What is erythrocytosis?

What is Erythrocytosis?

Erythrocytosis is a blood disorder characterized by an abnormal elevation of red blood cell mass, defined by hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, and hematocrit >49% in men or >48% in women. 1, 2

Definition and Clinical Significance

Erythrocytosis represents an isolated elevation of red blood cells, distinct from polycythemia which involves elevation of all three myeloid cell lines (erythrocytes, leukocytes, and platelets). 1 The term "erythrocytosis" is often used synonymously with "polycythemia" in clinical practice, though technically they describe different conditions. 1

This condition is clinically significant because it exponentially increases blood viscosity, leading to serious thrombotic complications and increased mortality when undiagnosed or untreated. 3, 4

Classification Framework

Erythrocytosis is classified into three major categories: 1

Primary Erythrocytosis

• Polycythemia vera (PV): A JAK2-mutated myeloproliferative neoplasm present in >95% of cases, characterized by clonal erythrocytosis with low or inappropriately normal serum erythropoietin (EPO) levels. 1
• Familial erythrocytosis: Congenital disorders associated with variants in genes including EPOR (type 1), VHL/EGLN1/EPAS1/EPO (types 2-5), and hemoglobin genes HBB/HBA1/HBA2/BPGM (types 6-8). 5

Secondary Erythrocytosis

Secondary erythrocytosis results from external stimuli to the bone marrow and is more common than primary forms. 2 It divides into: 1

• Hypoxia-driven causes: Chronic lung disease, obstructive sleep apnea (29% of cases in referral centers), high altitude exposure, heavy smoking. 1, 6
• Hypoxia-independent causes: EPO-secreting tumors, post-renal transplant erythrocytosis, cystic kidney diseases, androgen therapy, SGLT2 inhibitor use. 1, 4

Apparent Erythrocytosis

• Relative erythrocytosis: Caused by plasma volume depletion from dehydration, diuretics, or burns rather than true red cell mass elevation. 1

Diagnostic Approach

Serum EPO level serves as the critical diagnostic discriminator: 1

• Low or inappropriately normal EPO suggests primary polycythemia vera, requiring JAK2 mutation testing (JAK2V617F screening). 1, 4
• Elevated EPO points toward secondary erythrocytosis, requiring evaluation for hypoxic conditions, tumors, or congenital causes. 1

After excluding common acquired causes, screening for JAK2V617F mutation is essential, particularly in patients on SGLT2 inhibitors which can unmask previously undiagnosed PV. 4

Clinical Consequences and Complications

Thrombotic Risk

The incidence of thrombosis varies significantly by etiology, with polycythemia vera and chronic lung disease showing comparable thrombotic risk (4.51 and 6.24 cases per 100 person-years respectively) compared to obstructive sleep apnea (1.46 cases per 100 person-years). 6 Thromboembolic events occur even in young patients with congenital forms. 7

Renal Impact

Erythrocytosis exponentially increases blood viscosity, directly impairing renal hemodynamics and microcirculation. 3 In chronic cyanotic conditions, renal glomeruli become hypercellular, congested, and eventually progress to sclerosis. 3 Patients require proper hydration before contrast procedures and cautious use of nephrotoxic medications. 3

Mortality

Mortality rates are significantly elevated in polycythemia vera and chronic lung disease with erythrocytosis (2.72 and 2.43 deaths per 100 person-years) compared to obstructive sleep apnea (0.17 deaths per 100 person-years). 6

Management Considerations

Therapeutic phlebotomy should be considered only when hemoglobin exceeds 20 g/dL and hematocrit is greater than 65% with associated hyperviscosity symptoms. 3 Aspirin and venesection to target hematocrit should be considered for thrombotic risk reduction. 7

Regular renal function assessment and maintaining proper hydration are critical to mitigate viscosity-related complications. 3 Treatment should primarily address the underlying cause when identified. 2

Idiopathic Erythrocytosis

Despite comprehensive evaluation, more than 70% of patients remain without an identified genetic cause and are labeled as having idiopathic erythrocytosis. 5 However, with next-generation sequencing becoming standard practice, this category is progressively shrinking as previously unidentified genetic variants are discovered. 7