Erythrocytosis Definition
Erythrocytosis is defined as an isolated elevation of red blood cell concentration characterized 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
Core Terminology
- Erythrocytosis specifically refers to isolated elevation of red blood cells only, whereas polycythemia technically describes elevation of all three myeloid cell lines (erythrocytes, leukocytes, and platelets). 1
- In clinical practice, these terms are often used interchangeably, though this is technically imprecise. 1
- The condition reflects an increased red cell mass above age- and sex-specific normal levels. 2
Classification Framework
Erythrocytosis is categorized into three major types based on underlying mechanism: 1
Primary Erythrocytosis
- Represents a clonal disorder intrinsic to the bone marrow's myeloid compartment. 3
- Polycythemia vera is the classic example, characterized by JAK2 mutation (present in >95% of cases), low or inappropriately normal serum erythropoietin (EPO) levels, and panmyeloid hyperplasia. 1
- Often accompanied by thrombocytosis (53% of cases) and leukocytosis (49% of cases). 1
Secondary Erythrocytosis
- Results from external stimuli driving excessive red cell production in an otherwise normal bone marrow. 3
- Hypoxia-driven causes include chronic lung disease, sleep apnea, high altitude exposure, and smoking. 1
- Hypoxia-independent causes include EPO-secreting tumors, post-renal transplant states, and mutations in the HIF pathway (VHL, PHD2, HIF2A genes). 1, 4
- Secondary erythrocytosis is more common than primary forms. 3
Apparent (Relative) Erythrocytosis
- Occurs when plasma volume is depleted (from dehydration, diuretics, or burns) without true increase in red cell mass. 1
- The hemoglobin and hematocrit are elevated due to hemoconcentration rather than increased red cell production. 5
Diagnostic Discrimination
Serum EPO level serves as the critical initial discriminator: 1
- Low or inappropriately normal EPO → suggests primary polycythemia vera, requiring JAK2 mutation testing. 1
- Elevated EPO → points toward secondary erythrocytosis, requiring evaluation for hypoxic conditions, tumors, or congenital HIF pathway mutations. 1, 4
Clinical Significance
- Undiagnosed and untreated erythrocytosis can lead to serious thromboembolic events and increased mortality. 2
- Young patients with HIF pathway mutations may experience major thromboembolic complications. 4
- The condition requires specific understanding to provide optimal care, as management differs fundamentally between primary and secondary causes. 2
Important Caveats
- Red cell mass measurement must be adjusted for the individual's height and weight to avoid misinterpretation in obese patients when using ml/kg expressions. 5
- Idiopathic erythrocytosis is a diagnosis of exclusion used when neither primary nor secondary causes can be established after thorough investigation. 5, 6
- Recent recognition that SGLT2 inhibitors can induce erythrocytosis, potentially unmasking underlying polycythemia vera through HIF-2α activation. 2