Polycythemia vera
Encyclopedia
Polycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the increased red blood cells. It is more common in the elderly and may be symptomatic or asymptomatic.
study in Olmsted County, Minnesota
found that the highest incidence was in people aged 70–79 years. The overall incidence in the Minnesota population was 1.9 per 100,000 person-years, and the disease was more common in men than women. A cluster around a toxic site was confirmed in northeast Pennsylvania in 2008.
. A classic symptom of polycythemia vera is pruritus or itch
ing, particularly after exposure to warm water (such as when taking a bath), which may be due to abnormal histamine
release or prostaglandin
production. Such itching is present in approximately 40% of patients with polycythemia vera. Gouty arthritis
may be present in up to 20% of patients. Peptic ulcer disease is also common in patients with polycythemia vera; the reasons for this are unclear, but may be related to an increased susceptibility to infection with the ulcer-causing bacterium H. pylori
. Another possible mechanism for the development for peptic ulcer is increased histamine release and gastric hyperacidity related with polycythemia vera.
A rare but classic symptom of polycythemia vera (and the related myeloproliferative disease essential thrombocythemia) is erythromelalgia
. This is a sudden, severe burning pain in the hands or feet, usually accompanied by a reddish or bluish
coloration of the skin. Erythromelalgia is caused by an increased platelet count or increased platelet "stickiness" (aggregation), resulting in the formation of tiny blood clots in the vessels of the extremity; it responds rapidly to treatment with aspirin
.
Patients with polycythemia vera are prone to the development of blood clots (thrombosis
). A major thrombotic complication (e.g. heart attack
, stroke
, deep venous thrombosis, or Budd-Chiari syndrome
) may sometimes be the first symptom or indication that a person has polycythemia vera.
Headaches, lack of concentration and fatigue are common symptoms that occur in patients with polycythemia vera as well.
, plethora, or gouty nodules
. The diagnosis is often suspected on the basis of laboratory tests. Common findings include an elevated hemoglobin level or hematocrit
, reflecting the increased number of red blood cells; the platelet count or white blood cell count may also be increased. The erythrocyte sedimentation rate
(ESR) is decreased due to an increase in zeta potential
. Because polycythemia vera results from an essential increase in erythrocyte production, patients have a low erythropoietin
(EPO) level.
In primary polycythemia, there may be 8 to 9 million and occasionally 11 million erythrocytes per cubic millimeter of blood (a normal range for adults is 4-6), and the hematocrit
may be as high as 70 to 80%. In addition, the total blood volume sometimes increases to as much as twice normal. The entire vascular system can become markedly engorged with blood, and circulation times for blood throughout the body can increase up to twice the normal value. The increased numbers of erythrocytes can cause the viscosity
of the blood to increase as much as five times normal. Capillaries can become plugged by the very viscous blood, and the flow of blood through the vessels tends to be extremely sluggish.
As a consequence of the above, people with untreated polycythemia vera are at a risk of various thrombotic
events (deep venous thrombosis, pulmonary embolism
), heart attack
and stroke
, and have a substantial risk of Budd-Chiari syndrome
(hepatic vein thrombosis), or myelofibrosis
. The condition is considered chronic; no cure exists. Symptomatic treatment (see below) can normalize the blood count and most patients can live a normal life for years.
The disease appears more common in Jews of European extraction than in most non-Jewish populations. Some familial forms of polycythemia vera are noted, but the mode of inheritance is not clear.
Recently, in 2005, a mutation in the JAK2 kinase (V617F) was found by multiple research groups to be strongly associated with polycythemia vera. JAK2 is a member of the Janus kinase
family and makes the erythroid precursors hypersensitive to erythropoietin (EPO). This mutation may be helpful in making a diagnosis or as a target for future therapy.
As the condition cannot be cured, treatment focuses on treating symptoms and reducing thrombotic complications by reducing the erythrocyte levels.
Bloodletting
(called venesection or phlebotomy) is one form of treatment, which often may be combined with other therapies. The removal of blood from the body reduces the blood volume and brings down the hematocrit levels; in patients with polycythemia vera, this reduces the risk of blood clots. Venesection is typically performed in people with polycythemia vera to bring their hematocrit
(red blood cell percentage) down below 45 for men or 42 for women. It has been observed that phlebotomy also improves cognitive impairment.
Low dose aspirin
(75–81 mg daily) is often prescribed. Research has shown that aspirin reduces the risk for various thrombotic complications.
Chemotherapy
for polycythemia may be used, either for maintenance, or when the rate of bloodlettings required to maintain normal hematocrit is not acceptable, or when there is significant thrombocytosis
or intractable pruritis. This is usually with a "cytoreductive agent" (hydroxyurea
, also known as hydroxycarbamide).
