Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) caused by acquired mutations in hematopoietic stem cells, primarily characterized by an abnormal increase in red blood cells. It is often accompanied by elevated white blood cell and platelet counts, as well as splenomegaly. Thrombosis and bleeding are the primary clinical manifestations. The condition is more common in the elderly, with a median onset age of 60 years and a male-to-female ratio of 1.8:1.
Pathogenesis
The JAK2 V617F gene mutation is found in 90–95% of PV patients, while approximately 3% harbor JAK2 EXON 12 mutations. Abnormalities in other genes may also be present.
Clinical Manifestations
The onset is insidious, and the majority of patients are diagnosed during routine medical check-ups. About 1/3 of patients may experience symptoms. Elevated blood viscosity may cause slow blood flow and tissue hypoxia, leading to the following clinical symptoms:
Non-specific Symptoms
Symptoms such as headaches, weakness, and night sweats may occur.
Plethoric Appearance
A reddish-purple complexion, conjunctival congestion, and related findings are often observed.
Thrombosis and Bleeding
Thrombosis is the most common complication and is present in approximately 1/3 of newly diagnosed patients. Arterial thrombosis occurs more frequently than venous thrombosis. Common thrombotic events include cerebrovascular accidents, myocardial infarction, deep vein thrombosis, and pulmonary embolism. Bleeding occurs in only a small proportion of patients (1–10%) and is associated with factors such as vascular injury and platelet dysfunction.
Pruritus
Approximately 40% of PV patients experience pruritus, which worsens with warm water exposure or scratching. The exact cause remains unclear.
Hepatosplenomegaly
About 70% of patients exhibit splenomegaly, and 40% have hepatomegaly. Symptoms may include discomfort in the upper abdomen and indigestion. Splenic infarctions can result in pain in the splenic region.
Other Manifestations
Hyperuricemia is common, with some patients developing secondary gout, kidney stones, or renal impairment. Increased blood volume leads to secondary hypertension in approximately half of the patients. Additionally, 10–16% of patients develop peptic ulcers.
Laboratory Testing
Complete Blood Count
Red blood cell count (RBC), hemoglobin (Hb), and hematocrit (HCT) levels are elevated. Microcytic hypochromic anemia may occur in cases of gastrointestinal bleeding or excessive phlebotomy. Anemia may also develop in late-stage PV with coexisting bone marrow fibrosis, and tear-drop-shaped red blood cells may be observed in the peripheral blood. White blood cell counts are elevated in 60% of patients, with immature granulocytes appearing in the peripheral blood in advanced stages. Elevated neutrophil alkaline phosphatase (NAP) scores are also noted. Platelet counts are increased in 50% of patients. A platelet count exceeding (1,000–1,500) ×109/L is associated with a higher risk of bleeding but is not related to thrombotic risk.
Bone Marrow Analysis
Bone marrow smears or biopsies typically demonstrate hypercellularity across erythroid, granulocytic, and megakaryocytic lineages. Reticulin staining of the bone marrow is required to confirm the presence or absence of fibrosis.
Biochemical Testing
Most patients exhibit elevated uric acid levels, along with decreased or normal levels of erythropoietin (EPO).
Genetic Testing
JAK2 V617F or JAK2 EXON 12 mutations are frequently detected. Other mutations may include TET2 (22%), ASXL1 (12%), and SH2B3, among others.
Cytogenetic Analysis
Chromosomal abnormalities are identified in 15–20% of patients.
Erythroid Colony Formation
Burst-forming unit-erythroid (BFU-E) from PV patients can grow in EPO-free culture media, forming endogenous erythroid colonies, which was once the most specific diagnostic test for PV.
Diagnosis and Differential Diagnosis
Diagnosis (2022 WHO Criteria)
Major Criteria:
- Hemoglobin (Hb) levels: >165 g/L for males, >160 g/L for females; or hematocrit (HCT): >0.49 for males, >0.48 for females.
- Bone marrow biopsy indicates panmyelosis relative to age, with significant erythroid and granulocytic proliferation, as well as polymorphic, variably sized, and mature megakaryocyte proliferation.
- Presence of JAK2 V617F mutation or JAK2 EXON12 mutation.
Minor Criterion:
- Serum erythropoietin (EPO) levels lower than normal.
Major Criterion 2 may not be required when Major Criterion 3 and the Minor Criterion are fulfilled, and Hb levels are >185 g/L for males or >165 g/L for females; or HCT is >0.55 for males or >0.49 for females.
A diagnosis of PV requires meeting all three Major Criteria or the first two Major Criteria along with the Minor Criterion.
Differential Diagnosis
Distinguishing PV from secondary erythrocytosis and relative erythrocytosis is necessary.
Secondary Erythrocytosis
Secondary erythrocytosis is primarily caused by increased EPO levels due to various factors that stimulate excessive bone marrow erythroid activity. Common causes include high altitude, chronic obstructive pulmonary disease (COPD), cyanotic congenital heart disease, carbon monoxide poisoning, smoking, and kidney diseases.
Relative Erythrocytosis
Relative erythrocytosis is usually a result of reduced plasma volume, leading to a pseudo-increase in red blood cell levels.
Treatment
The objectives of treatment are to prevent thrombosis, control disease-related symptoms, and delay disease progression. During the polycythemic phase, maintaining HCT levels below 0.45 is essential.
Phlebotomy
At the initial stage, phlebotomy is performed 1–2 times per week, with each session removing 300–450 mL of blood. Once HCT levels fall below 0.45, the intervals between phlebotomies can be extended. For patients with concomitant cardiovascular or cerebrovascular conditions, small-volume, frequent phlebotomies are preferred. Red blood cell apheresis is an effective method for rapidly reducing HCT levels in a short period.
Thrombosis Prevention
Low-dose aspirin is the first-line choice, at a daily dose of 100 mg. For patients intolerant to aspirin, clopidogrel or dipyridamole may be considered.
Cytoreductive Therapy
High-risk patients should receive cytoreductive treatment, with hydroxyurea or interferon being considered first-line options. Interferon is more likely than hydroxyurea to achieve both hematological and molecular responses. For younger patients (<60 years old), interferon is preferred. Commonly used agents include interferon-α (9–25 × 106 U per week, administered in three subcutaneous injections) and hydroxyurea (10–20 mg/kg/day), with the dose adjusted based on the complete blood count.
JAK2 Inhibitors
In December 2014, the U.S. FDA approved ruxolitinib for use in patients who are resistant or intolerant to hydroxyurea. The starting dose is 10 mg twice daily, administered orally. Gradual tapering over 7–10 days is required to discontinue ruxolitinib to avoid abrupt withdrawal.
Prognosis
Untreated symptomatic PV patients have a median survival time of 6–18 months from diagnosis. In contrast, treated PV patients achieve a median survival time of 14–18.9 years. Assessment of thrombotic risk and survival can be performed using thrombotic risk stratification and the International Working Group for PV Prognostic Scoring System (IWG-PV).