In the Kobe Journal of Medical Sciences, Okomato and colleagues presented a report of a case of refractory cold agglutinin disease (CAD) with splenectomy.
CAD is a subset of autoimmune hemolytic anemia, accounting for around 1 in 10 such cases. It is characterized by the agglutination of erythrocytes below the normal core body temperature. It can be driven by a number of pathologies, such as autoimmune diseases, viral infections (including possibly COVID-19), and malignancies.
The case as presented by the authors of the report details a 60-year-old man who presented with fatigue. Blood investigations revealed a hemoglobin level of 7.8 g/dL and indirect bilirubin of 7.7 mg/dL. Further laboratory investigations revealed that he had elevated cold agglutinin levels; his direct Coombs test was C3d-positive and immunoglobulin G (IgG)-negative. An abdominal computed tomography (CT) scan was performed, revealing mild splenomegaly.
“In this case, the clinical findings of anemia and jaundice and the laboratory findings of decreased hemoglobin levels and reticulocytosis met the diagnostic criteria for hemolytic anemia,” Okomato et al wrote.
Read more about CAD etiology
Further history-taking revealed that his condition worsened when exposed to cold weather, pointing his physicians to a possible diagnosis of CAD. A bone marrow examination demonstrated a group of clonal cells; his physicians suspected that the patient’s CAD was secondary to a primary ailment. However, further tests did not lead to a definite diagnosis of malignant lymphoma or any other underlying conditions and his diagnosis was revised to primary CAD.
During the winter period, the patient experienced severe anemia, with hemoglobin levels falling to 5 g/dL. His physicians treated him with warming and blood transfusions once a week. As the months progressed into summer, his hemoglobin levels recovered to 13 g/dL.
Continued Clinical Deterioration
The patient remained under close observation. The following summer, 2 years after his CAD diagnosis, his anemia remained low and his splenomegaly worsened. His physicians were worried once again that he might have malignant lymphoma with refractory hemolytic anemia. The patient revealed that he had no prior medical history of note; however, his aunt had once been diagnosed with malignant lymphoma.
Upon further examination, it was discovered that he had lost 10 kg in 3 years. Upon physical abdominal examination, his spleen was palpable. Laboratory investigations revealed mild jaundice with indirect hyperbilirubinemia (associated with hemolytic anemia). An abdominal CT scan once again revealed splenomegaly, which had grown in size (and was now 26.5×8.5×17.0 cm).
In light of his worsening symptoms and increasing enlarged spleen, a decision was made to perform a splenectomy. The surgery proceeded uneventfully, with the extracted spleen weighing 2200 g. There were no obvious mass lesions on the spleen; however, a surface antigen analysis revealed a kappa-positive cell population. Histopathologically, there was no evidence of malignant lymphoma.
Having ruled out more serious causes of his symptoms, the patient’s diagnosis remained primary CAD. Eighteen months later, his hemolytic anemia had slowly improved, and he no longer required blood transfusions. Nevertheless, his cold agglutinin levels remained high, between 128 and 512. Upon follow-up, physician’s found that the patient’s IgG had turned positive during the course of treatment, and his diagnosis was revised to mixed-type autoimmune hemolytic anemia.
CAD and Splenectomy
There is a paucity of medical literature surrounding autoimmune hemolytic anemia of any subtype due to the rarity of the disorder. A survey of studies conducted of CAD in recent years demonstrates little progress in our understanding of the disease or how to treat it.
In the Journal of Veterinary Internal Medicine, Bestwick and colleagues assessed the merits of splenectomy in dogs diagnosed with primary immune-mediated hemolytic anemia or primary immune-mediated thrombocytopenia. They hypothesized that splenectomy would allow for a reduction in the prescription of immunosuppressive therapies.
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Among the 7 dogs with primary immune-mediated hemolytic anemia, splenectomy was carried out in 4, resulting in 2 complete and 2 partial responses. Overall, the data was insufficient for a conclusion to be made either way regarding the effects of splenectomy.
The benefits of splenectomy in human subjects with CAD are likewise controversial. Some scientists contend that splenectomy is generally ineffective in CAD because the main site of extravascular hemolysis is the liver through the action of IgM and Kupffer cells. However, in warm autoimmune hemolytic anemia, extravascular hemolysis occurs mainly in the spleen through the action of IgG, making splenectomy a more promising procedure.
“The most effective treatments for CAD are temperature control and warming,” Okomato and colleagues wrote.
As inconvenient as it may be, one of the best solutions to managing CAD is for the patient to relocate to a place with a warmer climate, at least during the winter months, when symptoms tend to be at their worst. In the event that this is impossible, physicians should include in-line blood warmers during blood transfusions as treatment for anemia.
The main problem in the field of CAD care is that the rarity of this condition makes it difficult for clinicians to conduct large-scale trials to test new theories or experiment on new therapies. Until the situation improves, the bulk of CAD care remains conservative: ensuring that the patient stays warm, and administering blood transfusions in the face of persistent anemia.
Okamoto S, Urade T, Yakushijin K, et al. Successful management of refractory autoimmune hemolytic anemia with cold agglutinin disease with splenectomy: a case report with review of literature. Kobe J Med Sci. 2023;68(1):E30-E34.
Bestwick JP, Skelly BJ, Swann JW, et al. Splenectomy in the management of primary immune-mediated hemolytic anemia and primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2022;36(4):1267-1280. doi:10.1111/jvim.16469