Polycythemia Vera


What is Polycythemia Vera?

Definition and Characteristics: Polycythemia Vera (PV) is a rare type of blood cancer classified as a myeloproliferative neoplasm, which is characterized by the bone marrow's abnormal and uncontrolled cell growth. This results in an excessive production of blood cells, notably red blood cells (erythrocytes), but also white blood cells (leukocytes) and platelets (thrombocytes). A key feature of PV, distinguishing it from most other blood cancers, is the significant increase in red blood cells, a condition known as erythrocytosis or "many cells in the blood."

Prevalence and Demographics:

  • PV is more commonly diagnosed in men than in women.
  • It is rare in individuals under 40 years old and becomes more prevalent with age.
  • Annually, 1 in 36,000 men and 1 in 77,000 women are diagnosed with PV.
  • About 1 in 4,500 people are affected by PV at any given time.

Genetics and Mutation:

  • PV is generally not inherited and originates from a somatic genetic mutation post-conception.
  • Most patients with PV have a mutation in the Janus Kinase 2 (JAK2) gene, crucial for cell signaling and regulation within the bone marrow. This mutation leads to uncontrolled cell production.

Primary vs. Secondary Polycythemia:

  • Primary Polycythemia (Polycythemia Vera): A malignant overproduction of cells in the bone marrow due to a cancerous process.
  • Secondary Polycythemia: Caused by increased red blood cell production due to factors outside the bone marrow, such as low oxygen conditions or hormonal triggers, and not related to a cancerous process.

Non-Cancerous Causes: Conditions like sleep apnea, COPD, smoking, alcohol use, and the use of diuretics can lead to non-cancerous forms of polycythemia or erythrocytosis by stimulating the production of erythropoietin, a hormone that signals the bone marrow to produce more red blood cells.

Polycythemia Vera is a complex condition with specific genetic underpinnings and significant implications for blood cell production. Its diagnosis and treatment require careful differentiation from other forms of polycythemia, with a focus on managing the uncontrolled production of blood cells and the factors contributing to secondary forms of the condition.

Signs and Symptoms

Detecting Polycythemia Vera: Understanding Blood Work Indicators

Identification Challenges:

  • Many individuals with Polycythemia Vera (PV) may be unaware of their condition due to its gradual onset.
  • PV often comes to light during routine blood tests, like a Complete Blood Count (CBC), which can reveal anomalies hinting at the disease.

Key CBC Findings in PV:

  • Increased Red Blood Cell (RBC) Count: A significant indicator of PV, reflecting the overproduction of RBCs.
  • Elevated Hemoglobin Levels: Hemoglobin, the major protein in RBCs responsible for oxygen transport, also increases as RBC count rises.
  • Higher Hematocrit Percentage: Indicates a higher proportion of RBCs in blood volume. Hematocrit is the percentage of blood volume occupied by RBCs, with the remainder mostly being plasma.
  • Possible Increase in White Blood Cells and Platelets: Some individuals may also experience a slight, typically non-malignant, increase in these cell counts.

Normal Blood Count Ranges:

  • RBC Count: Approximately 4.5 to 6.0×10^12/L for men and 4.0 to 5×10^12/L for women.
  • Hemoglobin Levels: Typically 14 to 17 grams per deciliter (dL) for men and 12 to 15 g/dL for women.
  • Hematocrit Range: Between 40-50% for men and 35-45% for women.
  • It's important to note that normal ranges can slightly vary by location due to differences in lab equipment and population.

Clinical Implications:

  • Values above these normal ranges, along with other symptoms, may prompt a healthcare provider to suspect PV.
  • Such findings necessitate further investigation to confirm the diagnosis and understand the extent of the condition.

Normal Blood Counts per MayoClinic laboratories

Polycythemia vera is dangerous however, because with an increase of Red Blood Cells beyond what is normal, the blood starts to become thicker and less viscous. This makes circulating the blood throughout the body much more difficult and can lead to dangerous situations such as blood clots and strokes. The situation in which the thickening, or an increase of viscosity of the blood, is called hyperviscosity syndrome. It is not specific to PV, and patient's with other hematologic malignancies such as Waldenstroms macroglobulinemia, leukemias, Multiple Myeloma, etc. Patient's with PV that start to experience hyperviscosity syndrome can expect to see most non-specific symptoms such as 
  • Headache
  • Nausea
  • Vision Changes and retinopathy
  • Dizziness/Vertigo
  • Seizures and potentially even coma. 
  • Dyspnea (Shortness of breath)
  • Fatigue/Weakness
  • Stroke
  • Night Sweats
  • Bruising / Extended Bleeding
  • Weight Loss

Circulatory Clots:

  • About 20% of PV patients experience clots within their circulatory system, significantly increasing the risk of strokes and Transient Ischemic Attacks (TIAs).
  • The increased blood viscosity associated with PV leads to decreased blood flow and higher risk of thrombotic events, potentially causing organ damage and heart attacks.

Symptoms Overview:

  • Erythromelalgia: Characterized by blotchy, discolored, red skin, often warm to the touch and accompanied by a burning pain. This is due to increased red blood cells and slower circulation, causing periodic blockage in extremities.

