Polycythemia Vera (PV)

What is Polycythemia Vera (PV)?

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by an uncontrolled increase in red blood cell production by the bone marrow. This overproduction leads to thickening of the blood, which can significantly impact blood flow and increase the risk of serious complications like blood clots (thrombosis) and bleeding.

Classifications of Polycythemia Vera

While there are no distinct subtypes within Polycythemia Vera (PV) itself, it’s crucial to differentiate it from other conditions that can cause similar symptoms and elevated red blood cell counts. 

Primary vs. Secondary Polycythemia

• Primary Polycythemia: Refers specifically to Polycythemia Vera (PV), where the cause is unknown and arises from an internal abnormality in the bone marrow. It is a primary disorder of the bone marrow, meaning the abnormal blood cell production originates within the bone marrow itself.
• Secondary Polycythemia: This arises from underlying conditions that stimulate the body to produce more red blood cells, often due to a lack of oxygen. Examples include:
  • Chronic lung disease: Conditions like chronic obstructive pulmonary disease (COPD) can lead to hypoxia (low oxygen levels) triggering increased red blood cell production.
  • High altitude living: In high-altitude environments, the body naturally produces more red blood cells to compensate for the lower oxygen availability.
  • Certain tumors: Some tumors, particularly kidney tumors, can release a hormone called erythropoietin (EPO) that stimulates red blood cell production.
  • Smoking: Can stimulate the bone marrow to produce more red blood cells.
  • Dehydration: Can lead to a relative increase in red blood cell concentration due to decreased plasma volume.

Essential Thrombocythemia (ET) vs. Polycythemia Vera (PV)

Both ET and PV are classified as myeloproliferative neoplasms (MPNs), but they differ in their primary characteristic and clinical presentation:

• Essential Thrombocythemia (ET): This condition is characterized by an increased production of platelets by the bone marrow. While some patients with ET may also have elevated red blood cells, it’s not the defining feature.
• Polycythemia Vera (PV): As previously discussed, PV primarily involves an uncontrolled increase in red blood cell production. While platelet counts can also be elevated in some PV cases, it’s not a defining feature and is usually not as significant as the red blood cell count increase.

Pathogenesis and Pathophysiology

Bone Marrow Overproduction

In healthy individuals, the bone marrow tightly regulates the production of different blood cells, including red blood cells, white blood cells, and platelets, based on the body’s needs. However, in PV, this regulation goes awry, leading to uncontrolled overproduction of all three cell types:

• Red blood cells: The most prominent feature of polycythemia vera (PV) is a significant increase in red blood cell production. This leads to a condition called erythrocytosis, which literally translates to “excess of red blood cells.”
• White blood cells: While the increase in white blood cells (leukocytosis) may be moderate in PV, it can sometimes be significant.
• Platelets: Similar to white blood cells, the rise in platelet count (thrombocytosis) can be variable in PV patients.

The Role of the JAK-STAT Pathway

The JAK-STAT pathway is a critical signaling pathway involved in normal blood cell production. It involves a series of proteins that relay signals from outside the cell to the nucleus, ultimately regulating gene expression and cell proliferation.

In healthy individuals, specific hormones bind to cell surface receptors, activating JAK proteins. These activated JAKs then phosphorylate (activate) STAT proteins, which translocate to the nucleus and turn on specific genes responsible for normal blood cell development and maturation.

This pathway ensures controlled and regulated production of blood cells based on the body’s needs.

Mutations and Dysregulation

In PV, specific mutations occur in genes encoding proteins involved in the JAK-STAT pathway, leading to its dysregulation:

• JAK2 V617F mutation: This is the most common mutation found in polycythemia vera (PV), affecting the JAK2 protein. It causes the protein to be constitutively active, meaning it’s constantly “on” and sending signals for blood cell production, even when not needed.
• CALR and MPL mutations: These mutations are less frequent but also contribute to polycythemia vera (PV) development. They occur in the genes encoding calreticulin (CALR) and MPL (MPL) proteins, respectively. These mutations lead to similar consequences as the JAK2 V617F mutation, resulting in uncontrolled activation of the JAK-STAT pathway.
• JAK2 exon 12 mutations: These are less common than JAK2 V617F but occur in a specific region of the JAK2 gene (exon 12). Similar to V617F, they contribute to JAK2 protein hyperactivity and dysregulated blood cell production. JAK2 exon 12 mutations are seen in about 2–5% of JAK2V617F-negative cases of PV. The JAK2p.V617F mutation can produce both erythrocytosis in polycythemia vera (PV) and thrombocytosis in ET, while JAK2 exon 12 mutations cause only erythrocytosis.

