Case Presentation: This is a case of a 65-year-old man with a history of prostate cancer who presented with a 3-day history of fatigue and shortness of breath. Initial diagnostic work-up revealed a hemoglobin of 7.8 g/dL (10.1 g/dL the day prior), normal platelets, and an indirect hyperbilirubinemia. Lactate dehydrogenase was elevated, haptoglobin was undetectable and the reticulocyte count was elevated raising the suspicion for a hemolytic anemia. Peripheral smear showed normocytic, normochromic anemia with occasional spherocytes and absence of schistocytes. On hospital day 1, his hemoglobin further dropped to 5.8 g/dL. DAT returned positive for C3 and negative for IgG. He was diagnosed with a cold agglutinin autoimmune hemolytic anemia. Evaluation for an underlying etiology was as follows: cryoglobulins, mycoplasma IgM, EBV PCR, and parvovirus PCR were negative. CT chest, abdomen, and pelvis were negative for evidence of underlying malignancy. SPEP revealed MGUS. Bone marrow biopsy was mildly hypocellular with no evidence of a clonal process.Despite the implementation of measures for cold avoidance and initiation of IV solumedrol, the patient continued to have rapid hemolysis requiring daily warmed blood transfusions. He was next initiated on IVIG as a means to temporarily halt hemolysis in addition to being treated with Rituximab monotherapy and the complement inhibitor, Eculizumab. He continued to have active hemolysis with significantly elevated cold agglutinin titers after 4 weeks of hospitalization. His hemolysis finally responded to combination rituximab-bendamustine (BR) therapy. Cold agglutinin titer was negative on discharge. His hospital course was complicated by the development of a deep vein thrombosis and iron overload requiring anticoagulation and iron chelation therapy.
Discussion: Cold agglutinin autoimmune hemolytic anemia or cold agglutinin disease (CAD) has been reported to account for one-fifth to one-quarter of all cases of autoimmune hemolytic anemia [1,2]. CAD can be subdivided into primary CAD in which there is no identifiable underlying cause and secondary cold agglutinin syndrome which is associated with an underling etiology such as a viral infection, autoimmune disorder, or lymphoid malignancy. Primary CAD is rare with an estimated incidence of 1 per million [3,4]. CAD is IgM and complement mediated. Management of primary CAD ranges from supportive care, including cold avoidance and warmed IV fluid and blood infusions to therapies targeted at autoantibody activity to anti B-cell therapy. Anti B-cell therapy targets clonal cells producing the cold agglutinin. Patients should be monitored for complications of severe anemia including end organ damage as well as complications from management including drug side effects and iron overload. A retrospective study showed a higher risk of thrombotic events in patients with CAD vs matched controls [5].Our patient was diagnosed with CAD who eventually responded to anti B-cell therapy. He required over70 blood transfusions during his hospitalization. Despite lowering the transfusion threshold to 5 g/dL, he developed signs of hepatic iron overload requiring iron chelation therapy. He also developed a lower extremity venous thromboembolism.
Conclusions: We present a case of refractory cold agglutinin autoimmune hemolytic anemia as a reminder to the hospitalist of the condition, its diagnosis, its management, and complications.