What is the differential diagnosis for an adult patient with elevated hemoglobin (HGB), hematocrit (HCT), and platelets?

Differential Diagnosis for Elevated Hemoglobin, Hematocrit, and Platelets

The combination of elevated hemoglobin, hematocrit, AND platelets strongly suggests polycythemia vera (PV) as the primary diagnosis, which requires immediate JAK2 mutation testing to confirm. 1, 2, 3

Primary Myeloproliferative Neoplasm

Polycythemia Vera (Most Likely)

• The presence of thrombocytosis (platelets >400 × 10⁹/L) alongside erythrocytosis is characteristic of PV and distinguishes it from secondary polycythemia, as PV causes trilineage myeloproliferation (red cells, white cells, and platelets). 3
• JAK2 mutations are present in >95% of PV cases, with JAK2 V617F being the most common variant. 1, 4, 5
• WHO diagnostic criteria require hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women (or sustained increase ≥2 g/dL from baseline) PLUS JAK2 mutation PLUS one minor criterion (bone marrow hypercellularity, subnormal erythropoietin, or endogenous erythroid colonies). 1, 2
• Associated features include splenomegaly (36%), pruritus (33%), erythromelalgia (5.3%), and transient visual changes (14%). 4
• Thrombotic risk is significantly elevated, with 16% experiencing arterial thrombosis and 7% venous thrombosis at or before diagnosis, including unusual sites like splanchnic veins. 4

Essential Thrombocythemia (Less Likely)

• Characterized by isolated thrombocytosis (platelets ≥450 × 10⁹/L) without significant erythrocytosis. 1
• JAK2 mutations occur in ~55%, CALR mutations in ~25%, and MPL mutations in ~3% of cases. 5
• Requires bone marrow biopsy showing megakaryocytic proliferation and exclusion of PV, prefibrotic myelofibrosis, CML, and MDS. 1

Secondary Causes of Erythrocytosis (With Reactive Thrombocytosis)

Hypoxia-Driven Erythrocytosis

• Cyanotic congenital heart disease with right-to-left shunting causes arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport. 1, 3
• Chronic obstructive pulmonary disease (COPD) produces chronic tissue hypoxia stimulating erythropoietin production. 2
• Obstructive sleep apnea causes nocturnal hypoxemia that drives erythropoietin production. 2
• High-altitude residence causes physiologic erythrocytosis, with hemoglobin increases of 0.2-4.5 g/dL depending on elevation (1000-4500 meters). 2, 3
• Smoking leads to "smoker's polycythemia" due to chronic carbon monoxide exposure causing tissue hypoxia. 2

Hypoxia-Independent Erythrocytosis

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently. 2
• Testosterone therapy (prescribed or unprescribed) causes erythrocytosis and should be considered in young adults. 2
• Erythropoietin therapy directly increases red cell mass. 2

Reactive Thrombocytosis (Accompanying Secondary Erythrocytosis)

• Iron deficiency can cause reactive thrombocytosis while coexisting with erythrocytosis. 1, 2
• Inflammation, infection, or tissue damage can trigger reactive platelet elevation. 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause relative polycythemia due to plasma volume depletion. 2
• This typically does NOT cause true thrombocytosis, helping distinguish it from PV. 1

Rare Genetic Disorders

• High-oxygen-affinity hemoglobin variants cause tissue hypoxia despite normal arterial oxygen saturation. 2
• Erythropoietin receptor mutations cause constitutive activation of erythroid precursors. 2
• Chuvash polycythemia (von Hippel-Lindau gene mutation) causes impaired oxygen sensing. 2

Critical Diagnostic Algorithm

Immediate Laboratory Evaluation

• Complete blood count with differential to assess all three cell lines (erythrocytes, leukocytes, platelets). 2
• JAK2 mutation testing (both exon 14 V617F and exon 12) to distinguish PV from secondary causes. 1, 2, 3
• Serum erythropoietin level: low/normal suggests PV, elevated suggests secondary erythrocytosis. 1, 2
• Iron studies (serum ferritin, transferrin saturation) to exclude iron deficiency masking PV or causing reactive thrombocytosis. 2, 3
• Peripheral blood smear to assess cell morphology and identify abnormalities. 2, 3

Secondary Cause Evaluation (If JAK2 Negative)

• Chest imaging and pulmonary function tests for COPD. 2, 3
• Sleep study for obstructive sleep apnea if nocturnal symptoms present. 2
• Renal/abdominal imaging (ultrasound or CT) to exclude erythropoietin-producing tumors. 2, 3
• Medication review for testosterone, erythropoietin, or diuretics. 2
• Smoking history and carbon monoxide exposure assessment. 2

Bone Marrow Biopsy Indications

• JAK2 mutation positive to confirm PV diagnosis and assess for trilineage myeloproliferation. 1, 2
• Diagnosis remains unclear after initial workup to exclude other myeloid neoplasms. 1, 2

Common Diagnostic Pitfalls

• Overlooking masked PV: A subset of patients have normal hemoglobin/hematocrit due to blood dilution or coincidental blood loss anemia but still have underlying PV with JAK2 mutation. 6
• Failing to test for JAK2 mutations in patients with unusual site thrombosis (portal vein, splanchnic veins) even with normal blood counts. 6
• Missing iron deficiency coexisting with erythrocytosis: High RDW with normal/low MCV suggests this combination, and MCV is unreliable for screening iron deficiency in erythrocytosis. 2
• Using standard PV diagnostic thresholds at high altitude without adjustment for physiologic adaptation. 2
• Confusing reactive thrombocytosis with essential thrombocythemia: Reactive thrombocytosis typically accompanies an identifiable trigger (infection, inflammation, iron deficiency) and lacks clonal markers. 1