The incidence of lymphoproliferative disorder is higher in patients with C3d-positive autoimmune hemolytic anemia, according to a new study published in HemaSphere. Therefore, the value of routine bone marrow biopsy is higher in patients who are C3d-positive.

The team of researchers led by Greg Hapgood, MD, PhD, conducted a single-center retrospective study of all patients undergoing routine bone marrow biopsy to screen for lymphoproliferative disorder and found that autoimmune hemolytic anemia was secondary to lymphoproliferative disorder in 22% of cases.

Of those, only 1.1% was warm antibody hemolytic anemia while 8% was cold agglutinin disease (CAD) and 21.8% had both warm (IgG) and cold (C3d) antibodies.

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“Our data provide an evidence base for the use of [bone marrow] biopsy in this context and to support guideline recommendations,” the researchers wrote. They added that their findings provide the first systematic assessment of the role of routine bone marrow biopsy in autoimmune hemolytic anemia to detect lymphoproliferative disorder.

Read more about CAD overview

These findings support a recent international guideline, which recommends a bone marrow biopsy and flow cytometry in patients with CAD and those with warm and mixed autoimmune hemolytic anemia who relapse after steroid therapy.

Lymphoproliferative disorder is the name given to a group of diseases characterized by the excess production of lymphocytes. It accounts for 15% to 25% of secondary cases of autoimmune hemolytic anemia in which the body mistakenly produces antibodies that attack its own red blood cells.

There are 2 main types of autoimmune hemolytic anemia: warm antibody hemolytic anemia where the body produces IgG antibodies that attack red blood cells at body temperature, and CAD where it produces C3d antibodies that attack them at cold temperatures.


Campbell A, Podbury B, Yue M, Mollee P, Bird R, Hapgood G. The role of a routine bone marrow biopsy in autoimmune hemolytic anemia for the detection of an underlying lymphoproliferative disorder. Hemasphere. 2021;6(1):e674. doi:10.1097/HS9.0000000000000674