What is the most common cause of polycythemia?

While polycythemia is a rare blood disorder, the most common specific type is polycythemia vera (PV), which is caused by an acquired genetic mutation in the JAK2 gene. Understanding what is the most common cause of polycythemia requires distinguishing between the primary form and secondary conditions.

Quick Summary

The most common cause of polycythemia, specifically polycythemia vera, is an acquired genetic mutation in the JAK2 gene, which triggers the bone marrow to overproduce blood cells. This contrasts with secondary polycythemia, which is typically a response to other factors like chronic low oxygen levels.

Key Points

• The most common type: Polycythemia Vera (PV) is the most common primary form of polycythemia and is typically caused by an acquired genetic mutation.

• Genetic mutation: In over 90% of PV cases, the JAK2 V617F gene mutation is responsible, causing the bone marrow to overproduce blood cells.

• Secondary causes: Secondary polycythemia results from other conditions, like chronic low oxygen levels (hypoxia) from lung disease, high altitude, or smoking.

• Distinguishing feature: Blood test results often reveal key differences; primary polycythemia is associated with low erythropoietin (EPO) levels, while secondary polycythemia typically has normal or high EPO.

• Main risks: The biggest risk for any type of polycythemia is the formation of blood clots, which can lead to serious complications like stroke or heart attack.

Distinguishing Primary and Secondary Polycythemia

Polycythemia is a general term for a high concentration of red blood cells in the blood. For an accurate diagnosis and treatment, it is critical to distinguish between its primary and secondary forms. The most common cause is tied to one of these types: Polycythemia Vera (PV).

The Most Common Cause: Polycythemia Vera (Primary)

Polycythemia vera is a rare blood cancer and the most frequent type of primary polycythemia. It is not inherited in most cases but is instead caused by an acquired mutation in a gene known as Janus kinase 2, or JAK2. This mutation occurs within the bone marrow, the soft tissue inside your bones where blood cells are produced.

The JAK2 Gene Mutation

In over 90% of polycythemia vera cases, the JAK2 V617F mutation is present. This specific mutation leads to a persistently active JAK2 protein, which is normally responsible for promoting cell growth and division. The constant "on" signal from the mutated gene causes hematopoietic stem cells in the bone marrow to proliferate uncontrollably, leading to an overproduction of red blood cells and sometimes white blood cells and platelets as well. This causes the blood to thicken, increasing the risk of serious complications such as blood clots.

Secondary Polycythemia: A Response to Low Oxygen

Secondary polycythemia is caused by an external condition or factor, not an intrinsic bone marrow issue like PV. It develops in response to chronically low oxygen levels (hypoxia), which triggers the kidneys to produce more of the hormone erythropoietin (EPO). EPO, in turn, stimulates the bone marrow to produce more red blood cells to compensate for the lack of oxygen.

Common Causes of Secondary Polycythemia

• Chronic Lung Disease: Conditions like Chronic Obstructive Pulmonary Disease (COPD) and sleep apnea cause poor oxygen exchange in the lungs, leading to hypoxia.
• High Altitude Living: Individuals who live at very high altitudes experience lower ambient oxygen concentrations, prompting their bodies to increase red blood cell production.
• Chronic Carbon Monoxide Exposure: Heavy smoking or other sources of long-term carbon monoxide exposure can reduce the blood's oxygen-carrying capacity, tricking the body into overproducing red blood cells.
• Kidney Conditions: Certain kidney diseases, cysts, or tumors can inappropriately produce or increase levels of erythropoietin, independently of oxygen levels.
• Hormone-Related Causes: Anabolic steroid use and testosterone replacement therapy can also stimulate red blood cell production.

Symptoms and Complications of Polycythemia

Regardless of the cause, an excess of red blood cells can lead to a variety of symptoms and complications due to thicker, slower-moving blood. Common symptoms include fatigue, headaches, dizziness, blurred vision, and itching, particularly after a warm bath or shower. More severe complications include:

• Thrombosis: An increased risk of blood clots, which can lead to heart attack, stroke, or pulmonary embolism.
• Enlarged Spleen (Splenomegaly): The spleen works harder to filter the excess blood cells and can become enlarged and painful.
• Gout and Ulcers: Rapid cell turnover can increase uric acid levels, leading to gout. High histamine levels can cause stomach ulcers.
• Progression to Other Blood Cancers: In rare cases, especially with PV, the condition can transform into more aggressive diseases like myelofibrosis or acute myeloid leukemia.

