Diagnostic Approach to Elevated RBC and RDW
The combination of elevated RBC count with elevated RDW should prompt immediate investigation for polycythemia vera with concurrent iron deficiency, as iron deficiency can mask the true severity of polycythemia and delay diagnosis.
Initial Diagnostic Workup
The following tests must be obtained immediately to differentiate between polycythemia vera, secondary polycythemia with iron deficiency, and other causes:
- Complete blood count with differential - Look specifically for elevated white blood cell count, which suggests a myeloproliferative disorder rather than secondary polycythemia 1
- Serum ferritin and transferrin saturation - Ferritin <30 μg/L (or <100 μg/L with inflammation) with transferrin saturation <16-20% confirms iron deficiency 2
- Serum erythropoietin level - Low erythropoietin with elevated RBC strongly suggests polycythemia vera rather than secondary causes 1
- JAK2 mutation testing - Positive JAK2 mutation confirms polycythemia vera diagnosis 1
- Reticulocyte count and peripheral blood smear - Essential to assess red cell morphology and production 2, 3
Understanding the Clinical Pattern
The elevated RDW in this context has critical diagnostic significance:
- RDW becomes abnormal 4+ weeks before MCV changes when iron deficiency develops, making it the earliest marker of iron depletion 4
- In polycythemia vera patients, elevated RDW indicates concurrent iron deficiency, which can mask the true polycythemic state by preventing RBC count from reaching its full potential 1, 5
- The combination of high RBC count with high RDW (>14.0%) distinguishes polycythemia with iron deficiency from thalassemia minor, which typically shows normal or only mildly elevated RDW 2, 6
Differential Diagnosis Algorithm
If Erythropoietin is LOW:
- Suspect polycythemia vera - Proceed with JAK2 mutation testing 1
- Check for splenomegaly and elevated white blood cell/platelet counts 1
- The iron deficiency may be masking higher RBC counts that would appear after iron repletion 1, 6
If Erythropoietin is NORMAL or HIGH:
- Suspect secondary polycythemia with iron deficiency - Investigate hypoxic causes (chronic lung disease, sleep apnea, high altitude, smoking) or renal causes (hypernephroma) 6
- In secondary polycythemia cases given iron supplementation, RBC count remains elevated while MCV normalizes, confirming the diagnosis 6
Critical Diagnostic Pitfall
Do not dismiss polycythemia vera in patients with normal or only moderately elevated RBC counts if iron deficiency is present - menorrhagia, gastrointestinal blood loss, or other sources of iron loss can significantly delay diagnosis by suppressing the RBC count 1. One case report documented a patient where polycythemia vera diagnosis was delayed specifically because menorrhagia-induced iron deficiency masked the true polycythemic state 1.
Management Based on Diagnosis
If Polycythemia Vera is Confirmed:
- Hematology referral is mandatory for myelosuppressive therapy consideration 5
- Correct iron deficiency cautiously - Iron repletion will unmask the full extent of polycythemia and may require adjustment of myelosuppressive therapy 5
- Monitor RDW during treatment, as it transiently increases during the transition from microcytes to normal cells 5
If Secondary Polycythemia with Iron Deficiency:
- Address the underlying cause of polycythemia (treat hypoxia, remove renal tumor, etc.) 6
- Initiate iron supplementation (oral or intravenous) 2, 7
- Investigate gastrointestinal blood loss - All adult men and post-menopausal women require upper and lower endoscopy to exclude malignancy 7
Monitoring Considerations
- RDW will normalize with successful iron repletion in secondary polycythemia, but may remain elevated or increase transiently in polycythemia vera during treatment 5
- Repeat CBC after iron repletion to assess true RBC count without iron limitation 6
- In polycythemia vera, RDW reflects the pathologic hematopoietic status and may be higher during polycythemic periods than during myelofibrotic transformation 5