Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches.

Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.

Thrombosis may complicate autoimmune hemolytic anemia (AIHA), but its predictors are still lacking, and no clear‐cut indications for anticoagulant prophylaxis are available. To characterize frequency and severity of thromboses in AIHA patients and identify risk factors for thrombosis that may advise primary anticoagulant prophylaxis. A total of 287 consecutive AIHA patients diagnosed and followed from 1978 at a tertiary Italian center were retrospectively studied; 174 of them were prospectively evaluated from January 2020 until December 2021. AIHA relapse, thrombosis occurrence, and primary anticoagulant prophylaxis were evaluated. Thirty‐three AIHA patients (11.4%) experienced thrombosis, 70% of whom hospitalized. The cumulative thrombosis incidence was higher in patients with lactate dehydrogenase (LDH) ≥ 1.5 (hazard ratio [HR] 3.22), in those experiencing infections (HR 3.57), receiving transfusions (HR 3.06), rituximab (HR 3.3), or cyclophosphamide (HR 2.67). By multivariable analysis, LDH, transfusions, rituximab, and cyclophosphamide treatment emerged as independent factors associated with thrombosis. Among 174 patients prospectively followed in the past 2 years, we observed 70 acute hemolytic episodes in 45 patients; 33/45 displayed LDH ≥1.5 × upper limit of normal, and 17 received anticoagulant prophylaxis with low molecular weight heparin for a median of 70 days (30–300). In those receiving prophylaxis no thrombotic complications occurred, whereas five thrombotic episodes were registered in the remaining 16 cases. Thrombosis was observed in about 11% of AIHA patients, mainly grade 3, and associated with intravascular hemolysis, need of transfusions, multitreatment, and infections, advising primary anticoagulant prophylaxis in these settings.

Autoimmune hemolytic anemia (AIHA) may be frequently challenged by infectious complications, mainly as a result of immunosuppressive treatments administered. Furthermore, infectious agents are known triggers of AIHA onset and relapse. Although being risk factors for mortality, infections are an underestimated issue in AIHA. This review will collect the available evidence on the frequency and type of infectious complications in AIHA, detailing the risk related to each treatment (i.e., steroids, rituximab, splenectomy, classic immunosuppressive agents, and new target drugs). Moreover, we will briefly discuss the infectious complications in AIHA secondary to other diseases that harbor an intrinsic infectious risk (e.g., primary immunodeficiencies, systemic autoimmune diseases, lymphoproliferative disorders, solid organ and hematopoietic stem cell transplants). Finally, viral and bacterial reactivations during immune suppressive therapies will be discussed, along with suggested screening and prophylactic strategies.

Background: Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) show good responses to frontline steroids. About two-third of cases relapse and require second-line treatment, including rituximab, mainly effective in AIHA, and thrombopoietin-receptor agonists (TPO-RAs) in ITP, while the use of splenectomy progressively decreased due to concerns for infectious/thrombotic complications. For those failing second line, immunosuppressants may be considered. Objectives: The aim of this study was to evaluate the efficacy of cyclosporine treatment in patients with ITP and AIHA. Design: In this retrospective study, we evaluated the efficacy and safety of cyclosporine A (CyA) in ITP ( N = 29) and AIHA ( N = 10) patients followed at two reference centers in Milan, Italy. Methods: Responses were classified as partial [Hb > 10 or at least 2 g/dl increase from baseline, platelets (PLT) > 30 × 10⁹/l with at least doubling from baseline] and complete (Hb > 12 g/dl or PLT > 100 × 10⁹/l) and evaluated at 3, 6, and 12 months. Treatment emergent adverse events were also registered. Results: The median time from diagnosis to CyA was 35 months (3–293), and patients had required a median of 4 (1–8) previous therapy lines. Median duration of CyA was 28 (2–140) months and responses were achieved in 86% of ITP and 50% of AIHA subjects. Responders could reduce or discontinue concomitant treatment and resolved PLT fluctuations on TPO-RA. CyA was generally well tolerated, and only two serious infectious complications in elderly patients on concomitant steroids suggesting caution in this patient population. Conclusion: CyA may be advisable in ITP, which is not well controlled under TPO-RA, and in AIHA failing rituximab, particularly if ineligible in clinical trial.

Autoimmune hemolytic anemia (AIHA) is diagnosed in the presence of anemia, hemolysis, and direct antiglobulin test (DAT) positivity with monospecific antisera. Many confounders of anemia and hemolytic markers should be included in the initial workup (i.e., nutrients deficiencies, chronic liver or kidney diseases, infections, and cancers). Besides classical presentation, there are difficult cases that may challenge the treating physician. These include DAT negative AIHA, diagnosed after the exclusion of other causes of hemolysis, and supported by the response to steroids, and secondary cases (infections, drugs, lymphoproliferative disorders, immunodeficiencies, etc.) that should be suspected and investigated through careful anamnesis physical examination, and specific tests in selected cases. The latter include autoantibody screening in patients with signs/symptoms of systemic autoimmune diseases, immunoglobulins (Ig) levels in case of frequent infections or suspected immunodeficiency, and ultrasound/ computed tomography (CT) studies and bone marrow evaluation to exclude hematologic diseases. AIHA occurring in pregnancy is a specific situation, usually manageable with steroids and intravenous (iv) Ig, although refractory cases have been described. Finally, AIHA may complicate specific clinical settings, including intensive care unit (ICU) admission, reticulocytopenia, treatment with novel anti-cancer drugs, and transplant. These cases are often severe, more frequently DAT negative, and require multiple treatments in a short time.