The tendency of some practitioners to avoid chemotherapy if possible, especially in young patients, is a result of research indicating possible increased risk of transformation to acute myelogenous leukemia (AML)
. While hydroxyurea is considered safer in this aspect, there is still some debate about its long-term safety.
In the past, injection of radioactive isotopes (principally Phosphorus-32
) was used as another means to suppress the bone marrow. Such treatment is now avoided due to a high rate of AML transformation.
Other therapies include interferon
injections, and in cases where secondary thrombocytosis
(high platelet
count) is present, anagrelide
may be prescribed.
Bone marrow transplant
s are rarely undertaken in polycythemia patients; since this condition is non-fatal if treated and monitored, the benefits rarely outweigh the risks involved in such a procedure.
There are indications that with certain genetic markers, Erlotinib
may be an additional treatment option for this condition.
Selective JAK2 inhibitor
s are being investigated in vitro
and in clinical trials.
Epidemiology
Polycythemia vera occurs in all age groups, although the incidence increases with age. One study found the median age at diagnosis to be 60 years, while a Mayo ClinicMayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
study in Olmsted County, Minnesota
Olmsted County, Minnesota
As of the census of 2000, there were 124,277 people, 47,807 households, and 32,317 families residing in the county. The population density was 190 people per square mile . There were 49,422 housing units at an average density of 76 per square mile...
found that the highest incidence was in people aged 70–79 years. The overall incidence in the Minnesota population was 1.9 per 100,000 person-years, and the disease was more common in men than women. A cluster around a toxic site was confirmed in northeast Pennsylvania in 2008.
Symptoms
Patients with polycythemia vera can be asymptomaticAsymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
. A classic symptom of polycythemia vera is pruritus or itch
Itch
Itch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
ing, particularly after exposure to warm water (such as when taking a bath), which may be due to abnormal histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release or prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
production. Such itching is present in approximately 40% of patients with polycythemia vera. Gouty arthritis
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
may be present in up to 20% of patients. Peptic ulcer disease is also common in patients with polycythemia vera; the reasons for this are unclear, but may be related to an increased susceptibility to infection with the ulcer-causing bacterium H. pylori
Helicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
. Another possible mechanism for the development for peptic ulcer is increased histamine release and gastric hyperacidity related with polycythemia vera.
A rare but classic symptom of polycythemia vera (and the related myeloproliferative disease essential thrombocythemia) is erythromelalgia
Erythromelalgia
Erythromelalgia, also known as Mitchell's disease , acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities , are episodically blocked , then become hyperemic and inflamed...
. This is a sudden, severe burning pain in the hands or feet, usually accompanied by a reddish or bluish
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
coloration of the skin. Erythromelalgia is caused by an increased platelet count or increased platelet "stickiness" (aggregation), resulting in the formation of tiny blood clots in the vessels of the extremity; it responds rapidly to treatment with aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
.
Patients with polycythemia vera are prone to the development of blood clots (thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
). A major thrombotic complication (e.g. heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, deep venous thrombosis, or Budd-Chiari syndrome
Budd-Chiari syndrome
In medicine , Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or...
) may sometimes be the first symptom or indication that a person has polycythemia vera.
Headaches, lack of concentration and fatigue are common symptoms that occur in patients with polycythemia vera as well.
Diagnosis
Physical exam findings are non-specific, but may include enlarged liver or spleenHepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
, plethora, or gouty nodules
Tophus
A tophus is a deposit of monosodium urate crystals in people with longstanding high levels of uric acid in the blood. Tophi are pathognomonic for the disease gout...
. The diagnosis is often suspected on the basis of laboratory tests. Common findings include an elevated hemoglobin level or hematocrit
Hematocrit
The hematocrit or packed cell volume or erythrocyte volume fraction is the percentage of the concentration of red blood cells in blood. It is normally about 45% for men and 40% for women...
, reflecting the increased number of red blood cells; the platelet count or white blood cell count may also be increased. The erythrocyte sedimentation rate
Erythrocyte sedimentation rate
The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...
(ESR) is decreased due to an increase in zeta potential
Zeta potential
Zeta potential is a scientific term for electrokinetic potential in colloidal systems. In the colloidal chemistry literature, it is usually denoted using the Greek letter zeta, hence ζ-potential...
. Because polycythemia vera results from an essential increase in erythrocyte production, patients have a low erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
(EPO) level.
