What are Nucleated Red Blood Cells (NRBCs)?

What are Nucleated Red Blood Cells (NRBCs)?

Nucleated red blood cells (NRBCs) are immature erythrocyte precursors that normally reside only in the bone marrow as part of erythropoiesis and should not be present in the peripheral blood of healthy adults beyond the neonatal period. 1

Normal Physiology and Development

• NRBCs are premature red blood cell precursors that undergo differentiation in the bone marrow before losing their nuclei and entering circulation as mature erythrocytes 1, 2
• After differentiation, blood cells must cross the blood-marrow barrier to enter the bloodstream, and NRBCs cannot easily distort to escape this barrier under normal conditions 2
• NRBCs can be found circulating normally in fetuses and neonates but are absent in healthy adults 1
• Beyond the neonatal period, the presence of NRBCs in peripheral blood is always pathologic 2

Clinical Significance and Pathophysiology

The appearance of NRBCs in adult peripheral blood indicates either extremely high demand for red blood cell production with premature release, or damage to the bone marrow microarchitecture. 3, 2

Mechanisms of NRBC Release

• Increased erythropoiesis drives premature release of immature cells into circulation 2
• Bone marrow micro-architectural damage caused by inflammation and/or decreased tissue oxygenation disrupts the normal barrier function 2
• Ineffective erythropoiesis or stress erythropoiesis can result in NRBC appearance 4

Associated Conditions

NRBCs appear in numerous pathologic states including:

• Hematologic disorders: anemia, myelofibrosis, thalassemia, bone marrow malignancies (myelomas, leukemias, lymphomas), and hemolysis 1, 3, 4
• Critical illness: sepsis, trauma, ARDS, acute pancreatitis, severe cardiovascular disease 1, 3
• Hypoxemia and tissue hypoxia: prolonged hypoxemia, cardiac failure 3, 2
• Neonatal conditions: neonatal hypoxia, asphyxia 1
• Other conditions: miliary tuberculosis, decompensated liver cirrhosis 3, 2

Prognostic Implications

The presence of NRBCs is an independent predictor of poor outcome and higher mortality, with mortality increasing proportionally to NRBC concentration. 3, 2

Mortality Data

• In ICU-admitted patients, the incidence of NRBCs is 62.5%, with overall mortality of 30% in NRBC-positive patients compared to 14% in NRBC-negative patients 3
• A cutoff of ≥2.50 NRBCs shows high risk of mortality with 91% sensitivity 3
• NRBCs typically appear 1-3 days before death in critically ill patients, making them an early warning sign 2
• The highest mortality rates occur in patients with malignancy (100%) and sepsis (58.8%) 3

Clinical Indications for NRBC Testing

Specific clinical scenarios warrant NRBC evaluation:

• In small cell lung cancer staging: unilateral bone marrow aspirates and biopsies may be indicated in select patients with NRBCs on peripheral blood smear, neutropenia, or thrombocytopenia when no other evidence of metastatic disease exists 5
• Bone marrow involvement as the only site of extensive-stage disease occurs in fewer than 5% of patients with small cell lung cancer 5
• In critically ill ICU patients: screening for NRBCs aids in early identification of patients at high risk and supports decisions regarding ongoing intensive care 2

Laboratory Detection and Reference Intervals

• Modern automated hematology analyzers (e.g., Sysmex XN-9000, XE2100) can detect NRBCs at very low levels compared to traditional manual morphometric methods 3, 4, 6
• Updated reference interval: the upper limit of normal has been revised from 0.01 × 10⁶/μL to 0.10 × 10⁶/μL based on analysis of 66,498 healthy nonhospitalized individuals 6
• Values >0.10 × 10⁶/μL should be considered pathologic and warrant clinical investigation 6
• NRBC count is a cost-effective laboratory test that remains underutilized in everyday clinical practice 1

Clinical Pitfalls

• Do not dismiss low-level NRBC elevations in critically ill patients, as even modest increases correlate with worse outcomes 3, 2
• NRBCs are frequently found during chemotherapy and absent at remission in hematologic malignancies, so timing of testing matters 4
• The appearance of NRBCs is not related to one particular cause of death, but rather reflects overall disease severity and physiologic stress 2