What indicates the presence of nucleated Red Blood Cells (RBCs) in a Complete Blood Count (CBC)?

What Indicates the Presence of Nucleated RBCs in CBC

Nucleated red blood cells (NRBCs) in peripheral blood are detected either through automated hematology analyzer flagging or by direct visualization on peripheral blood smear examination, and their presence in adults always represents a pathologic finding requiring further investigation. 1, 2

Detection Methods

Automated Hematology Analyzers

• Modern automated analyzers (such as Sysmex XE-2100 and XN-9000) can detect and quantify NRBCs as part of routine CBC processing 2, 3, 4
• The analyzer flags the presence of NRBCs, which triggers either automated quantification or manual peripheral smear review 5, 3
• Automated detection has made NRBC screening more reliable and routine compared to manual methods alone 3, 4

Peripheral Blood Smear Examination

• Direct microscopic visualization on peripheral blood smear remains essential for confirming NRBC presence 6
• NRBCs appear as red cells that retain their nuclei, indicating premature release from bone marrow 1
• The NCCN guidelines require examination of peripheral smear as part of initial evaluation when hematologic disorders are suspected 6

Clinical Significance and Indications for NRBC Presence

Hematologic Malignancies

• Myelodysplastic syndromes (MDS): NRBCs on peripheral blood smear are listed as a selection criterion for bone marrow biopsy in MDS evaluation 6
• The European Society for Medical Oncology identifies presence of nucleated erythroid precursors as a sign of dysplasia in MDS 6
• NRBCs are found in nearly all onco-hematological diseases at diagnosis, though not in every individual patient 3

Bone Marrow Stress or Damage

• NRBC appearance results from either increased erythropoiesis or bone marrow micro-architectural damage caused by inflammation and/or decreased tissue oxygenation 1
• Conditions causing ineffective erythropoiesis, stress erythropoiesis, or primary hematopoietic alterations lead to NRBC release 3
• The blood-marrow barrier is disrupted, allowing these normally retained cells to enter circulation 1

Critical Illness and Prognostic Marker

• NRBCs appear in 7.5% of hospitalized patients overall, with highest incidence (20%) in intensive care unit patients 4
• The incidence of NRBCs in ICU-admitted patients reaches 62.5%, with significantly higher mortality (30%) compared to NRBC-negative patients (14%) 2
• NRBCs are detected on average 21 days (median 13 days) before death, serving as an early mortality indicator 4
• A cutoff of ≥2.5 NRBCs shows 91% sensitivity for predicting mortality in critically ill patients 2

When to Suspect and Investigate NRBCs

Specific Clinical Scenarios Requiring NRBC Evaluation

• Pancytopenia with low reticulocyte count: Bone marrow evaluation is mandatory, including peripheral smear examination for NRBCs 7
• Small cell lung cancer staging: Bone marrow biopsy is indicated in select patients with nucleated RBCs on peripheral blood smear, neutropenia, or thrombocytopenia 6
• Suspected MDS: Required workup includes CBC with differential and peripheral smear examination 6
• Critical illness: Routine CBC processing with automated analyzers will flag NRBC presence 2, 4

Important Caveats

• Neonatal period exception: NRBCs are normally present in neonates and during pregnancy; their presence is only pathologic outside these contexts 5
• False WBC elevation: NRBCs falsely elevate automated white blood cell counts, requiring manual correction when present above certain thresholds (commonly 5 or 10 NRBCs per 100 WBCs) 5
• Not disease-specific: While NRBCs indicate serious pathology, they do not point to one particular cause of death or specific diagnosis 1

Diagnostic Workup When NRBCs Are Detected

Immediate Laboratory Assessment

• Complete blood count with differential and reticulocyte count 7
• Comprehensive metabolic panel, LDH, and indirect bilirubin 7
• Vitamin B12, folate, ferritin, and transferrin saturation 7

Bone Marrow Evaluation

• Bone marrow aspiration with cytomorphology, trephine biopsy, cytogenetics, and iron staining are mandatory when NRBCs are present with cytopenias 6, 7
• Flow cytometry for PNH markers and possible lymphoproliferative disorders 7
• Consider next-generation sequencing if morphology and cytogenetics are inconclusive 7

Risk Stratification

• Quantify NRBC concentration, as mortality increases with increasing NRBC levels 2, 4
• NRBC presence shows 57.9% sensitivity and 93.9% specificity for in-hospital mortality 4
• Monitor NRBC trends during treatment, as they typically disappear at hematological remission 3