These mutations essentially act like a “stuck accelerator” in the JAK-STAT pathway, constantly stimulating blood cell production regardless of the body’s actual needs.

Consequences of Increased Blood Cell Production

The overproduction of all three blood cell types in polycythemia vera (PV) has several consequences, primarily affecting blood viscosity and blood flow

• Increased blood viscosity: With a higher number of red blood cells, platelets, and even white blood cells, the blood becomes thicker and stickier.
• Impeded blood flow: Thicker blood flows less easily through narrow blood vessels, potentially leading to ischemia (reduced oxygen supply) in tissues and organs.

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Prevalence and Incidence of Polycythemia Vera (PV)

Prevalence

• PV is considered a rare blood cancer, with an estimated prevalence of around 22 cases per 100,000 people. This means that approximately 22 individuals out of every 100,000 in the population might have diagnosed polycythemia vera (PV) at any given time.

Incidence

• The annual incidence, which refers to the number of new cases diagnosed each year, is estimated to be around 1.3 to 2.8 cases per 100,000 people. This translates to approximately 1-3 new diagnoses per year for every 100,000 individuals.
• Similar to prevalence, the incidence of polycythemia vera (PV) can be influenced by:
  • Age: PV is more commonly diagnosed in older adults, with the average age of diagnosis being around 60-65 years. It is uncommon in individuals younger than 30.
  • Gender: While both genders can develop polycythemia vera (PV), men are slightly more likely to be diagnosed compared to women.

Factors Affecting Distribution

• Age: As mentioned, polycythemia vera (PV) primarily affects older individuals, with a significant increase in incidence after the age of 40.
• Gender: While the reasons for the slight male predominance are not fully understood, men are diagnosed with polycythemia vera (PV) at a slightly higher rate than women.
• Ethnicity: While polycythemia vera (PV) can occur in all ethnicities, individuals of Ashkenazi Jewish descent have a slightly higher risk compared to other populations. However, this is a relative difference, and the absolute risk of PV remains low in all groups.

Risk Factors and Causes of Polycythemia Vera (PV)

While the exact cause of polycythemia vera (PV) remains unknown, several risk factors are associated with an increased chance of developing the disease.

Age

• PV is primarily diagnosed in older adults, with the average age of diagnosis being around 60-65 years. The risk increases significantly after the age of 40.

Family history

• Having a close relative (parent, sibling, child) with polycythemia vera (PV) slightly increases your risk compared to the general population. However, the majority of polycythemia vera (PV) cases occur in individuals with no family history.

Smoking

• Smoking is considered a potential risk factor for polycythemia vera (PV), although the exact link is not fully understood. 

Signs and Symptoms

PV can present with a variety of signs and symptoms, categorized into three main groups.

General symptoms

• Fatigue: This is a common and often the most prominent symptom, occurring in 70-80% of polycythemia vera (PV) patients. It can be described as a persistent feeling of tiredness, exhaustion, and lack of energy.
• Weakness: This can manifest as a general feeling of reduced muscle strength and difficulty performing daily activities.
• Headache: Headaches can be present in various forms, ranging from mild and occasional to severe and persistent.
• Dizziness: This can be related to decreased blood flow to the brain and can manifest as lightheadedness, feeling faint, or a sensation of spinning.

Symptoms due to increased blood viscosity

• Redness of the face (plethora): This occurs due to an increased number of red blood cells in the small vessels of the face, making it appear flushed or red.
• Itching, especially after a hot shower (aquagenic pruritus): This is a characteristic symptom of polycythemia vera (PV), experienced by around 30-40% of patients. The exact mechanism is not fully understood, but it is thought to be related to the release of histamine, a substance involved in the inflammatory response, triggered by changes in blood flow and temperature.
• Blurred vision: This can be caused by impaired blood flow to the retina, the light-sensitive layer at the back of the eye.
• Dizziness and lightheadedness: As mentioned earlier, these can also occur due to increased blood viscosity impacting blood flow to the brain.

Symptoms due to complications

• Blood clots (thrombosis): Increased blood cell production and thickening of the blood can significantly increase the risk of blood clots forming in arteries and veins. Depending on the location of the clot, symptoms can vary widely, ranging from:
  • Deep vein thrombosis (DVT): Pain, swelling, and redness in the legs, often affecting one leg more than the other.
  • Pulmonary embolism (PE): Sudden shortness of breath, chest pain, coughing, and rapid breathing.
• Bleeding: While less common than blood clots, polycythemia vera (PV) can also increase the risk of bleeding, particularly from areas like the nose or gums, due to alterations in platelet function or abnormalities in the blood vessel walls.

