Marked Monocytic Erythrophagocytosis in a Patient With Cold Agglutinin Disease

Abbreviations

DAT

direct antiglobulin test

IFE

immunofixation electrophoresis

PCR

polymerase chain reaction

1. Case

An 82‐year‐old woman with a history of cold‐agglutinin hemolytic anemia was admitted with nausea and diarrhea due to infectious gastroenteritis. Her course was complicated by pneumonia. Blood culture and respiratory virus PCR panel were negative. No lymphadenopathy or splenomegaly was identified. Laboratory studies revealed hemoglobin 10.2 g/dL, bilirubin 5.9 mg/dL, LDH 889 U/L, and haptoglobin 2 mg/dL. DAT was positive for IgG (very weak+) and C3 (weak 1+), cold‐agglutinin test showed a high‐titer to adult red cells (1:10,240), and cold‐autoantibody with “I” specificity. Serology for anti‐Mycoplasma‐pneumoniae IgM was negative. Peripheral blood smear demonstrated red cell agglutination (Figure 1A; 20x objective, Wright–Giemsa‐stain), monocytosis (40%) with striking erythrophagocytosis by monocytes (Figure 1A, insets; 100x objective), and platelet clumping. Flow cytometry revealed a small kappa‐restricted B‐cell population (0.4%), which was CD5(partial dim+), CD10(‐), CD19(+), CD20(+), CD22(+), CD23(−), CD103(−), CD25(−)CD38(+) (Figure 1B–D). Monocytes showed normal immunophenotype. IFE detected a faint IgM‐kappa monoclonal gammopathy (Figure 1E, asterisks). The patient declined any additional evaluation or intervention and was discharged to hospice care.

FIGURE 1.

Cold agglutinin disease with prominent monocytic erythrophagocytosis. (A) Peripheral blood smear demonstrating marked red blood cell agglutination consistent with cold agglutinin‐mediated hemolysis (Wright–Giemsa stain, 20 × objective). Insets show representative monocytes from the same peripheral blood smear exhibiting erythrophagocytosis (Wright–Giemsa stain, 100 × objective). Platelet clumping is also present. (B–D) Peripheral blood flow cytometry identified a small kappa light chain‐restricted B‐cell population (0.4% of total events) with the following immunophenotype: CD5 partial/dim+, CD10−, CD19+, CD20+. (E) Serum immunofixation electrophoresis demonstrating a faint IgM‐kappa monoclonal gammopathy. The combination of a high‐titer cold agglutinin with anti‐I specificity, complement‐mediated hemolysis, a small clonal B‐cell population, and an IgM‐kappa paraprotein supports the diagnosis of cold agglutinin disease.

Cold agglutinin‐mediated autoimmune hemolytic anemia (AIHA) may occur as a primary clonal lymphoproliferative disorder, termed cold agglutinin disease (CAD), or as a secondary condition, referred to as cold agglutinin syndrome (CAS), which can be associated with infections, overt lymphoid neoplasms, autoimmune diseases, and other inflammatory disorders [1]. In the present case, the patient had a prior diagnosis of CAD based on chronic cold agglutinin‐mediated hemolysis, a high‐titer cold agglutinin (1:10,240) with anti‐I specificity, an IgM‐kappa monoclonal gammopathy, and a small kappa‐restricted B‐cell population identified by peripheral blood flow cytometry. Although a bone marrow examination would have been helpful to further characterize the underlying clonal disorder, this could not be further characterized because the patient declined additional diagnostic evaluation.

The direct antiglobulin test was weakly positive for both IgG and C3. While CAD is classically associated with C3 positivity alone, weak IgG reactivity has occasionally been reported and may reflect low‐level warm autoantibody reactivity or nonspecific immunoglobulin binding [2]. The high‐titer cold agglutinin with anti‐I specificity and the clinical presentation were considered most consistent with cold agglutinin‐mediated hemolysis. An eluate was not performed. Paroxysmal cold hemoglobinuria was considered in the differential diagnosis of erythrophagocytosis; however, the presence of a high‐titer cold agglutinin with anti‐I specificity argued against this diagnosis.

Erythrophagocytosis is an uncommon morphologic finding that should prompt consideration of viral and Mycoplasma infections, hematologic malignancies (including monocytic leukemias), paroxysmal cold hemoglobinuria, and AIHAs [3, 4, 5, 6]. In contrast to paroxysmal cold hemoglobinuria, where erythrophagocytosis is typically mediated by neutrophils, the phagocytic cells in this case were predominantly monocytes. Although erythrophagocytosis has been previously described in association with cold‐reactive antibodies, the present case is notable for the particularly prominent degree of erythrophagocytosis and the predominance of monocytes, rather than neutrophils, as the phagocytic cells.

Author Contributions

Tran B. Nguyen: writing – review and editing. Eric D. Carlsen: writing – review and editing. Luis F. Carrillo: writing – review and editing, figure.

Funding

The authors have nothing to report.

Ethics Statement

The information presented in this manuscript is deidentified, and there is minimal risk to the patient's privacy or confidentiality. No material from other sources is included in this manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Nguyen T. B., Carlsen E. D., and Carrillo L. F., “Marked Monocytic Erythrophagocytosis in a Patient With Cold Agglutinin Disease.” eJHaem 7, no. 5 (2026): e70439. 10.1002/jha2.70439

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.