What causes elevations in red blood cell (RBC) count, hemoglobin, and hematocrit?

Causes of Elevated RBC Count, Hemoglobin, and Hematocrit

Elevations in RBC count, hemoglobin, and hematocrit result from either primary bone marrow disorders (polycythemia vera), secondary physiological responses to hypoxia or other stimuli, or relative polycythemia from plasma volume depletion. 1

Primary Polycythemia (Polycythemia Vera)

Primary polycythemia is a clonal myeloproliferative disorder where bone marrow overproduces red blood cells independent of physiological need. 2

• Polycythemia vera (PV) is characterized by JAK2 mutations (present in >95% of cases), with bone marrow showing autonomous erythroid proliferation that occurs without appropriate erythropoietin signaling 1, 3
• PV typically presents with more marked elevations (hemoglobin >18.5 g/dL in men, >16.5 g/dL in women; hematocrit >55% in men, >49.5% in women) compared to secondary causes 1
• Diagnosis requires JAK2 mutation testing (both exon 14 and exon 12) and often bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation 1, 4
• Erythroid progenitors in PV form endogenous erythroid colonies (EEC) in vitro without exogenous erythropoietin, distinguishing it from secondary causes 3

Secondary Polycythemia (Hypoxia-Driven)

Secondary erythrocytosis represents a physiological compensatory response to tissue hypoxia, where increased red cell mass improves oxygen delivery. 5, 1

Chronic Hypoxic Conditions

• Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production, particularly in obese patients (BMI >30), and resolves with CPAP therapy 1, 4
• Chronic obstructive pulmonary disease (COPD) and other chronic lung diseases cause persistent hypoxemia stimulating compensatory erythrocytosis 1
• Cyanotic congenital heart disease causes right-to-left shunting with resultant hypoxemia; the secondary erythrocytosis is a compensatory mechanism to optimize oxygen transport 5
• High altitude residence causes physiological increases in hemoglobin (e.g., +1.9 g/dL at 3,000 meters, +3.5 g/dL at 4,000 meters) as adaptation to lower atmospheric oxygen 1

Smoking-Related Polycythemia

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which binds hemoglobin and causes tissue hypoxia, stimulating erythropoietin production 1
• This condition resolves with smoking cessation 1

High-Oxygen-Affinity Disorders

• High-oxygen-affinity hemoglobin variants prevent adequate oxygen release to tissues, creating functional hypoxia despite normal arterial oxygen saturation 1
• 2,3-BPG mutase deficiency similarly impairs oxygen delivery, triggering compensatory erythrocytosis 3

Secondary Polycythemia (Hypoxia-Independent)

Certain conditions produce erythrocytosis through inappropriate or autonomous erythropoietin production unrelated to tissue oxygen needs. 1

Malignancy-Associated Erythrocytosis

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin autonomously, causing paraneoplastic erythrocytosis 1

Genetic Disorders of Oxygen Sensing

• Chuvash polycythemia (von Hippel-Lindau gene mutation) causes inappropriately high erythropoietin levels due to dysregulated hypoxia-inducible factor-1 (HIF-1) expression in normoxic conditions 1, 3
• Erythropoietin receptor mutations result in truncated receptors lacking negative regulatory domains, causing hypersensitivity to erythropoietin 3

Iatrogenic Causes

• Exogenous erythropoietin therapy directly stimulates red cell production 1
• Testosterone therapy (prescribed or unprescribed) stimulates erythropoiesis and commonly causes erythrocytosis in young adults; hematocrit should be monitored closely with dose adjustment if levels rise 1

Relative Polycythemia (Plasma Volume Depletion)

Relative polycythemia occurs when plasma volume decreases without true increase in red cell mass, causing hemoconcentration. 1

• Dehydration from any cause (inadequate intake, vomiting, diarrhea, excessive sweating) concentrates red cells 1
• Diuretic use reduces plasma volume pharmacologically 1
• Burns cause plasma extravasation and volume loss 1
• Stress polycythemia (Gaisböck syndrome) is a chronic condition of reduced plasma volume, often in hypertensive, obese males 1

Physiological Variations

Normal hemoglobin and hematocrit values vary by sex, age, and altitude, which must be considered before diagnosing pathological erythrocytosis. 1

• Males/post-menopausal females: hemoglobin 15.5 ± 2.0 g/dL, hematocrit 47 ± 6% 1
• Menstruating females: hemoglobin 14.0 ± 2.0 g/dL, hematocrit 41 ± 5% 1
• Gender differences emerge at puberty due to testosterone (stimulates erythropoiesis) and estrogen (suppresses erythropoiesis) effects 1

Critical Diagnostic Pitfalls

• Iron deficiency can coexist with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera, causing microcytic polycythemia with elevated RBC count but reduced hemoglobin 5, 6
• Iron-deficient red cells have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk despite lower hemoglobin 5, 1
• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; serum ferritin, transferrin saturation, and iron levels are required 5
• Hematocrit can falsely increase by 2-4% with prolonged sample storage due to MCV changes, while hemoglobin remains stable; hemoglobin is therefore the more accurate measure 1
• Hyperglycemia falsely elevates MCV and calculated hematocrit but does not affect hemoglobin measurement 1