(P-HC-2) Cold Agglutinin Syndrome with a Negative Antibody Detection Test: A Report of Eight Cases

Background/Case Studies: Cold agglutinin syndrome (CAS) usually presents with severe anemia, interference with ABO reverse typing, a pan-reactive antibody screen/panel, and positive C3 direct antiglobulin test (DAT). Across laboratories, there is a general lack of consensus for CAS workups. We report a series of eight cases of CAS with a negative antibody screen that may have been missed if a DAT had been omitted from the anemia evaluation.

Study

Design/Methods: Blood bank records were reviewed to find patients who were diagnosed with CAS, and had a negative antibody screen.

Results/Findings: The major clinical and laboratory features are noted in Table 1. The hemoglobin on presentation ranged from 8.1 to 11.5 g/dL and the haptoglobin was undetectable (< 10 mg/dL) in all cases. The age range was 45 to 91 years and five of the patients were male. The DAT was positive for complement (C3) and negative for IgG in all cases. The thermal amplitude (agglutination at 30 C) was positive in three cases, negative in four, and not performed in one. The titer at 4 C ranged from 64 to >2048 (see Table 1). Of these cases, two (Case 1 and 7) were considered primary CAS (cold agglutinin disease) and the remaining six were secondary. One was secondary to a Mycoplasma pneumoniae infection, another to smoldering multiple myeloma (SMM), and the remaining four to an underlying malignancy (see Table 1 for details). Both cases of primary CAS improved with rituximab, one with complete resolution of anemia (Case 7). Case 2 succumbed to pancreatic cancer about two years after his diagnosis of CAS. Case 3 has shown improvement in her anemia (Hgb 9.2 to 11.7 g/dL) without treatment. Case 4 has shown an improvement in his anemia with zanubrutinib (Hgb 9.0 to 11.3 g/dL). Case 5 required two red blood cell (RBC) transfusions, and showed improvement in his anemia at discharge. Case 6 has had stable hemoglobin levels and is asymptomatic. Case 8 has had resolution of anemia with steroid therapy.

Conclusions: The criteria for diagnosis of CAS are hemolytic anemia, positive C3 on DAT, and either a positive thermal amplitude study or a cold agglutinin titer of >64 at 4 C. All but one of our cases (Case 4) had all of these laboratory tests performed and in that case the diagnosis was presumed because of anemia, undetectable haptoglobin, positive C3 on DAT and the history of CLL which is commonly associated with CAS. These cases show that CAS can present with a negative antibody screen and that clinically significant cold agglutinins may not always interfere with ABO reverse typing. The DAT is a very important part of the diagnosis of CAS and plays a vital role in the work-up of anemia. Additional studies are needed to further characterize patients with CAS and develop broader consensus of the diagnostic workup across laboratories. The anemia in our short series was mild to moderate and in only one case RBC transfusions were required.