What are the medical explanations, other than polycythemia vera (PV), for elevated red blood cell count, hematocrit, and hemoglobin levels in a patient?

Differential Diagnosis of Elevated Red Blood Cells, Hematocrit, and Hemoglobin

Secondary causes of erythrocytosis—particularly chronic hypoxia from conditions like obstructive sleep apnea, chronic lung disease, high altitude exposure, and renal disorders—are far more common than polycythemia vera and must be systematically excluded before considering a primary myeloproliferative disorder. 1

Primary Categories of Non-PV Erythrocytosis

Secondary Polycythemia from Hypoxia (Most Common)

• Chronic pulmonary disease causes compensatory erythrocytosis due to chronic hypoxemia, with elevated or high-normal erythropoietin levels 1, 2
• Obstructive sleep apnea produces chronic intermittent hypoxia leading to compensatory erythrocytosis, particularly in obese patients 3
• High altitude exposure triggers physiologic erythrocytosis as an adaptive response to reduced atmospheric oxygen 2
• Heavy smoking causes functional hypoxemia through carboxyhemoglobin formation and chronic lung damage 1
• Cyanotic heart disease with right-to-left shunting produces systemic hypoxemia 2

Renal Causes

• Renal cell carcinoma and other EPO-secreting tumors produce autonomous erythropoietin secretion 1, 2
• Polycystic kidney disease can cause inappropriate EPO production 1
• Renal artery stenosis triggers increased EPO release due to renal hypoxia 2
• Post-renal transplant erythrocytosis occurs in some transplant recipients 2

Congenital Erythrocytosis

• Erythropoietin receptor gene mutations cause primary familial congenital polycythemia with hypersensitivity to EPO 2
• High-oxygen-affinity hemoglobin variants prevent normal oxygen release to tissues, triggering compensatory erythrocytosis 2
• 2,3-bisphosphoglycerate mutase deficiency alters oxygen-hemoglobin dissociation 2
• Disturbances of renal oxygen sensing from mutations in VHL, PHD2, or HIF2A genes 2

Other Acquired Causes

• Testosterone therapy or anabolic steroid use stimulates erythropoiesis 2
• Erythropoietin doping in athletes creates iatrogenic erythrocytosis 2
• Post-splenectomy or functional hyposplenism can elevate red cell parameters 4
• Hepatocellular carcinoma and other EPO-producing tumors 1

Critical Diagnostic Distinctions

Key Laboratory Differences

• Erythropoietin levels are elevated or high-normal in secondary polycythemia, whereas they are suppressed (below normal range) in PV 5, 3
• JAK2 V617F mutation is present in >95% of PV cases but absent in secondary causes 3, 2
• Mild elevations (hemoglobin <18.5 g/dL in men) are more typical of secondary causes than PV, which usually presents with higher values 3

Bone Marrow Findings

• PV shows panmyelosis with trilineage proliferation (erythroid, megakaryocytic, and granulocytic), whereas secondary causes show isolated erythroid hyperplasia 5, 3
• Bone marrow biopsy is not typically needed for secondary polycythemia if the underlying cause is identified 1

Diagnostic Algorithm

Step 1: Exclude Relative Polycythemia

• Dehydration, diuretic use, or plasma volume contraction can cause spuriously elevated hematocrit without true increase in red cell mass 1
• Measure red cell mass if uncertainty exists between true and relative polycythemia 1

Step 2: Identify Secondary Causes

• Obtain arterial blood gas or pulse oximetry to document hypoxemia 3
• Order polysomnography if obesity, fatigue, or snoring suggest sleep apnea 3
• Measure serum erythropoietin level—elevated/normal suggests secondary cause, suppressed suggests PV 5, 3
• Obtain chest imaging to evaluate for chronic lung disease 1
• Perform renal imaging to exclude renal masses or polycystic disease 1

Step 3: Consider Congenital Causes if Secondary Excluded

• Hemoglobin electrophoresis to detect high-oxygen-affinity variants 2
• Family history of erythrocytosis suggests congenital etiology 2
• EPO receptor gene testing if familial pattern exists 2

Step 4: Evaluate for PV Only After Exclusions

• JAK2 V617F mutation testing is required for PV diagnosis 5, 2
• Bone marrow biopsy showing MPD-consistent histology supports PV 5
• Presence of splenomegaly favors PV over secondary causes 1

Common Pitfalls to Avoid

• Do not assume adequate sleep rules out sleep apnea—patients with OSA are unaware of sleep fragmentation and nocturnal hypoxemia 3
• Do not rush to diagnose PV without excluding secondary causes, especially in obese patients with fatigue or smokers with lung disease 3, 1
• Iron deficiency can mask PV by lowering hemoglobin; formal PV diagnosis requires meeting criteria after iron replacement 5
• Normal hemoglobin does not exclude PV in rare "masked PV" cases with blood dilution or coincidental blood loss, particularly if presenting with thrombosis 6, 7
• Pre-analytical variables affect measurements—time between collection and analysis, and anticoagulant ratios in high hematocrit samples can distort results 4