Investigation And Management Of Erythrocytosis 2021

Erythrocytosis, characterized by an elevated red blood cell mass, requires thorough investigation to determine its underlying cause and appropriate management strategies. This article provides a comprehensive overview of the investigation and management of erythrocytosis, reflecting guidelines and understanding as of 2021.

Understanding Erythrocytosis

Erythrocytosis, also known as polycythemia, refers to an increase in the number of red blood cells in the bloodstream. This condition leads to an elevated hemoglobin level and hematocrit, potentially causing increased blood viscosity and associated complications. It's crucial to distinguish between absolute erythrocytosis, where there is a true increase in red blood cell mass, and relative erythrocytosis, where the red blood cell count appears elevated due to a decrease in plasma volume.

Types of Erythrocytosis

• Primary Erythrocytosis: This originates from inherent issues within the bone marrow itself. Polycythemia vera (PV) is the most common cause, a myeloproliferative neoplasm characterized by the autonomous production of red blood cells, often associated with a JAK2 mutation.
• Secondary Erythrocytosis: This arises due to external factors that stimulate red blood cell production. Common causes include chronic hypoxia (low oxygen levels), certain tumors that produce erythropoietin (EPO), and some medications.
• Relative Erythrocytosis: Also known as Gaisböck syndrome or stress erythrocytosis, this is not a true increase in red cell mass but rather a decrease in plasma volume, often associated with obesity, hypertension, and diuretic use.

Initial Assessment and Clinical Evaluation

The first step in managing erythrocytosis involves a detailed assessment to confirm the diagnosis and differentiate between its various types.

History and Physical Examination

A comprehensive medical history should include:

• Symptoms: Enquire about symptoms such as headache, dizziness, fatigue, visual disturbances, pruritus (itching, especially after a warm bath), and erythromelalgia (burning pain and redness in extremities).
• Risk Factors: Identify potential risk factors, including smoking, chronic lung disease, sleep apnea, cardiovascular disease, and exposure to high altitudes.
• Medications: Review all medications, as some drugs can induce erythrocytosis.
• Family History: Explore family history of blood disorders, particularly polycythemia vera.

The physical examination should focus on:

• Vital Signs: Assess blood pressure, heart rate, and oxygen saturation.
• Skin Examination: Look for signs of plethora (ruddy complexion), cyanosis, or splenomegaly (enlarged spleen).
• Cardiovascular and Respiratory Systems: Evaluate for signs of underlying heart or lung disease.

Laboratory Investigations

Initial laboratory tests are critical for confirming the diagnosis and guiding further investigations:

1. Complete Blood Count (CBC): Confirm elevated hemoglobin and hematocrit levels. Note the red blood cell count and indices (MCV, MCH, MCHC).
2. Peripheral Blood Smear: Examine for abnormal red blood cell morphology and presence of other blood cell abnormalities.
3. Arterial Blood Gas (ABG): Assess oxygen saturation and partial pressure of oxygen (PaO2) to rule out chronic hypoxia.
4. Serum Erythropoietin (EPO) Level: Measure EPO levels to differentiate between primary and secondary erythrocytosis. Low or normal EPO suggests primary erythrocytosis, while elevated EPO suggests secondary erythrocytosis.
5. Iron Studies: Check iron levels, as iron deficiency can sometimes mask underlying erythrocytosis.

Differentiating Primary from Secondary Erythrocytosis

Distinguishing between primary and secondary erythrocytosis is essential for targeted management. The diagnostic algorithm often involves further specialized testing.

Diagnostic Criteria for Polycythemia Vera (PV)

The 2016 revised World Health Organization (WHO) diagnostic criteria for PV include both major and minor criteria:

Major Criteria:

1. Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, or hematocrit >49% in men or >48% in women, or red cell mass >25% above normal predicted.
2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (erythroid, granulocytic, and megakaryocytic proliferation).
3. Presence of JAK2 V617F mutation or JAK2 exon 12 mutation.

Minor Criterion:

1. Serum EPO level below the reference range.

Diagnosis requires meeting all three major criteria or the first two major criteria and the minor criterion.

JAK2 Mutation Testing

The JAK2 V617F mutation is present in approximately 95% of patients with PV. Testing for this mutation is crucial in the diagnostic workup. If the JAK2 V617F mutation is negative, consider testing for JAK2 exon 12 mutations, which are found in a small subset of PV patients.

Bone Marrow Biopsy

Bone marrow biopsy is essential when JAK2 mutation testing is negative or when there is diagnostic uncertainty. It helps to assess cellularity, megakaryocyte morphology, and exclude other myeloproliferative neoplasms.

Investigating Secondary Erythrocytosis

If secondary erythrocytosis is suspected based on elevated EPO levels, further investigations are needed to identify the underlying cause.

Evaluation for Chronic Hypoxia

• Pulmonary Function Tests (PFTs): Assess lung function to identify underlying lung diseases such as COPD or interstitial lung disease.
• Sleep Study (Polysomnography): Evaluate for sleep apnea, which can cause nocturnal hypoxia.
• High-Resolution CT Scan of the Chest: Investigate for structural lung abnormalities.

Evaluation for Erythropoietin-Secreting Tumors

• Abdominal Ultrasound or CT Scan: Screen for renal cell carcinoma, hepatocellular carcinoma, and other EPO-producing tumors.
• Magnetic Resonance Imaging (MRI): May be necessary to evaluate for tumors in the brain or other locations.

Other Causes of Secondary Erythrocytosis

• Anabolic Steroids: Review medication history for anabolic steroid use, which can stimulate red blood cell production.
• Carbon Monoxide Exposure: Consider chronic carbon monoxide exposure in individuals living in poorly ventilated environments.
• High Altitude: Determine if the patient resides at high altitude, as chronic hypoxia can lead to erythrocytosis.

