Sigbjørn Berentsen, MD, PhD, is a consultant hematologist and senior researcher in the Department of Research and Innovation at Haugesund Hospital in Norway. He has authored a number of studies on autoimmune hemolytic anemia (AIHA), and its cold agglutinin disease (CAD) subtype. He is a respected expert on the subject in a field in which there aren’t many.
Dr. Berentsen authored a study titled “How I treat cold agglutinin disease,” which is published in the journal Blood as part of its “How I Treat” series. In the study, he described 3 case studies; in this article, we will examine 1 of them.
A Complicated Disease Course
A woman with a 20-year history of CAD participated in a clinical trial at 68 years of age. Upon her first hospital presentation, these were the findings:
- Hemoglobin: 9.4 g/dL
- Lactate dehydrogenase (LDH): 375 U/L
- Total bilirubin: 39 μmol/L
- Haptoglobin was not detectable, and reticulocyte count was not recorded
- Direct antiglobulin test (DAT): positive for C3d and negative for IgG
- Cold agglutinin (CA) titer: 16384 at 4°C
Some years after diagnosis, the patient had monoclonal IgMκ with a total IgM of 6.2 g/L. A bone marrow biopsy showed 20% lymphoid infiltration, which is interpreted as immunocytoma, according to the Kiel classification. She continued to receive prednisolone without further complications until her readmission to the hematology department.
A fuller picture of her medical history indicated that she received prednisolone and oral cyclophosphamide for more than 2 years each, despite having no effect on the patient.
Read more about CAD etiology
The patient then underwent splenectomy, but hemolytic anemia remained. She then received rituximab as part of a clinical trial. It was the first drug that elicited a meaningful clinical response, which lasted for approximately a year. She then received a second series of rituximab infusions, after which a new and short-lived remission followed.
During this patient’s disease course, she experienced both pneumonia and acute cholecystitis; a marked drop in hemoglobin levels occurred following each disease. After living for 24 years with CAD, the patient died due to a stroke.
Here we discuss the thought processes underlying some of the clinical decisions made by Dr. Berentsen. With regards to a proper AIHA diagnostic workup, he emphasized the importance of a targeted history and clinical examination. A diagnosis of hemolytic anemia can be made based on hemoglobin levels and other markers of hemolysis.
A monospecific DAT should be performed to confirm autoimmune pathogenesis and to detect complement activation.
“The typical DAT pattern in CAD is a strongly positive test for C3 (usually C3d) only, but in up to 20% of patients, DAT is weakly positive for IgG as well,” Dr. Berentsen wrote. “Because DAT can be positive for C3 only, even in IgM-mediated warm AIHA, CA titration is mandatory for diagnosis.”
Read more about CAD diagnosis
In another study on autoimmune hemolytic anemia, Michalak et al stressed the importance of a peripheral blood smear as part of the diagnostic workup.
“In AIHA, as in the course of other hemolytic anemias, normocytic anemia with spherocytes is found in the peripheral blood smear,” they wrote. “Reticulocytosis (although reticulocytopenia sometimes occurs) is a typical finding in hemolytic anemia but not a specific marker and indicates an active and accelerated, compensatory production of erythrocytes in the bone marrow in response to hemolysis.”
Once a diagnosis of CAD is made, physicians must then decide whether to treat the condition. Dr. Berentsen wrote, “Patients with mild anemia or compensated hemolysis and no clinical symptoms have not been shown to benefit from treatment.” However, he cautioned that the standard conservative attitude towards drug therapy may have stemmed from the poor efficacy of older therapies. Michalak et al agree on this point; they wrote, “Treatment of mild CAD is not recommended, especially for patients when Hb is >10 g/dL.”
However, there is 1 therapy we should offer to all CAD patients: thermal protection. “All patients, including those for whom pharmacologic treatment is not indicated, should be counseled on thermal protection,” Dr. Berentsen wrote. Michalak et al concur; they wrote, “In CAD patients, thermal protection of distal parts of the body against cooling is advised.”
Currently, the first-line therapy for treating severe CAD is rituximab (hence the improvement of the patient in the case study upon receiving the medication). Alternatively, a combination therapy of rituximab and bendamustine recorded a response of 71%, including a 40% complete response rate with tolerable toxicity in fit patients. Eculizumab has also shown promise in recent clinical studies; a study demonstrated that it decreased hemolysis severity and the need for blood transfusions in patients with CAD.
The 1 medication that Berentsen advised against using is corticosteroids. This is because the incidence of adverse events is significant in patients with unspecified AIHA (although its incidence among CAD patients remains unknown). Splenectomy should generally be avoided because the extravascular hemolysis predominantly takes place in the liver. In severe symptomatic anemia, transfusion of red blood cells using warmer blood may be necessary.
Berentsen S. How I treat cold agglutinin disease. Blood. Published online March 11, 2021. doi:10.1182/blood.2019003809
Michalak SS, Olewicz-Gawlik A, Rupa-Matysek J, Wolny-Rokicka E, Nowakowska E, Gil L. Autoimmune hemolytic anemia: current knowledge and perspectives. Immun Ageing. Published online November 20, 2020. doi:10.1186/s12979-020-00208-7