Impossible MCHC in a Patient with Acrocyanosis
A 71-year-old woman presents in winter with fatigue, painful blue fingertips, and mottled earlobes. A CBC is drawn into EDTA and transported at room temperature; it is run 3 hours later. Results: RBC 2.10 x 10^12/L, hemoglobin 8.9 g/dL, hematocrit 24.0%, MCV 114 fL, MCHC 37.1 g/dL, RDW 18.6%, WBC 8.2 x 10^9/L, platelets 220 x 10^9/L. The analyzer flags 'RBC agglutination?'. The Wright-stained smear made from the tube at room temperature shows large irregular clumps of red cells with spaces between them. The clinician has already been told by the covering provider that the patient has macrocytic anemia, possibly B12 deficiency, and a Schilling test workup is being arranged.
1. Which result identifies the problem, and what is the mechanism?
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The MCHC is the giveaway. An MCHC above roughly 36 g/dL is physiologically implausible; 37.1 g/dL here is computed from a hemoglobin of 8.9 g/dL and a hematocrit of 24%.
Mechanism - cold agglutinin interference. An IgM cold agglutinin clumps red cells at room temperature. The impedance/optical analyzer counts each clump as one large particle, so:
- RBC count falls falsely (2.10 x 10^12/L),
- MCV rises falsely (114 fL, an artifact of clump size),
- Hematocrit falls falsely, because modern analyzers calculate it as RBC x MCV rather than spinning it,
- Hemoglobin is relatively preserved, because it is measured spectrophotometrically after red cell lysis,
- so MCHC = Hgb / Hct rises artifactually - the classic signature.
The smear confirms it: irregular clumps with clear spaces, not true rouleaux and not macrocytes. The 'macrocytic anemia' is an artifact, and a B12 workup based on it is premature. True anemia is likely present but its severity is overstated.
2. How do you obtain accurate results on this patient, and what do you report?
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Warm the specimen. Incubate the EDTA tube at 37 °C for 15–30 minutes, mix gently, and rerun immediately on the analyzer (prewarmed diluent if available). If the analyzer results normalize, report those values.
If agglutination persists:
- Perform the saline replacement method: centrifuge the warmed sample, remove the plasma, replace it with an equal volume of warmed isotonic saline, resuspend, and repeat - this removes the IgM and yields a true RBC count, MCV, and MCHC.
- Alternatively, perform a manual microhematocrit (spun) and manual hemoglobin (Drabkin) to obtain values independent of the impedance count.
- Prepare and examine the film at 37 °C to avoid re-agglutination.
Reporting. Issue corrected results with a comment that the initial values were affected by cold agglutination, and state the method used. Add a note that future specimens should be collected in a prewarmed tube and transported at 37 °C. Inform the clinician directly so that the pending B12 evaluation is paused or reinterpreted - acting on the spurious macrocytosis could lead to unnecessary and expensive testing.
3. What follow-up testing and clinical communication does this finding prompt?
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Serologic and etiologic follow-up:
- Cold agglutinin titer performed at 4 °C and at 37 °C; a high thermal amplitude (reacting near 30–37 °C) correlates with clinical hemolysis.
- DAT - in cold agglutinin disease the DAT is typically positive for complement (C3d) only, with IgG negative.
- Hemolysis markers: reticulocyte count, LDH, haptoglobin, bilirubin.
- Search for an underlying cause: Mycoplasma pneumoniae, Epstein-Barr virus, and, in an older adult with chronic disease, a clonal lymphoproliferative disorder (serum protein electrophoresis, immunofixation, flow cytometry for a monoclonal B-cell population).
Communication points for the clinician:
- The reported indices were artifacts; the MCHC and MCV should not be used to drive a macrocytic anemia workup.
- The patient needs evaluation for cold agglutinin disease, and the acrocyanosis is consistent with it.
- Any future CBC should use prewarmed collection and transport, and the order should carry a note so the phlebotomy team and the analyzer operator both know.
- Warn that other room-temperature-dependent results (e.g., some HbA1c methods, potassium if the sample is old) may also be unreliable in this patient.