What is the next step in managing a patient with persistent erythrocytosis (elevated Red Blood Cell (RBC) count), no respiratory symptoms, and a history of diabetes mellitus, before considering referral to a hematologist?

Workup for Persistent Erythrocytosis in a Diabetic Patient

Before referring to hematology, measure serum erythropoietin (EPO) level, obtain arterial blood gas (ABG) or pulse oximetry to assess oxygenation, check renal function with creatinine and estimated GFR, and obtain a complete blood count with peripheral smear to evaluate all cell lines.

Essential Laboratory Evaluation

The next diagnostic steps should systematically rule out secondary causes of erythrocytosis before hematology referral:

Complete Blood Count Analysis

• Obtain a complete blood count (CBC) with white blood cells, hemoglobin, and platelets to assess bone marrow function 1
• Abnormalities in two or more cell lines warrant immediate hematology consultation, as this suggests a primary bone marrow disorder rather than isolated erythrocytosis 1
• Request a peripheral blood smear to evaluate red blood cell morphology and rule out abnormal cell populations 1

Oxygenation Assessment

• Measure arterial oxygen saturation via ABG or reliable pulse oximetry to exclude occult hypoxemia as a driver of compensatory erythrocytosis 1
• Even without respiratory symptoms or reported snoring, occult hypoxemia from undiagnosed sleep apnea, pulmonary disease, or right-to-left shunting can stimulate erythropoietin production 1

Serum Erythropoietin Level

• Measure serum EPO level to differentiate between EPO-driven (secondary) and EPO-independent (primary) erythrocytosis 1
• Elevated or inappropriately normal EPO suggests secondary erythrocytosis from hypoxemia, renal pathology, or EPO-secreting tumors
• Low or low-normal EPO points toward primary polycythemia vera, warranting hematology referral

Renal Function Evaluation

• Check serum creatinine and calculate estimated glomerular filtration rate (eGFR) 1
• Diabetic nephropathy can paradoxically cause either anemia (more common) or erythrocytosis through altered EPO regulation 1
• Obtain urinalysis to screen for proteinuria or hematuria that might indicate renal parenchymal disease 1

Diabetes-Specific Considerations

Glycemic Control Assessment

• Review HbA1c levels, as poor glycemic control in diabetes affects red blood cell rheology and can influence hematocrit measurements 2, 3
• Diabetes causes hemorheological abnormalities including increased blood viscosity and altered RBC deformability, which may complicate interpretation of elevated RBC counts 2, 3

Microvascular Complications

• Screen for diabetic microvascular complications (retinopathy, nephropathy), as these share pathophysiologic mechanisms with altered erythropoiesis 4
• Erythrocyte membrane abnormalities in diabetes correlate with microvascular disease and may represent systemic endothelial dysfunction 4

Additional Targeted Testing

Iron Studies

• Obtain serum ferritin and transferrin saturation to assess iron status 1
• Iron deficiency can mask underlying erythrocytosis; conversely, iron overload may contribute to secondary erythrocytosis 1

Exclude Secondary Causes

• Consider carboxyhemoglobin level if there is any smoking history (even remote or secondhand exposure) 1
• Evaluate for medications that might affect RBC production, including testosterone supplementation or other androgens
• Consider renal imaging (ultrasound) if renal function is abnormal or EPO is elevated, to exclude renal cysts or tumors that secrete EPO 1

Common Pitfalls to Avoid

• Do not assume diabetes automatically causes anemia—while diabetic patients have higher anemia prevalence at all stages of kidney function 1, erythrocytosis requires full evaluation
• Do not overlook occult hypoxemia in the absence of respiratory symptoms; obtain objective oxygen saturation measurement 1
• Avoid premature hematology referral without completing basic secondary cause workup, as most erythrocytosis is secondary rather than primary 1
• Remember that hematocrit can be falsely elevated by dehydration or falsely normal in the setting of plasma volume expansion 1

When to Refer to Hematology

Refer to hematology if:

• EPO level is low or inappropriately normal for the degree of erythrocytosis
• Multiple cell lines are abnormal on CBC 1
• No secondary cause is identified after the above workup
• Hemoglobin exceeds 20 g/dL or hematocrit exceeds 65% with symptoms of hyperviscosity 1
• Peripheral smear shows abnormal morphology suggesting myeloproliferative disorder