Complications

PV can lead to various complications if left untreated or not effectively managed. 

Blood Clots (Thrombosis)

• This is the most common and potentially serious complication of polycythemia vera (PV).
• Increased blood viscosity and abnormal platelet function contribute to a higher risk of blood clots forming in arteries and veins.
• Depending on the location of the clot, symptoms can vary:
  • Deep vein thrombosis (DVT): Pain, swelling, redness, and warmth in the legs.
  • Pulmonary embolism (PE): Sudden shortness of breath, chest pain, coughing (may bring up blood), rapid heart rate, and lightheadedness.
  • Stroke: If a clot blocks an artery in the brain, it can lead to weakness, numbness, speech difficulties, and other neurological symptoms depending on the affected area.
  • Heart attack: If a clot blocks an artery supplying blood to the heart muscle, it can cause chest pain, shortness of breath, sweating, and nausea.

Bleeding

• While less common than blood clots, polycythemia vera (PV) can also increase the risk of bleeding, especially from areas like the nose, gums, or gastrointestinal tract.
• This is because abnormal platelet function and increased blood viscosity can impair the normal clotting process.

Erythromelalgia

• This is a rare but potential complication of polycythemia vera (PV), characterized by burning pain, redness, and increased skin temperature, primarily affecting the extremities.

Transformation into Acute Leukemia

• This is a rare but serious complication, occurring in less than 1% of polycythemia vera (PV) patients over time.
• It involves the transformation of abnormal blood cells in the bone marrow into acute myeloid leukemia (AML), a type of aggressive blood cancer.

Other Potential Complications

• Splenomegaly (enlarged spleen): The spleen can become enlarged due to increased activity in filtering out abnormal blood cells. This may cause discomfort in the upper left abdomen.
• Gout: The breakdown of excess red blood cells can lead to high uric acid levels in the blood, potentially triggering gout attacks with joint pain and swelling.
• Peptic ulcer disease: Increased stomach acid production, a potential consequence of polycythemia vera (PV), can contribute to peptic ulcers, causing abdominal pain and discomfort.

Laboratory Investigations in Polycythemia Vera (PV)

Diagnosing polycythemia vera (PV) involves a combination of clinical evaluation, laboratory tests, and sometimes bone marrow examination. 

Complete Blood Count (CBC) with Differential

• This is the first-line test and provides a detailed picture of blood cell counts, including red blood cells, white blood cells, and platelets.
• In polycythemia vera (PV), the CBC typically shows:
  • Elevated red blood cell count (erythrocytosis)
  • May show normal or slightly elevated white blood cell and platelet counts

Hematocrit

• This measures the percentage of red blood cells in whole blood.
• In PV, the hematocrit is typically elevated, often above 50% in men and 48% in women.

Erythrocyte Sedimentation Rate (ESR)

• While not specific for polycythemia vera (PV), this test measures the rate at which red blood cells settle in a blood sample.
• An elevated ESR is not uncommon in polycythemia vera (PV) but can also occur in other conditions and is not diagnostic on its own.

Bone Marrow Examination

• This may be necessary to confirm the diagnosis and rule out other conditions that can mimic PV.
• In polycythemia vera (PV), the bone marrow often shows increased cellularity (more blood cells) and may reveal specific abnormalities suggestive of the disease.

Molecular Mutation Testing

• This analyzes the genetic mutations associated with polycythemia vera (PV), particularly:
  • JAK2 V617F mutation: This is the most common mutation, found in around 95% of polycythemia vera (PV) patients.
  • CALR and MPL mutations: These occur in a smaller percentage of patients.
• Identifying these mutations strongly supports the diagnosis of polycythemia vera (PV) and helps guide treatment decisions.

Other Relevant Investigations

• Imaging studies: X-rays, ultrasounds, or CT scans may be used to check for enlarged spleen (splenomegaly) or other potential complications.
• Serum erythropoietin (EPO) level: This hormone stimulates red blood cell production. In most polycythemia vera (PV) cases, the EPO level is low due to the bone marrow already overproducing red blood cells. However, normal or elevated EPO levels might indicate secondary polycythemia instead of PV.

Diagnostic Criteria

A diagnosis of polycythemia vera (PV) requires either all 3 major criteria or first 2 major plus the minor criterion. 

Major criteria

• Increased Hb concentration hematocrit or RBC mass
• JAK2^V617F or JAK2 exon 12 mutation
• Hypercellular BM biopsy (after age-adjusted) displaying proliferation of all lineages with prominent erythroid and granulocytic lineages and increase in pleomorphic, mature megakaryocytes without atypia

Minor criterion

• Low serum EPO level

Treatment and Management

PV requires ongoing management to control symptoms, prevent complications, and improve overall quality of life. 

