
inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free
radicals as they are involved in the reduction NDPs.
In the treatment of sickle-cell disease, hydroxycarbamide increases the
concentration of fetal hemoglobin. The precise mechanism of action is not
yet clear, but it appears that hydroxycarbamide increases nitric oxide levels,
causing soluble guanylyl cyclase activation with a resultant rise in cyclic
GMP, and the activation of gamma globin chain synthesis necessary for fetal
hemoglobin production (which inhibits the formation of sickle hemoglobin
aggregates). A few red cell clones called F cells are progeny of a small pool of

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immature committed erythroid precursors (BFU-e) that retain the ability to

produce HbF.

MECHLORETHAMINE HCL:
Chlormethine mechlorethamine also known as mustine and HN2 and in
former USSR known as Embichin is a nitrogen mustard sold under the
brand name Mustargen. It is the prototype of alkylating agents, a group of
anticancer

chemotherapeutic

drugs.

It

works

by

binding

to

DNA,

crosslinking two strands and preventing cell duplication. It binds to the N7

nitrogen on the DNA base guanine. As the chemical is a blister agent, its use
is strongly restricted within the Chemical Weapons Convention where it is
classified as a Schedule 1 substance.
Mechlorethamine belongs to the group of nitrogen mustard alkylating
agents.
Mechanism of Action:
Mechlorethamine, as an alkylating agent, interferes with DNA replication
and transcription of RNA and ultimately results in the disruption of nucleic
acid function. Mechlorethamine also possesses weak immunosuppressive
activity.

[14]

Mechlorethamine, as an alkylating agent, interferes with DNA replication

and transcription of RNA, and ultimately results in the disruption of nucleic
acid function.
Alkylating agents work by three different mechanisms: 1) attachment of
alkyl groups to DNA bases, resulting in the DNA being fragmented by repair
enzymes in their attempts to replace the alkylated bases, preventing DNA
synthesis and RNA transcription from the affected DNA, 2) DNA damage via
the formation of cross-links (bonds between atoms in the DNA) which
prevents DNA from being separated for synthesis or transcription, and 3) the
induction

of

mispairing

of

the

nucleotides

leading

to

mutations.

Mechlorethamine is cell cycle phase-nonspecific.

PROCARBAZINE HCL:
Procarbazine (Matulane (US), Natulan (Canada), Indicarb (India) is an
antineoplastic chemotherapy drug for the treatment of Hodgkin's lymphoma
and certain brain cancers (such as glioblastoma multiforme). It is a member
of a group of medicines called alkylating agents. It gained FDA Approved in
July 1969. The drug is metabolized and activated in the liver. It also inhibits
MAO thus increasing the effects of sympathomimetics, TCAs, and tyramine.
It is on the World Health Organization's List of Essential Medicines, a list of
the most important medication needed in a basic health system.
Mechanism of Action:
Procarbazine is an alkylating agent. The exact mechanism of antineoplastic
action is unknown but is thought to resemble that of the alkylating agents;

[15]

procarbazine is cell cyclespecific for the S phase of cell division.

Procarbazine is thought to inhibit DNA, RNA, and protein synthesis.
Procarbazine causes weak inhibition of monoamine oxidase (MAO). MAO
inhibitors

prevent

the

inactivation

of

tyramine

by

hepatic

and

gastrointestinal monoamine oxidase. Tyramine in the bloodstream releases

norepinephrine from the sympathetic nerve terminals and produces a
sudden increase in blood pressure.
The precise mode of cytotoxic action of procarbazine has not been clearly
defined. There is evidence that the drug may act by inhibition of protein,
RNA and DNA synthesis. Studies have suggested that procarbazine may
inhibit transmethylation of methyl groups of methionine into t-RNA. The
absence of functional t-RNA could cause the cessation of protein synthesis
and consequently DNA and RNA synthesis. In addition, procarbazine may
directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation
of the drug, may attack protein sulfhydryl groups contained in residual
protein which is tightly bound to DNA.
Reference:
http://en.wikipedia.org/wiki/Polycythemia
http://www.medicinenet.com/polycythemia_high_red_blood_cell_count/arti
cle.htm
http://chealth.canoe.ca/channel_condition_info_details.asp?
disease_id=280&channel_id=2022&relation_id=16451
http://en.wikipedia.org/wiki/Hydroxycarbamide
http://en.wikipedia.org/wiki/Chlormethine

[16]

http://www.drugbank.ca/drugs/DB00888
http://www.webmd.com/drugs/condition-556-Polycythemia+Vera.aspx?
diseaseid=556&diseasename=Polycythemia+Vera&source=0
http://www.drugs.com/mmx/procarbazine-hydrochloride.html
http://pubchem.ncbi.nlm.nih.gov/compound/procarbazine#section=Mecha
nism-of-Action