Diagnosis: Differentiating the Causes

When a healthcare provider suspects polycythemia, they will order a series of tests to confirm the diagnosis and determine the specific cause. This process is crucial for effective treatment.

1. Blood Tests: A complete blood count (CBC) will show elevated hemoglobin, hematocrit, or red blood cell count. In PV, platelets and white blood cells may also be high.
2. Erythropoietin (EPO) Level Test: This is a key step in distinguishing between primary and secondary polycythemia. A low EPO level suggests primary polycythemia (PV), as the overproduction of red blood cells suppresses the hormone's production. A high EPO level points toward secondary polycythemia, as the body is appropriately responding to a stimulus like hypoxia.
3. Genetic Testing: Testing for the JAK2 mutation is standard for diagnosing polycythemia vera.
4. Bone Marrow Biopsy: In some cases, a bone marrow biopsy may be performed to examine the cellular composition and confirm the diagnosis.

Treatment Approaches

Treatment for polycythemia focuses on reducing the number of excess blood cells to alleviate symptoms and minimize the risk of complications. The approach depends heavily on whether the cause is primary or secondary.

• Phlebotomy: A procedure to remove blood, similar to donating, is the most common treatment for PV. This reduces blood volume and cell count, which is particularly effective in controlling symptoms caused by high blood viscosity.
• Medication: For PV, doctors may prescribe medications like hydroxyurea to suppress bone marrow production of blood cells. Other options like interferon or JAK inhibitors may also be used. For secondary polycythemia, treating the underlying condition is the main strategy.
• Lifestyle Adjustments: Regular exercise, staying hydrated, avoiding smoking, and avoiding high altitudes can help manage symptoms and reduce risk.

Comparison of Primary vs. Secondary Polycythemia

Feature	Primary Polycythemia (Polycythemia Vera)	Secondary Polycythemia
Cause	Genetic mutation (most often JAK2) in bone marrow stem cells.	External factors causing chronic low oxygen or excess EPO.
EPO Level	Low or subnormal.	High or normal.
Other Cells	Often elevated white blood cells and platelets.	Typically only red blood cells are elevated.
Onset	Slow, often developing gradually over many years.	Can be slower or faster depending on the underlying condition.
Risk	Higher risk of thrombosis and progression to other blood cancers.	Risk primarily from underlying condition and hyperviscosity.

Conclusion

While a variety of factors can cause an excess of red blood cells, when asking what is the most common cause of polycythemia, the specific answer points to an acquired JAK2 gene mutation leading to polycythemia vera. This condition, along with secondary polycythemias caused by other medical issues, requires careful diagnosis by a medical professional to ensure appropriate management and prevent severe complications. For more in-depth information on polycythemia vera, visit the Cleveland Clinic on Polycythemia Vera.

Frequently Asked Questions

What is the most common cause of polycythemia vera?

The most common cause of polycythemia vera, a specific type of polycythemia, is a mutation in the JAK2 gene. This mutation is acquired during a person's lifetime and is present in over 90% of cases, causing uncontrolled blood cell production.

What is the difference between primary and secondary polycythemia?

Primary polycythemia (Polycythemia Vera) originates from a problem within the bone marrow, usually a genetic mutation. Secondary polycythemia is a response to an external factor, most often chronic low oxygen, which triggers increased red blood cell production.

Can living at a high altitude cause polycythemia?

Yes, living at high altitudes can cause a type of secondary polycythemia. The lower oxygen levels stimulate the body to produce more red blood cells to compensate, a normal physiological response.

What role does the JAK2 mutation play in polycythemia?

The JAK2 mutation causes the JAK2 protein to be constantly active, which leads to the uncontrolled proliferation of blood-forming stem cells in the bone marrow. This results in the overproduction of red blood cells, and sometimes white blood cells and platelets, seen in polycythemia vera.

Are there other genetic causes besides JAK2?

While the JAK2 mutation is by far the most common genetic cause of polycythemia vera, other less common genetic changes, such as mutations in the TET2 gene, have also been observed. In rare cases, polycythemia can be inherited.

How is the most common cause of polycythemia diagnosed?

Diagnosis involves several steps, including a complete blood count (CBC) to measure cell levels, checking erythropoietin (EPO) levels, and conducting genetic testing to look for the specific JAK2 mutation. A bone marrow biopsy may also be performed.

Is smoking a cause of polycythemia?

Yes, chronic heavy smoking is a risk factor for secondary polycythemia. The carbon monoxide in smoke reduces the oxygen-carrying capacity of the blood, leading the body to produce more red blood cells to compensate.