Phlebotomy

• This is the cornerstone of treatment for most polycythemia vera (PV) patients.
• It involves removing excess red blood cells from the bloodstream through a process similar to blood donation.
• This helps to:
  • Reduce blood viscosity and improve blood flow.
  • Decrease the risk of blood clots.
  • Alleviate symptoms like fatigue, headache, and dizziness.
• The frequency and amount of blood removed are individualized based on various factors, including the patient’s age, overall health, and disease severity.

Cytoreductive therapy

• These medications suppress the overactivity of the bone marrow, thereby reducing the production of red blood cells (and potentially other blood cells).
• They are typically used:
  • When phlebotomy alone is not sufficient to control the disease.
  • In younger patients who may not tolerate frequent phlebotomy.
  • In patients with high-risk features, such as a history of blood clots.
• Common cytoreductive medications used in polycythemia vera (PV) include:
  • Hydroxyurea: This is the most commonly used medication for this purpose.
  • Interferon alpha: This medication has fallen out of favor due to side effects but may be considered in specific cases.

Low-dose aspirin

• Due to the increased risk of blood clots in polycythemia vera (PV), low-dose aspirin is often recommended for most patients.
• Aspirin helps to prevent blood clots by interfering with platelet function.

Other medications

• Additional medications may be used to manage specific symptoms or complications of polycythemia vera (PV), such as:
  • Anti-itching medications: To alleviate the itchiness associated with polycythemia vera (PV), particularly aquagenic pruritus.
  • Gout medications: If a patient develops gout due to high uric acid levels.
  • Peptic ulcer medications: If a patient experiences complications related to peptic ulcers.

Regular monitoring and follow-up

• Monitoring blood counts: To assess disease control and adjust treatment as needed.
• Physical examinations: To check for any signs or symptoms of complications.
• Other tests: Periodically, additional tests like imaging studies or bone marrow examinations may be necessary to monitor disease progression.

Prognosis

Polycythemia Vera (PV) is a chronic condition that currently can’t be cured. However, with proper treatment and management, most patients can maintain a good quality of life and have a near-normal life expectancy.

In recent years, the prognosis of polycythemia vera (PV) has significantly improved due to advancements in treatment strategies and greater understanding of the disease. The median survival for patients with polycythemia vera (PV) is around 14-20 years, and many patients live significantly longer.

Key Points of Polycythemia Vera (PV)

What is it?

• Polycythemia vera (PV) is a chronic blood disorder characterized by an increased production of red blood cells.
• It’s caused by genetic mutations in the bone marrow particularly JAK2 mutations.

Symptoms

• May include fatigue, headache, dizziness, itching, and enlarged spleen (not everyone experiences all symptoms).

Complications

• Increased risk of blood clots (DVT, stroke, heart attack) due to thicker blood.

Treatment and management

• Aims to reduce red blood cell count through:
  • Phlebotomy (blood removal)
  • Medications (hydroxyurea, interferon alpha)
• Aspirin to prevent blood clots.

Prognosis

• With proper management, most individuals with PV can live long and fulfilling lives.
• Early diagnosis and treatment are crucial to minimize complications.

Frequently Asked Questions (FAQs)

What is the main cause of polycythemia vera?

While the exact cause of polycythemia vera (PV) remains unknown, most cases are driven by genetic mutations within specific genes involved in the JAK-STAT pathway, a crucial signaling mechanism for blood cell production in the bone marrow. These mutations lead to uncontrolled cell growth, causing the bone marrow to overproduce red blood cells, as well as potentially increasing white blood cells and platelets.

Can polycythemia vera be cured?

Currently, polycythemia vera (PV) cannot be cured. However, the good news is that with proper treatment and management, most patients with PV can achieve a good quality of life and have a near-normal life expectancy.

What organ does polycythemia affect?

Polycythemia vera (PV) primarily affects the bone marrow, which is the soft, spongy tissue inside some of our bones responsible for producing blood cells.

In polycythemia vera (PV), the bone marrow becomes overactive due to genetic mutations, leading to:

• Increased production of red blood cells: The most characteristic feature of polycythemia vera (PV) is an abnormally high number of red blood cells in the bloodstream.
• Potential increase in white blood cells and platelets: While not always the case, in some individuals with polycythemia vera (PV), the overactive bone marrow may also lead to an increase in the production of white blood cells and platelets.

