Erythrocytosis

Overview of Erythrocytosis

Definition: An abnormal increase in the number of red blood cells (RBCs) in the blood, leading to an elevated hemoglobin (HGB) concentration and hematocrit (HCT) value
Alternative Terms: Polycythemia, erythremia
Classification:
- Relative Erythrocytosis: An apparent increase in RBC count due to a decrease in plasma volume
- Absolute Erythrocytosis: A true increase in the total red blood cell mass in the body
Causes: Can range from benign to life-threatening conditions
Symptoms: May be asymptomatic or present with a variety of symptoms, including headache, dizziness, fatigue, blurred vision, pruritus (itching), and thrombosis (blood clots)

Definition: An elevated hematocrit (HCT) and hemoglobin (HGB) concentration due to a decrease in plasma volume, rather than an actual increase in red blood cell mass
Causes:
- Dehydration:
  - Reduced fluid intake
  - Excessive fluid loss (e.g., vomiting, diarrhea, diuretic use, burns)
- Stress Erythrocytosis (Gaisböck Syndrome):
  - More common in middle-aged men who are obese, hypertensive, and smokers
  - Underlying mechanism is not fully understood but may involve increased catecholamines, which lead to decreased plasma volume
  - Often associated with anxiety and stress
Laboratory Findings:
- Elevated HGB and HCT
- Normal red blood cell mass
- Elevated RBC count
- Normal or elevated serum protein and albumin levels (due to hemoconcentration)
- Normal or low-normal Erythropoietin level (EPO)
- Normal Oxygen Saturation (SaO2)

Definition: A true increase in the total red blood cell mass in the body
Classification:
- Primary Erythrocytosis:
  - Caused by intrinsic abnormalities of the bone marrow, leading to uncontrolled RBC production
  - Independent of erythropoietin (EPO) levels
- Secondary Erythrocytosis:
  - Caused by factors external to the bone marrow that stimulate increased RBC production
  - Associated with elevated erythropoietin (EPO) levels

Polycythemia Vera (PV):
- A myeloproliferative neoplasm characterized by uncontrolled proliferation of all myeloid cell lines (RBCs, WBCs, and platelets), but with predominant increase in RBCs
- Cause: In most cases (>95%), caused by a mutation in the JAK2 gene (Janus kinase 2), which leads to constitutive activation of the EPO receptor signaling pathway
- Symptoms: Headache, dizziness, fatigue, pruritus (especially after a warm bath), erythromelalgia (burning pain and redness in the extremities), splenomegaly, and thrombosis (both arterial and venous)
- Laboratory Findings:
  - Elevated HGB and HCT
  - Elevated RBC count
  - Normal or decreased EPO level
  - Increased WBC count and platelet count in some cases
  - Positive JAK2 mutation
  - Bone marrow examination: Hypercellular marrow with increased erythroid, myeloid, and megakaryocytic lineages

Definition: Increased RBC production due to an underlying condition that stimulates erythropoietin (EPO) production
Causes:
- Hypoxia-Induced Erythrocytosis:
  - Chronic lung disease (e.g., COPD, emphysema)
  - High altitude
  - Obstructive sleep apnea
  - Cyanotic heart disease
  - Reduced oxygen levels stimulate EPO production by the kidneys
- EPO-Producing Tumors:
  - Renal cell carcinoma
  - Hepatocellular carcinoma
  - Hemangioblastoma
  - These tumors secrete EPO, leading to increased RBC production
- Other Causes:
  - Exogenous EPO administration (e.g., in athletes for performance enhancement)
  - Androgen use
  - Certain medications
  - Post-kidney transplant erythrocytosis
Laboratory Findings:
- Elevated HGB and HCT
- Elevated RBC count
- Elevated EPO level (except in cases of exogenous EPO administration)
- Normal or elevated WBC count and platelet count
- Arterial blood gas analysis: May show hypoxemia (low oxygen levels) in hypoxia-induced erythrocytosis
- Imaging studies: To detect EPO-producing tumors

Confirm Erythrocytosis:
- Check HGB and HCT levels
Rule Out Relative Erythrocytosis:
- Assess hydration status
- Check serum protein and albumin levels
Measure Red Blood Cell Mass:
- If available, direct measurement of RBC mass can differentiate between relative and absolute erythrocytosis
Measure Serum Erythropoietin (EPO) Level:
- Low or normal EPO: Suggests primary erythrocytosis (e.g., PV)
- Elevated EPO: Suggests secondary erythrocytosis
If EPO is Low or Normal:
- Test for JAK2 mutation (highly suggestive of PV)
- If JAK2 is negative, consider other myeloproliferative neoplasms or rare causes of primary erythrocytosis
- Bone marrow examination may be necessary
If EPO is Elevated:
- Assess for hypoxia:
  - Arterial blood gas analysis
  - Pulse oximetry
- Evaluate for EPO-producing tumors:
  - Imaging studies (e.g., CT scan, MRI)
- Consider other causes:
  - Exogenous EPO administration
  - Androgen use
  - Other medications

Thrombosis:
- Increased risk of blood clots due to increased blood viscosity and platelet activation
- Can lead to stroke, heart attack, pulmonary embolism, and deep vein thrombosis (DVT)
Bleeding:
- Paradoxically, some patients with PV may experience bleeding due to abnormal platelet function
Splenomegaly:
- Enlargement of the spleen due to increased workload
Myelofibrosis:
- In PV, bone marrow can become fibrotic over time, leading to cytopenias
Transformation to Acute Leukemia:
- Small risk of transformation to acute myeloid leukemia (AML) in PV, especially after treatment with certain agents

Relative Erythrocytosis:
- Address the underlying cause (e.g., rehydration)
Polycythemia Vera:
- Phlebotomy: To reduce HCT to <45%
- Low-dose aspirin: To reduce the risk of thrombosis
- Cytoreductive therapy:
  - Hydroxyurea: To suppress bone marrow proliferation
  - Ruxolitinib: A JAK2 inhibitor used in patients who are resistant to or intolerant of hydroxyurea
Secondary Erythrocytosis:
- Address the underlying cause:
  - Oxygen therapy for hypoxia
  - Surgical removal of EPO-producing tumors
- Phlebotomy: May be used to reduce Hct in symptomatic patients

Complete Blood Count (CBC):
- HGB and HCT: Elevated
- RBC count: Elevated
- WBC count: May be normal or elevated
- Platelet count: May be normal or elevated
Serum Erythropoietin (EPO) Level:
- Low or normal: Suggests primary erythrocytosis
- Elevated: Suggests secondary erythrocytosis
Arterial Blood Gas Analysis:
- To assess oxygen saturation and partial pressure of oxygen (PaO2) in hypoxia-induced erythrocytosis
JAK2 Mutation Analysis:
- To diagnose polycythemia vera
Bone Marrow Examination:
- To assess cellularity and morphology of hematopoietic cells
Imaging Studies (CT Scan, MRI):
- To detect EPO-producing tumors

Erythrocytosis: Increased red blood cell count
Polycythemia: Increased red blood cell count
Relative Erythrocytosis: Decreased plasma volume
Absolute Erythrocytosis: Increased red blood cell mass
Polycythemia Vera (PV): Myeloproliferative neoplasm with increased RBCs, WBCs, and PLTs
JAK2 Mutation: Mutation associated with PV
Erythropoietin (EPO): Hormone that stimulates RBC production
Phlebotomy: Removal of blood
Hydroxyurea: Cytoreductive agent
Ruxolitinib: JAK2 inhibitor