Management of Erythrocytosis

The management of erythrocytosis depends on the underlying cause and the patient's individual risk factors.

Management of Polycythemia Vera (PV)

The primary goals of PV management are to reduce the risk of thrombosis (blood clots) and control symptoms.

1. Phlebotomy: This is the cornerstone of initial therapy. The goal is to reduce the hematocrit to below 45% in men and 42% in women. Phlebotomy is typically performed regularly until the target hematocrit is achieved.

2. Low-Dose Aspirin: Aspirin (typically 81 mg daily) is recommended for most PV patients to reduce the risk of thrombosis, unless contraindicated.

3. Cytoreductive Therapy: This is indicated for patients at high risk of thrombosis (e.g., age >60 years, history of thrombosis) or those with uncontrolled symptoms. Options include:

   • Hydroxyurea: This is a commonly used first-line cytoreductive agent that suppresses bone marrow production of blood cells.
   • Interferon-alpha: This can be used in younger patients, particularly women of childbearing age, as it has fewer long-term risks than hydroxyurea.
   • Ruxolitinib: A JAK1/JAK2 inhibitor, ruxolitinib is approved for PV patients who are resistant to or intolerant of hydroxyurea. It can effectively control symptoms and reduce spleen size.

4. Management of Pruritus: Pruritus can be a troublesome symptom in PV. Management strategies include:

   • Antihistamines: Non-sedating antihistamines can provide some relief.
   • Selective Serotonin Reuptake Inhibitors (SSRIs): Paroxetine or other SSRIs can be effective in some patients.
   • Cholestyramine: This can bind bile acids and reduce pruritus.
   • PUVA Therapy: Phototherapy with psoralen and ultraviolet A (PUVA) light can be used in severe cases.

5. Monitoring and Follow-Up: Regular monitoring of blood counts, symptom control, and potential complications is essential. Patients should be educated about the signs and symptoms of thrombosis and advised to seek immediate medical attention if they occur.

Management of Secondary Erythrocytosis

The management of secondary erythrocytosis focuses on addressing the underlying cause.

1. Treatment of Chronic Hypoxia:

   • Supplemental Oxygen: Administer oxygen therapy to maintain adequate oxygen saturation in patients with chronic lung disease or sleep apnea.
   • CPAP Therapy: Continuous positive airway pressure (CPAP) therapy can improve oxygenation in patients with sleep apnea.
   • Smoking Cessation: Encourage smoking cessation to improve lung function.

2. Treatment of Erythropoietin-Secreting Tumors:

   • Surgical Resection: Surgical removal of the tumor is the primary treatment for EPO-secreting tumors.
   • Targeted Therapy: In cases of renal cell carcinoma, targeted therapies such as tyrosine kinase inhibitors (e.g., sunitinib, sorafenib) may be used.

3. Other Management Strategies:

   • Discontinuation of Anabolic Steroids: Advise patients to discontinue anabolic steroid use.
   • Management of Carbon Monoxide Exposure: Identify and eliminate sources of carbon monoxide exposure.
   • Phlebotomy: In some cases, phlebotomy may be necessary to reduce the hematocrit and alleviate symptoms, particularly if the underlying cause cannot be effectively treated.

Management of Relative Erythrocytosis

The management of relative erythrocytosis primarily involves addressing the underlying factors contributing to decreased plasma volume.

1. Lifestyle Modifications:

   • Weight Loss: Encourage weight loss in obese individuals.
   • Blood Pressure Control: Manage hypertension through lifestyle modifications and medications.
   • Hydration: Ensure adequate fluid intake to maintain plasma volume.
   • Diuretic Adjustment: Review and adjust diuretic medications, if appropriate.

2. Low-Dose Aspirin: May be considered in patients with cardiovascular risk factors.

3. Monitoring: Regular monitoring of blood pressure and hematocrit is recommended.

Potential Complications of Erythrocytosis

Regardless of the underlying cause, erythrocytosis can lead to several complications:

• Thrombosis: Increased blood viscosity increases the risk of blood clots, leading to stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism.
• Bleeding: Paradoxically, PV patients can also experience bleeding complications due to abnormal platelet function.
• Splenomegaly: Enlargement of the spleen can cause abdominal discomfort and cytopenias.
• Myelofibrosis: PV can transform into myelofibrosis, a more aggressive bone marrow disorder.
• Leukemic Transformation: Rarely, PV can transform into acute leukemia.
• Cardiovascular Complications: Increased blood volume and viscosity can strain the cardiovascular system, leading to hypertension and heart failure.

Emerging Therapies and Research

Research into erythrocytosis and related disorders is ongoing, with several promising therapies in development.

• Novel JAK2 Inhibitors: New JAK2 inhibitors with improved selectivity and safety profiles are being investigated.
• Hepcidin Mimetics: These agents aim to regulate iron metabolism and reduce the need for phlebotomy.
• Telomerase Inhibitors: These may target the underlying clonal abnormality in PV.
• Targeted Therapies for EPO-Secreting Tumors: Advances in targeted therapies for renal cell carcinoma and other tumors may improve outcomes in patients with secondary erythrocytosis.

Conclusion

The investigation and management of erythrocytosis require a systematic approach to identify the underlying cause, assess the risk of complications, and implement appropriate treatment strategies. Differentiating between primary, secondary, and relative erythrocytosis is crucial for guiding management decisions. Phlebotomy, low-dose aspirin, and cytoreductive therapies are the mainstays of PV management, while addressing the underlying cause is paramount in secondary erythrocytosis. Regular monitoring and follow-up are essential to prevent complications and improve patient outcomes. Continued research into novel therapies holds promise for further improving the management of erythrocytosis and related disorders.