Diagnostic Workup for Rouleaux Formation on Peripheral Blood Smear
When rouleaux formation is identified on a peripheral blood smear, a comprehensive evaluation for plasma cell disorders should be performed, as this is the most clinically significant cause requiring prompt intervention. 1
Initial Laboratory Evaluation
- Complete blood count with differential and peripheral blood smear review to assess for additional findings such as circulating plasma cells 1, 2
- Comprehensive chemistry panel including calcium, creatinine, albumin, and liver function tests 1, 3
- Serum protein electrophoresis (SPEP) and immunofixation to identify and characterize monoclonal proteins 1, 3
- Nephelometric quantification of serum immunoglobulins (IgG, IgA, IgM) 3, 1
- Serum free light chain assay to detect excess kappa or lambda light chains 3, 1
- 24-hour urine collection for protein electrophoresis and immunofixation (cannot be replaced by random urine samples) 3, 1
Further Evaluation if Monoclonal Protein Detected
- Bone marrow aspirate and biopsy to assess for clonal plasma cells (>10% clonal plasma cells confirms multiple myeloma in the presence of end-organ damage) 3, 1
- Cytogenetics (metaphase karyotype and FISH) on bone marrow sample 3
- Radiologic skeletal survey, including spine, pelvis, skull, humeri, and femurs 3, 1
- Serum β2-microglobulin and lactate dehydrogenase for prognostication 3
Diagnostic Criteria for Plasma Cell Disorders
- Multiple Myeloma: ≥10% clonal bone marrow plasma cells, presence of monoclonal protein in serum/urine, and evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, bone lesions) 1, 3
- Smoldering Multiple Myeloma: Serum monoclonal protein ≥3 g/dL and/or ≥10% clonal bone marrow plasma cells without end-organ damage 1, 3
- Monoclonal Gammopathy of Undetermined Significance (MGUS): Serum monoclonal protein <3 g/dL, <10% clonal bone marrow plasma cells, and absence of end-organ damage 1, 3
Risk Stratification for MGUS
- Low-risk MGUS: Serum monoclonal protein <15 g/L, IgG type, and normal free light chain ratio - follow with serum protein electrophoresis in 6 months, then every 2-3 years 3
- Intermediate/high-risk MGUS: Serum monoclonal protein >15 g/L, IgA or IgM type, or abnormal free light chain ratio - requires bone marrow examination at baseline and follow-up with serum protein electrophoresis every 6 months, then annually 3
Clinical Pearls and Pitfalls
- Rouleaux formation is a benign in vitro phenomenon where RBCs stack like coins due to increased plasma proteins, but it may indicate serious underlying pathology 4
- Nephelometric quantitation may overestimate monoclonal protein concentration when values are high 3, 1
- Immunofixation should be performed even if there is no measurable protein or peak on electrophoresis 3
- In cases with high clinical suspicion but negative initial workup, consider repeating testing in 3-6 months 3
- Distinguish rouleaux (which disperses when plasma is replaced with saline) from true agglutination (which persists after saline replacement) 4