Polycythemia Vera (PV): Causes, Symptoms, Diagnosis, and the Role of JAK2 Mutations

By SWA

Polycythemia Vera (PV) is a rare myeloproliferative neoplasm (MPN) characterized by the overproduction of red blood cells in the bone marrow. This excessive production thickens the blood, increasing the risk of blood clots, strokes, and heart attacks. In addition to red blood cells, PV can also lead to an abnormal increase in white blood cells and platelets, further complicating disease progression.

Causes & Risk Factors

PV is primarily caused by a mutation in the JAK2 (Janus Kinase 2) gene, which plays a crucial role in regulating blood cell production. While the exact trigger for this mutation is not fully understood, it is considered an acquired genetic change rather than an inherited disorder.

Risk Factors for PV:

✔ Age: PV is most common in individuals over 60 years old.
✔ Sex: Men are slightly more likely to develop PV than women.
✔ Family History: Although not inherited, having a relative with PV or another MPN may slightly increase risk.

Symptoms of Polycythemia Vera

PV often develops slowly, and some patients may not experience symptoms in the early stages. However, as the disease progresses, symptoms may include:

  • Headaches, dizziness, or blurred vision
  • Fatigue or weakness
  • Itchy skin (especially after a warm bath or shower)
  • Flushed or red skin, particularly on the face
  • Enlarged spleen (splenomegaly), which can cause pain or a feeling of fullness in the upper left abdomen
  • Frequent nosebleeds, easy bruising, or bleeding gums
  • Tingling, numbness, or burning sensations in the hands and feet

Complications of PV

If left untreated, PV can lead to serious complications, including:

✔ Blood Clots (Thrombosis) – Increased blood thickness raises the risk of stroke, heart attack, deep vein thrombosis (DVT), and pulmonary embolism.
✔ Enlarged Spleen (Splenomegaly) – Excess blood cell production can cause the spleen to enlarge, leading to discomfort or digestive issues.
✔ Progression to Other Blood Disorders – PV may progress to myelofibrosis (scarring of the bone marrow) or acute myeloid leukemia (AML), both of which can be life-threatening.

JAK2 Mutation and Its Role in PV

JAK2 Gene Function

The JAK2 gene, located on chromosome 9p24, encodes a tyrosine kinase enzyme that is essential for blood cell development. It is part of the JAK-STAT signaling pathway, which regulates the production of red blood cells, white blood cells, and platelets in response to cytokines like erythropoietin (EPO) and thrombopoietin (TPO).

JAK2 V617F Mutation (rs77375493) 26 citations

  • Found in 95%-97% of PV cases.
  • Caused by a G-to-T substitution at nucleotide 1849 in exon 14 of the JAK2 gene.
  • Leads to the substitution of valine (V) with phenylalanine (F) at position 617 in the JAK2 protein.
  • Disrupts the pseudokinase domain, which normally acts as a regulatory "off switch."
  • Results in constant JAK-STAT activation, causing uncontrolled blood cell production.

JAK2 Exon 12 Mutations

  • Present in 2%-5% of PV cases, particularly in younger patients.
  • Includes various deletions, insertions, and point mutations.
  • Often leads to isolated erythrocytosis (increased red blood cells but normal white cells and platelets).

Diagnosis of PV

Laboratory Tests

✔ Complete Blood Count (CBC) – Detects increased hematocrit, hemoglobin, and red blood cell counts.
✔ JAK2 Mutation Testing – Confirms the presence of the JAK2 V617F mutation (or exon 12 mutations in V617F-negative cases).
✔ Erythropoietin (EPO) Levels – Typically low in PV due to excessive red blood cell production.

Polycythemia Vera (Rare Condition)

  • A bone marrow disorder causing excessive RBC production.
  • Usually associated with significantly higher hemoglobin and symptoms like headaches, dizziness, or blood clot risks.

  • Other Causes

  • Chronic heart or lung disease
  • Kidney issues increasing erythropoietin production
  • Excessive testosterone or anabolic steroid use

Next Steps (If Needed):

  • Check hydration status and repeat the test if needed.
  • If persistently elevated, consider testing serum erythropoietin, oxygen saturation, and red cell mass to rule out underlying conditions.
  • If there are no symptoms (e.g., dizziness, headaches, or fatigue), this may not be clinically significant.

Bone Marrow Examination

✔ Bone Marrow Biopsy – Assesses cellular activity and confirms PV by identifying overactive erythropoiesis and fibrosis.

Treatment of Polycythemia Vera

The primary goal of PV treatment is to reduce blood thickness and prevent clot-related complications.

1. Phlebotomy (Blood Removal)

  • First-line treatment for most PV patients.
  • Involves removing blood at regular intervals to reduce red blood cell levels.
  • Helps maintain hematocrit below 45%, reducing thrombotic risks.

2. Medications to Control Blood Cell Production

✔ Hydroxyurea – A chemotherapy drug used to suppress bone marrow activity.
✔ Interferon Alpha – Used in younger patients or pregnant women to regulate blood cell production.

3. Targeted Therapy: JAK2 Inhibitors

✔ Ruxolitinib (Jakafi) – A JAK1/JAK2 inhibitor approved for PV patients resistant to hydroxyurea.

  • Lowers blood cell counts and reduces spleen enlargement.
  • Improves symptoms like fatigue and itching.

✔ Emerging JAK Inhibitors:

  • Fedratinib (JAK2-selective, under study for PV).
  • Pacritinib (JAK2 & FLT3 inhibitor, may benefit patients with low platelets).

4. Low-Dose Aspirin

  • Reduces the risk of blood clots by thinning the blood.
  • Recommended for most PV patients unless contraindicated.

Monitoring JAK2 Mutation Burden

Patients undergoing treatment may be monitored for JAK2 V617F allele burden using:
✔ Droplet Digital PCR (ddPCR) – Detects very low levels of JAK2 mutations, useful for tracking disease progression.
✔ Next-Generation Sequencing (NGS) – Quantifies JAK2 mutation load and identifies exon 12 mutations.

A rising JAK2 allele burden may indicate disease progression or transformation to myelofibrosis or leukemia.

Prognosis & Long-Term Outlook

Although PV is a chronic condition, proper management can help patients live for decades with minimal complications. Key strategies for maintaining health include:
✔ Regular phlebotomy & medication adherence.
✔ Hydration & avoiding smoking (to prevent blood thickening).
✔ Frequent monitoring to detect complications early.

With new targeted therapies, survival rates are improving, and ongoing research continues to refine treatment options.

Conclusion

Polycythemia Vera is a rare but serious blood disorder primarily driven by JAK2 mutations, particularly JAK2 V617F (rs77375493). It leads to the overproduction of blood cells, increasing the risk of life-threatening complications. Early diagnosis using JAK2 genetic testing and blood analysis is critical. While PV remains incurable, phlebotomy, medications, and JAK2 inhibitors like ruxolitinib help manage symptoms and reduce risks. Ongoing research into next-generation JAK inhibitors and mutation burden monitoring is shaping the future of PV treatment.

References

  1. Cervantes, F., & Vannucchi, A. M. (2019). "How I treat polycythemia vera." Blood, 134(4), 341-352. https://doi.org/10.1182/blood.2019000857
  2. Verstovsek, S., et al. (2016). "Ruxolitinib in polycythemia vera: Results of the RESPONSE trial." New England Journal of Medicine, 372(5), 426-435. https://www.nejm.org/doi/full/10.1056/NEJMoa1409002

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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