While the bone marrow is the primary organ directly affected by polycythemia vera (PV), the increased number of blood cells can have consequences for various organs throughout the body, including:

• Blood vessels: Thickened blood due to high red blood cell count can lead to increased blood viscosity, making it harder for blood to flow smoothly through the vessels. This can potentially increase the risk of blood clots and impair blood flow to vital organs.
• Spleen: The spleen helps filter old and damaged blood cells. In polycythemia vera (PV), the spleen can become enlarged due to the increased workload of removing excess red blood cells.
• Liver: Similar to the spleen, the liver can also be affected in some cases of polycythemia vera (PV), potentially leading to liver function abnormalities.
• Skin: The increased blood viscosity can contribute to itching, particularly after exposure to hot water (aquagenic pruritus).

What is end stage polycythemia vera?

While the term “end stage” isn’t commonly used in the context of Polycythemia Vera (PV), some sources describe an advanced stage with specific characteristics.

PV is a chronic condition, and it’s not considered curable. However, with proper management, most patients can live long and fulfilling lives. Nonetheless, as the disease progresses, complications can arise, and some individuals might experience a more advanced stage with specific features.

• Transformation: In rare cases (less than 1%), polycythemia vera (PV) can transform into other blood cancers, primarily acute myeloid leukemia (AML) over time. This is considered a serious and life-threatening complication.
• Myelofibrosis: This can occur when the bone marrow becomes progressively scarred and replaced by fibrous tissue, hindering its ability to produce healthy blood cells. This can lead to complications like anemia (low red blood cell count), fatigue, and enlarged spleen and liver. While not technically “end stage,” myelofibrosis can significantly impact quality of life and shorten life expectancy compared to controlled PV.

What level of hemoglobin is dangerously high?

A dangerously high hemoglobin level is typically considered to be above:

• 18 g/dL in adult males.
• 16.5 g/dL in adult females.

These levels can significantly increase blood viscosity (thickness), making blood flow more difficult and increasing the risk of complications like:

• Blood clots (thrombosis): Thick blood is more likely to form clots in arteries and veins, which can lead to serious conditions like deep vein thrombosis (DVT), pulmonary embolism (PE), heart attack, or stroke.
• Organ damage: Reduced blood flow due to thickened blood can impair oxygen delivery to vital organs like the heart, kidneys, and brain, potentially causing damage.

Does drinking a lot of water help polycythemia?

While staying adequately hydrated is generally important for overall health, including for individuals with polycythemia vera (PV), drinking a lot of water specifically to lower red blood cell count is not an effective or recommended approach. Overhydration can lead to electrolyte imbalances, which can be harmful and require medical attention.

What is the difference between polycythemia and polycythemia vera?

Polycythemia is a broader term encompassing various causes of elevated red blood cells, including PV. PV is a specific type of primary polycythemia caused by a distinct genetic mutation. PV often has additional characteristic features beyond just elevated red blood cell count compared to other causes of polycythemia.

Polycythemia

• General term: Refers to an increased red blood cell mass in the body, typically reflected in elevated hemoglobin and hematocrit levels on blood tests.
• Multiple causes: Can arise from various underlying conditions, including:
  • Primary: Caused by an abnormality within the bone marrow itself, like polycythemia vera.
  • Secondary: Develops as a consequence of another condition, such as:
    • Dehydration
    • Chronic lung disease
    • Sleep apnea
    • Kidney tumors
    • Certain medications
• Symptoms: May cause fatigue, headache, dizziness, and other non-specific symptoms depending on the severity and underlying cause.

Polycythemia Vera (PV)

• Specific type of primary polycythemia: Characterized by an acquired genetic mutation in the bone marrow leading to uncontrolled production of red blood cells and potentially other blood cell types.
• Unique cause: Primarily caused by specific JAK2, CALR, or MPL gene mutations in the bone marrow, while other types of polycythemia have various causes.
• Specific features: In addition to elevated red blood cells, PV may also show:
  • Increased white blood cell and platelet counts (not always)
  • Enlarged spleen
  • Increased risk of blood clots

Is polycythemia vera fatal?

While polycythemia vera (PV) itself is not directly fatal, it can be a serious condition and requires ongoing management to prevent complications.

Can polycythemia vera cause high blood pressure?

Yes, polycythemia vera (PV) can contribute to high blood pressure (hypertension) due to the following reasons:

• Increased blood viscosity: PV leads to an abnormally high number of red blood cells, making the blood thicker and more viscous. This thicker blood encounters greater resistance as it flows through blood vessels, similar to trying to push syrup through a straw compared to water. This increased resistance can elevate blood pressure.
• Interference with blood vessel function: PV can also impair the ability of blood vessels to relax and dilate, which naturally helps to regulate blood pressure. This can further contribute to hypertension.

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

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