What Is Erythrocytosis and How Is It Treated?

“The term erythrocytosis refers to an absolute or relative increase in circulating red blood cells,” explains Dr. Sannipoli, “defined by the following values:

• Hemoglobin (Hb) is a protein contained in red blood cells – greater than 16.5 g/dL in men and 16 g/dL in women;
• Hematocrit is a test that measures the proportion of red blood cells in the blood – greater than 49% in men and 48% in women.

These values must be confirmed in multiple measurements and interpreted in the context of the patient’s characteristics (such as weight, smoking history, residence at high altitudes, etc.).”

“There are several forms of erythrocytosis, which can be classified as primary or secondary, with either congenital or acquired causes,” he continues.

Primary Erythrocytosis

Primary forms result from genetic mutations that cause abnormal production of red blood cells and are categorized into:

• Congenital form (rare, typically diagnosed in childhood): caused by mutations in the erythropoietin (EPO) receptor, the main hormone that stimulates red blood cell production (erythropoiesis);
• Acquired form: the most common is Polycythemia Vera (PV), a myeloproliferative neoplasm of the bone marrow, almost always associated with mutations in the JAK2 gene. The most frequent mutation, JAK2V617F, causes the protein to become constitutively active, leading to uncontrolled proliferation of mature blood cells.

PV is one of the Philadelphia chromosome-negative Myeloproliferative Neoplasms (MPN Ph-), along with essential thrombocythemia and myelofibrosis. Unlike other forms of erythrocytosis, PV carries a significantly increased risk of thrombosis and bleeding, requiring hematological evaluation and management.

Secondary Erythrocytosis

Secondary erythrocytosis can result from numerous causes, including:

• Chronic obstructive pulmonary disease (COPD) and other chronic lung conditions, especially common in smokers;
• Obstructive Sleep Apnea Syndrome (OSAS): more frequent in obese patients, characterized by abnormal pauses in breathing during sleep that can lead to chronic low oxygen levels. Other indicative symptoms include daytime fatigue and loud snoring. Diagnosis is based on a polysomnography test, which records parameters like breathing patterns, blood oxygen levels, heart rate, and body movements during sleep. This test is painless, non-invasive, and can usually be performed at home;
• Congenital heart diseases: in certain anatomical abnormalities, a pathological communication between the heart’s left and right sides causes decreased arterial blood oxygenation, triggering compensatory erythrocytosis;
• Solid tumors, including cerebellar tumors, uterine fibroids, hepatocellular carcinomas, and renal cell carcinomas: in these cancers, tumor cells may produce high levels of erythropoietin, pathologically stimulating the bone marrow;
• Medications, such as certain antidiabetics, diuretics, testosterone, anabolic steroids, and corticosteroids;
• Renal artery stenosis;
• Other rare syndromes.

Relative erythrocytosis, due to osmotic dehydration (e.g., in diabetic patients with poor glycemic control), should also not be overlooked.

An increase in red blood cells can lead to higher blood viscosity, which may cause symptoms such as:

• Itching, tingling, or paresthesia;
• Dizziness, vertigo, and headaches;
• Red or flushed skin (plethoric facies), burning pain in the palms (erythromelalgia);
• Visual disturbances due to slowed retinal blood flow.

“In primary hematologic forms,” continues the specialist, “the JAK2 mutation can also cause enlargement of the spleen(splenomegaly), potentially leading to decreased appetite, weight loss, and pain in the left upper abdomen.

Furthermore, in patients with Polycythemia Vera (PV), erythrocytosis is often accompanied by a marked alteration in blood clotting, both with an increased thrombotic risk (frequently in atypical sites) and with unexplained spontaneous bleeding.”

“For secondary forms, treatment depends on the underlying cause. In cases linked to pulmonary diseases, erythrocytosis often acts as a compensatory mechanism and should be preserved to avoid worsening the condition. Smoking cessation is always recommended. The use of antiplatelet therapy and referral for specialist treatment (e.g., cardiologist or pulmonologist) should also be considered.

Improving respiratory function, oxygenation, and lifestyle changes can often lead to a natural reduction in erythrocytosis. In some cases, surgical correction of anatomical defects may be necessary.

For OSAS, weight loss, good sleep hygiene, and in more severe cases, use of nighttime CPAP devices may help. CPAP maintains constant airflow and prevents airway collapse during sleep. Once properly adjusted, it can be used independently at home.

In erythrocytosis caused by solid tumors, treatment must be handled by the appropriate oncology specialist and may involve chemotherapy, immunotherapy, radiotherapy, surgery, or a combination of these.”

For Polycythemia Vera, treatment is managed by a hematologist following a thorough diagnostic workup.

“Unless there are specific contraindications, all patients should receive low-dose antiplatelet therapy. For younger patients with no history of cardiovascular events, phlebotomy alone may be sufficient to control the disease and reduce red blood cell count.

For patients with higher cardiovascular risk due to age or comorbidities, or with prior thrombotic events, pharmacologic therapy is required to control erythrocytosis and reduce the risk of severe complications.

Standard treatment includes variable-dose hydroxyurea, a well-known drug with a clearly established toxicity profile. In recent years, new options have emerged, particularly interferon and ruxolitinib (a JAK pathway inhibitor).

Interferon, now available in a long-acting form, is administered subcutaneously every 15 days and has shown not only symptom control but also reduction of mutated cells in the bone marrow.

Ruxolitinib is a newer but well-established drug particularly useful for highly symptomatic patients and those with significant splenomegaly.

Consistent hematological care, management of cardiovascular risk factors, multidisciplinary support from cardiologists, nutritionists, and lipid specialists, and appropriate monotherapy or combination therapy, allow the vast majority of patients with Polycythemia Vera to maintain both a good life expectancy and quality of life,” concludes Dr. Sannipoli.