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Abstract
Autoimmune hemolytic anemia (AIHA) is characterized by immune mediated erythrocytes destruction by autoantibodies with or without complement activation. Additional pathologic mechanisms include cellular cytotoxicity, cytokline dysregulation, and inadequate bone marrow compensation with fibrosis/dyserythropoiesis. The latter resembles that of bone marrow failures, namely aplastic anemia and myelodysplastic syndromes. Paroxysmal nocturnal hemoglobinuria (PNH) clones are increasingly recognized in bone marrow failure syndromes, and their selection and expansion are thought to be mediated by immune mechanisms. In this study, we aimed to evaluate the prevalence of PNH clones in 99 patients with primary AIHA, and their correlations with disease features and outcomes. Moreover, in the attempt to disclose the physiopathology of PNH positivity in AIHA, serum levels of several immunomodulatory cytokines were tested. A PNH clone was found in 37 AIHA patients (37,4%), with a median size of 0.2% on granulocytes (range 0.03–85). Two patients showed a large clone (16 and 85%) and were therefore considered as AIHA/PNH association and not included in further analysis. Compared to PNH negative, PNH positive cases displayed a higher hemolytic pattern with adequate bone marrow compensation. AIHA type, response to therapy, complications and outcome were comparable between the two groups. Regarding cytokine levels, IFN-γ and IL-17 were lower in PNH positive vs. PNH negative AIHAs (0.3 ± 0.2 vs. 1.33 ± 2.5; 0.15 ± 0.3 vs. 3,7 ± 9.1, respectively, p = 0.07 for both). In PNH positive AIHAs, IFN-γ positively correlated with reticulocytes (r = 0.52, p = 0.01) and with the bone marrow responsiveness index (r = 0.69, p = 0.002). Conversely, IL-6 and IL-10 showed the same pattern in PNH positive and PNH negative AIHAs. IL-6 levels and TGF-β positively correlated with clone size (r = 0.35, p = 0.007, and r = 0.38, p = 0.05, respectively), as well as with LDH values (r = 0.69, p = 0.0003, and r = 0.34, p = 0.07, respectively). These data suggest testing PNH clones in AIHA since their prevalence is not negligible, and may correlate with a prominent hemolytic pattern, a higher thrombotic risk, and a different therapy indication. PNH testing is particularly advisable in complex cases with inadequate response to AIHA-specific therapy. Cytokine patterns of PNH positive and negative AIHAs may give hints about the pathogenesis of highly hemolytic AIHA.
Highlights
Autoimmune hemolytic anemia (AIHA) is a clinically heterogeneous disease ranging from mild/ compensated to very severe life-threatening hemolysis [1, 2]
One third of cases presented severe anemia and hemoglobin levels positively correlated with LDH > 1.5 x ULN (r = 0.21 p = 0.03), indicating active intravascular hemolysis, as well as with inadequate reticulocytosis (i.e., bone marrow responsiveness index (BMRI)
Bone marrow evaluation had been performed in 74 cases and showed hypercellularity and diserythropoiesis in about half of cases (52 and 57%, respectively), and reticulin fibrosis (MF-1) in 42%; the latter displayed reduced BMRI compared with MF-0 patients (107 vs. 137, p = 0.05)
Summary
Autoimmune hemolytic anemia (AIHA) is a clinically heterogeneous disease ranging from mild/ compensated to very severe life-threatening hemolysis [1, 2]. Since the last 10 years, the increased sensitivity of the cytofluorimetric techniques (up to ≥0.01% clone size) enabled the detection of small PNH clones in up to 60% of AA and 30% of MDS [7,8,9, 11] The significance of these clones is still unclear, with some evidences for better response to immunosuppressive therapy in PNH positive cases. These tests allowed the detection of small PNH populations even in diseases not commonly associated to PNH such as hypomegakaryocytic thrombocytopenia [12] and chronic benign neutropenia [13].
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