Autoimmune hemolytic anemia: clinical severity and laboratory heterogeneity in 157 patients

Autoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease classically divided in warm (WAIHA), cold (CHD), and mixed forms, based on the thermal and isotype characteristics of the anti-RBC antibody (IgG, IgM or both, respectively); in addition, atypical forms include DAT (direct antiglobulin test)-negative, IgA-positive, and warm IgM cases, which are often difficult to diagnose with consequent delay in treatment. We retrospectively evaluated 157 AIHA patients followed for a median of 26 months (range 6-271) from 1978 until September 2012, to investigate the prevalence of the different forms of AIHA, the severity of anemia, the number of therapy lines required, and the corresponding responses. Results showed that 40% of cases were WAIHA, 32% CHD, 19% mixed forms and 9% atypical (12 DAT negative and 1 DAT positive for IgA only). Considering the severity of anemia at onset 33% of cases had Hb levels<6 g/dL, 34% Hb 6-8 g/dL, 18% Hb 8-10 g/dL, and 15% Hb>10 g/dL; interestingly, reticulocytopenia (<100.000 mmc) was more frequently observed in cases with severe onset (14/52, 27%); the more severe AIHAs were mainly mixed (18/30, 60% p=0.001) and atypical (6/13, 46%) forms, whereas only a small fraction of CHD was characterized by a severe onset (8/51, 16% p=0.002). As regard therapy, 45% of cases were treated with I line steroid therapy only (mostly WAIHA), 23% with 2 lines, 10% with 3, and 6% with 4 or more lines, including splenectomy (20 cases, mostly mixed forms, p=0.001), cytotoxic drugs (23 patients), or rituximab (33 cases, mostly mixed and atypical forms, p=0.009); 16% of cases have never been treated, mainly CHD.Transfusions were performed in 65 cases, plasma-exchange in 3 (all with Hb<6 g/dL), and erythropoietin administered in 6 cases. Of note, the presence of an Hb value lower than 6 g/dL at onset was a risk factor for the requirement of 3 or more lines of therapy (odds ratio 3.148, CI 95% 1.312-7.552). Response rates to steroid therapy were similar in warm, cold, mixed and atypical AIHAs (on average 70%). Responses to rituximab were similar in cold and other AIHA forms (70-80%). Splenectomy, was ineffective in the 2 CHD who underwent surgery, whereas response rates were 63% in WAIHA and 80% in mixed and atypical cases. In conclusion, AIHAs showed a marked clinical heterogeneity, 1/3 of cases with a severe onset. These cases are frequently mixed or atypical forms and refractory to different therapies.