  • Itchy Skin: Experienced by nearly half of all PV patients, often triggered after warm baths/showers. It may be an early symptom, believed to be caused by abnormal histamine and cytokine release.

  • Gout: A form of painful arthritis from uric acid buildup, commonly affecting the big toe. In PV, high RBC turnover and possible organ damage contribute to excessive uric acid production.

  • Splenomegaly: The spleen enlarges as it filters an excessive number of red blood cells, leading to discomfort or pain in the affected area.

  • Myelofibrosis: Severe scarring of the bone marrow seen in PV progression, leading to a broad decrease in cell production (anemia, reduced white cells, and platelets). Up to 10% of PV patients may develop myelofibrosis, further increasing gout risk.

Deeper Insights:

  • PV's impact on blood viscosity and cell proliferation poses significant risks, from increased clotting to organ strain.
  • Distinct symptoms like erythromelalgia and itchy skin after exposure to warmth highlight the body's stressed state due to excessive cell counts.
  • Conditions like gout and myelofibrosis underscore the systemic effects of PV, affecting everything from joint health to bone marrow function.
  • Understanding these symptoms and complications is crucial for managing PV and mitigating its impacts on patient health.

Recognizing and Diagnosing Polycythemia Vera (PV)

Early Detection Challenges:

  • Patients with Polycythemia Vera may not realize they have the disease due to intermittent or vague symptoms such as headaches, fever, itchy skin, or dizziness. Some may notice an abdominal bulge from splenomegaly.

Diagnostic Process:

  • A Complete Blood Count (CBC) is crucial for diagnosing PV, revealing increased Red Blood Cell (RBC) mass—a key indicator of the condition.
    • For Men: A hemoglobin concentration above 16.5 g/dL, hematocrit over 50%, and an increased RBC count suggest PV.
    • For Women: Hemoglobin around 16g/dL and hematocrit about 48% could signal the disease.
  • Ruling out secondary causes (e.g., dehydration) for increased blood counts is essential for a closer PV diagnosis. Abnormally high numbers, especially with symptoms, support the diagnosis, while borderline numbers require further investigation.

Advanced Testing for Confirmation:

  • JAK2 Mutation Testing: Testing for mutations in the Janus Kinase 2 (JAK2) gene is a critical step. The common mutation "JAK2(V617F)" is found in most PV patients. Laboratories can also search for other mutations if JAK2(V617F) is not present.

  • Erythropoietin (EPO) Levels: PV patients usually have very low EPO levels due to a feedback mechanism; abundant RBCs and oxygenation negate the need for more EPO production. High RBC/Hgb/Hct counts from other causes don't show this drastic EPO reduction. Testing EPO levels in conjunction with JAK2 mutations can confirm PV.

  • Bone Marrow Biopsy: A definitive diagnosis may require a bone marrow biopsy or aspirate, often taken from the iliac crest. This procedure examines the marrow directly, typically revealing excessive RBC production.

Key Points:

  • Initial symptoms of PV can be easily overlooked or misattributed, highlighting the importance of thorough medical evaluations for accurate diagnosis.
  • The CBC plays a foundational role in signaling potential PV, with further tests like JAK2 mutation analysis and EPO level measurement providing critical confirmation.
  • A bone marrow biopsy offers a direct look at marrow activity, confirming the excessive production of blood cells characteristic of PV.

Treatment of Polycythemia Vera

Understanding the Disease and Risks:

  • Polycythemia Vera is an incurable blood cancer with treatments available to manage symptoms and improve outcomes.
  • Life expectancy is generally optimistic, with many living over 20 years post-diagnosis, provided they adhere to their treatment plan.
  • The primary risk for PV patients is clotting, with disease progression to conditions like myelofibrosis, Acute Myelogenous Leukemia (AML), or Myelodysplastic Syndrome (MDS) as secondary concerns.

Risk-Based Treatment Approach:

  • Treatment varies based on factors like age, health, disease severity, and clotting history.
  • Patients under 60 without clotting issues are considered lower risk compared to older patients or those with previous clotting events.

Key Treatment Methods:

  • Therapeutic Phlebotomy:

    • Involves removing up to 500mL of blood to reduce blood viscosity and alleviate symptoms.
    • Frequency is initially high until hematocrit normalizes, then reduces based on individual needs.
  • Aspirin Therapy:

    • Low-dose aspirin may be prescribed to lower clotting risk by inhibiting platelet function, suitable for low-risk patients without bleeding issues.
  • Antihistamines:

    • Helps manage increased itchiness, especially following exposure to warm water.
  • Hydroxyurea (HU):

    • A myelosuppressive drug for higher-risk patients, inhibiting DNA production in cells to reduce RBC and platelet counts.
    • While concerns exist regarding its link to leukemia progression, evidence suggests minimal risk.
  • Ruxolitinib (Jakafi or Jakavi):

    • A JAK1 and JAK2 enzyme inhibitor, particularly useful for patients with JAK2 mutations leading to uncontrolled cell production.
    • Prescribed when Hydroxyurea is ineffective or unsuitable.
  • Ropeginterferon Alfa-2b-njft (BESREMi):

    • An FDA-approved treatment since 2021, BESREMi modulates cell signaling to have anti-proliferative, immune-modulating, and pro-apoptotic effects.