Is it normal to have normal to high Red Blood Cell (RBC) count, Hematocrit, and Hemoglobin levels with low Erythropoietin (EPO), Ferritin, and Transferrin Saturation (TSAT)?

Is This Laboratory Pattern Normal?

No, this laboratory pattern is not normal and suggests either functional iron deficiency, an inflammatory iron block, or a rare genetic disorder of iron metabolism. The combination of normal-to-high hemoglobin parameters with low EPO, low ferritin (19 ng/mL), and low TSAT (19%) represents a discordant pattern that requires investigation 1.

Understanding the Discordance

Your ferritin of 19 ng/mL and TSAT of 19% both indicate iron deficiency in otherwise healthy individuals (absolute iron deficiency is defined as ferritin <12 ng/mL and TSAT <16% in healthy subjects, or ferritin <100 ng/mL and TSAT <20% in CKD patients) 1. However, the presence of normal-to-high RBC indices despite these low iron parameters is paradoxical and warrants explanation.

Key Diagnostic Considerations

The low EPO level (3) is particularly concerning because normally, low iron stores should trigger increased EPO production to stimulate erythropoiesis 1. This suppressed EPO suggests either:

• Polycythemia or relative erythrocytosis - The body is appropriately suppressing EPO because hemoglobin is already adequate or elevated, but iron stores are being depleted to maintain this 1
• Inflammatory iron block - Inflammation causes ferritin elevation (as an acute phase reactant) and TSAT depression, though your ferritin is actually low, making this less likely 1
• Genetic disorder of iron metabolism - Rare conditions like iron-refractory iron deficiency anemia (IRIDA) present with low TSAT and low-to-normal ferritin despite microcytic anemia 1

Immediate Diagnostic Workup Required

Obtain the following tests to clarify the clinical picture:

• Complete blood count with MCV - Determine if RBCs are microcytic, normocytic, or macrocytic 1, 2
• Reticulocyte count and reticulocyte hemoglobin content (CHr/RET-He) - CHr <28-32.5 pg indicates functional iron deficiency and is more sensitive than TSAT or ferritin in detecting iron-restricted erythropoiesis 3, 4
• Soluble transferrin receptor (sTfR) - Helps distinguish true iron deficiency from inflammatory block 5
• High-sensitivity CRP and inflammatory markers - Rule out inflammation masking true iron status 1, 6
• Serial ferritin measurements - A single low ferritin can be misleading; trending is essential 5

Investigate for occult blood loss - gastrointestinal bleeding, menstrual losses, or other sources that could explain iron depletion despite adequate hemoglobin 5, 2.

Critical Pitfalls to Avoid

Do not assume normal hemoglobin excludes iron deficiency. Standard CBC measures (hemoglobin, hematocrit, RBC count) decrease only when severe iron depletion is present and can be misleading 2. Iron-depleted individuals can maintain normal hemoglobin temporarily while depleting stores, then rapidly develop iron deficiency anemia 2.

Do not empirically supplement with iron without confirming true deficiency. If this represents a condition like thalassemia trait or polycythemia, iron supplementation could lead to dangerous iron overload 5. TSAT should not be chronically maintained ≥50% and ferritin should not exceed 800 ng/mL 5.

Ferritin is an acute phase reactant - levels can be falsely elevated by inflammation or falsely reassuring when actually depleted 1, 5. Your ferritin of 19 ng/mL is genuinely low and not masked by inflammation.

Specific Conditions to Consider

If MCV is low (microcytic):

• IRIDA (TMPRSS6 mutations) - Presents with microcytic anemia, remarkably low TSAT, low-to-normal ferritin, and failure to respond to oral iron 1
• Thalassemia trait - Can have normal-to-high RBC count with low MCV, and paradoxical iron metabolism where reticulocyte hemoglobin content is unreliable 5
• Genetic sideroblastic anemias - Present with microcytic anemia and variable iron parameters 1

If MCV is normal or high:

• Polycythemia vera or secondary polycythemia - Appropriately suppressed EPO with iron depletion from increased RBC mass 1
• Recent blood loss with compensated erythropoiesis - Hemoglobin maintained but iron stores depleted 2

Management Algorithm

1. Verify the diagnosis - Repeat CBC, ferritin, TSAT, and add CHr, sTfR, and inflammatory markers 5, 2

2. If CHr <28 pg and sTfR elevated - Confirms functional iron deficiency; investigate blood loss and consider trial of oral iron supplementation with close monitoring 4, 5

3. If inflammatory markers elevated - Distinguish functional iron deficiency from inflammatory block by giving weekly IV iron (50-125 mg) for 8-10 doses; if no erythropoietic response occurs, inflammatory block is likely 1

4. If genetic disorder suspected (family history, refractory to iron, unusual pattern) - Refer to hematology for genetic testing 1

5. Monitor closely - Recheck CBC, ferritin, TSAT 4-8 weeks after any intervention to avoid overshoot into iron overload 5

The low EPO with adequate hemoglobin suggests your body is not signaling for more RBC production, yet iron stores are depleted - this discordance mandates investigation before any treatment 1.