All that hemolyzes with complement is not cold agglutinin syndrome

Abstract

Sion et al. recently described a 2-year-old child with apparent autoimmune hemolysis in the setting of human adenovirus infection. 1 Per the authors, the patient developed signs of intravascular hemolysis with hemoglobinuria and a precipitous hemoglobin drop from 11.6 to 2.6 g/dL. The authors appropriately performed a direct antiglobulin test (DAT), which was positive for complement (C3d), and an indirect antiglobulin test (IAT) at 4°C, which was also positive, though further details are not provided. The authors ultimately attributed this to cold agglutinin (CA) syndrome (CAS). Unfortunately, immunohematological evaluation is insufficient to definitively conclude a diagnosis of CAS, and most likely may be explained by paroxysmal cold hemoglobinuria (PCH).CAS is characterized by autoantibodies, typically of the IgM isotype, which are optimally reactive at 4°C. These autoantibodies bind complement, and although complement is capable of proceeding through the membrane attack complex (MAC) with subsequent intravascular hemolysis, intravascular hemolysis is significantly rarer than extravascular hemolysis via phagocytosis of C3b-opsonized red blood cells (RBCs) by Kupfer cells in the liver. 2 Diagnosis of CAS requires demonstration of CAs at 4°C, which almost always display a titer ³64, often in the range of 100s to 1,000s. 3 However, thermal amplitude (TA), or the highest temperature at which the autoantibody is capable of mediating hemolysis, is more indicative of its potential significance, with clinically-significant CAs displaying TA ³28-30°C. 3 Unfortunately, the authors either did not test for, or at least report, the titer and TA of the implicated CA in this particular case. Moreover, additional tests to support a diagnosis of CAS, including a 4°C and a 37°C autocontrol and IAT and antibody specificity, were not reported.