In primary polycythemia, there may be 8 to 9 million and occasionally 11 million erythrocytes per cubic millimeter of blood (a normal range for adults is 4-6), and the hematocrit
Hematocrit
The hematocrit or packed cell volume or erythrocyte volume fraction is the percentage of the concentration of red blood cells in blood. It is normally about 45% for men and 40% for women...
may be as high as 70 to 80%. In addition, the total blood volume sometimes increases to as much as twice normal. The entire vascular system can become markedly engorged with blood, and circulation times for blood throughout the body can increase up to twice the normal value. The increased numbers of erythrocytes can cause the viscosity
Viscosity
Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. In everyday terms , viscosity is "thickness" or "internal friction". Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher viscosity...
of the blood to increase as much as five times normal. Capillaries can become plugged by the very viscous blood, and the flow of blood through the vessels tends to be extremely sluggish.
As a consequence of the above, people with untreated polycythemia vera are at a risk of various thrombotic
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
events (deep venous thrombosis, pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
), heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, and have a substantial risk of Budd-Chiari syndrome
Budd-Chiari syndrome
In medicine , Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or...
(hepatic vein thrombosis), or myelofibrosis
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
. The condition is considered chronic; no cure exists. Symptomatic treatment (see below) can normalize the blood count and most patients can live a normal life for years.
The disease appears more common in Jews of European extraction than in most non-Jewish populations. Some familial forms of polycythemia vera are noted, but the mode of inheritance is not clear.
Recently, in 2005, a mutation in the JAK2 kinase (V617F) was found by multiple research groups to be strongly associated with polycythemia vera. JAK2 is a member of the Janus kinase
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...
family and makes the erythroid precursors hypersensitive to erythropoietin (EPO). This mutation may be helpful in making a diagnosis or as a target for future therapy.
Treatment
Untreated, polycythemia vera can be fatal. Research has found that the "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."As the condition cannot be cured, treatment focuses on treating symptoms and reducing thrombotic complications by reducing the erythrocyte levels.
Bloodletting
Bloodletting
Bloodletting is the withdrawal of often little quantities of blood from a patient to cure or prevent illness and disease. Bloodletting was based on an ancient system of medicine in which blood and other bodily fluid were considered to be "humors" the proper balance of which maintained health...
(called venesection or phlebotomy) is one form of treatment, which often may be combined with other therapies. The removal of blood from the body reduces the blood volume and brings down the hematocrit levels; in patients with polycythemia vera, this reduces the risk of blood clots. Venesection is typically performed in people with polycythemia vera to bring their hematocrit
Hematocrit
The hematocrit or packed cell volume or erythrocyte volume fraction is the percentage of the concentration of red blood cells in blood. It is normally about 45% for men and 40% for women...
(red blood cell percentage) down below 45 for men or 42 for women. It has been observed that phlebotomy also improves cognitive impairment.
Low dose aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
(75–81 mg daily) is often prescribed. Research has shown that aspirin reduces the risk for various thrombotic complications.
Chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
for polycythemia may be used, either for maintenance, or when the rate of bloodlettings required to maintain normal hematocrit is not acceptable, or when there is significant thrombocytosis
Thrombocytosis
Thrombocytosis is the presence of high platelet counts in the blood, and can be either primary or reactive...
or intractable pruritis. This is usually with a "cytoreductive agent" (hydroxyurea
Hydroxyurea
Hydroxycarbamide or hydroxyurea is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia...
, also known as hydroxycarbamide).
The tendency of some practitioners to avoid chemotherapy if possible, especially in young patients, is a result of research indicating possible increased risk of transformation to acute myelogenous leukemia (AML)
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
. While hydroxyurea is considered safer in this aspect, there is still some debate about its long-term safety.
In the past, injection of radioactive isotopes (principally Phosphorus-32
Phosphorus-32
Phosphorus-32 is a radioactive isotope of phosphorus. The nucleus of phosphorus-32 contains 15 protons and 17 neutrons, one more neutron than the most common isotope of phosphorus, phosphorus-31...
) was used as another means to suppress the bone marrow. Such treatment is now avoided due to a high rate of AML transformation.
Other therapies include interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
injections, and in cases where secondary thrombocytosis
Thrombocytosis
Thrombocytosis is the presence of high platelet counts in the blood, and can be either primary or reactive...
(high platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count) is present, anagrelide
Anagrelide
Anagrelide is a drug used for the treatment of essential thrombocytosis , or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia. -Mechanism:...
may be prescribed.
Bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
s are rarely undertaken in polycythemia patients; since this condition is non-fatal if treated and monitored, the benefits rarely outweigh the risks involved in such a procedure.
There are indications that with certain genetic markers, Erlotinib
Erlotinib
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
may be an additional treatment option for this condition.
Selective JAK2 inhibitor
CD177
CD177 antigen is a protein that in humans is encoded by the CD177 gene....
s are being investigated in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in clinical trials.