What is Erythrocytosis?
Erythrocytosis is a condition 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
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 differ in scope. 1, 2
The condition is clinically significant because undiagnosed and untreated erythrocytosis can lead to serious thrombotic events and higher mortality due to increased blood viscosity. 3
Classification Framework
Erythrocytosis is classified into three major categories: 1
Primary Erythrocytosis
- Polycythemia vera (PV): A JAK2-mutated myeloproliferative neoplasm with clonal erythrocytosis, present in >95% of cases. 1
- Characterized by low or inappropriately normal serum erythropoietin (EPO) levels. 1
- Represents an intrinsic defect in the erythroid progenitor cell. 4
Secondary Erythrocytosis
- More common than primary erythrocytosis and results from external stimuli to the bone marrow. 2
- Divided into hypoxia-driven causes (chronic lung disease, sleep apnea, high altitude, smoking) and hypoxia-independent causes (EPO-secreting tumors, post-renal transplant). 1
- Associated with CKD-related causes including cystic kidney diseases, kidney neoplasms, high-altitude renal syndrome, overdosage of erythropoietin-stimulating agents, androgen therapy, IgA nephropathy, and renal artery stenosis. 3
Apparent (Relative) Erythrocytosis
- Caused by plasma volume depletion from dehydration, diuretics, or burns. 1
- Red cell mass is actually normal, but concentration appears elevated. 5
Pathophysiology
The normal lifespan of erythrocytes is approximately 120 days. 6 Erythrocytes function beyond simple oxygen transport—they regulate vascular tone through nitric oxide bioavailability, participate in hemostasis (producing up to 40% of thrombin in certain pathological conditions), maintain redox equilibrium, and demonstrate immunological activity. 6
Erythrocytosis exponentially increases blood viscosity, directly affecting renal hemodynamics and microcirculation, decreasing blood flow in small capillaries and impairing tissue perfusion. 7
Genetic Mechanisms
Familial erythrocytosis has distinct genetic subtypes: 8
- Type 1: Hypersensitivity to erythropoietin (EPOR variants)
- Types 2-5: Defects in oxygen-sensing pathways (VHL, EGLN1, EPAS1, EPO variants)
- Types 6-8: Increased hemoglobin-oxygen affinity (HBB, HBA1, HBA2, BPGM variants)
Despite advances, more than 70% of patients remain labeled as idiopathic due to heterogeneous genetic backgrounds. 8
Diagnostic Approach
Serum EPO level is the critical diagnostic discriminator: 1
- Low or inappropriately normal EPO → suggests primary polycythemia vera (requires JAK2 mutation testing)
- Elevated EPO → points toward secondary erythrocytosis (requires evaluation for hypoxic or tumor-related causes)
Investigation should confirm raised hemoglobin on repeat testing and measure red cell mass when absolute erythrocytosis is defined as >125% of predicted value for sex and body mass. 5
Clinical Implications and Management
Renal Considerations
- Patients with erythrocytosis require proper hydration before contrast media procedures due to compromised renal function. 7
- Regular assessment of renal function is essential, as chronic erythrocytosis causes glomeruli to become abnormal, hypercellular, and congested, eventually progressing to sclerosis. 7
Treatment Principles
- Therapeutic phlebotomy should be considered only when hemoglobin exceeds 20 g/dL and hematocrit >65% with hyperviscosity symptoms. 7
- Low-dose aspirin and venesection to target hematocrit should be considered for thromboembolic risk reduction. 4, 5
- Treatment should primarily address the underlying cause. 2
Emerging Considerations
SGLT2 inhibitors can induce erythrocytosis by hypothetically activating hypoxia-inducible factor 2α (HIF-2α) and may unmask polycythemia vera, requiring timely JAK2 mutation screening. 3