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Cold agglutinin disease is a type of autoimmune hemolytic anemia. A total of 17 of 24 patients (71%) with cold agglutinin disease who received sutimlimab (a monoclonal antibody that targets the C1s protein, which activates the classic complement pathway) were transfusion-free at the end of the study.

Autoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease due to autoantibodies directed against erythrocytes, with or without complement activation. The clinical picture ranges from mild/compensated to life-threatening anemia, depending on the antibody's thermal amplitude, isotype and ability to fix complement, as well as on bone marrow compensation. Since few years ago, steroids, immunesuppressants and splenectomy have been the mainstay of treatment. More recently, several target therapies are increasingly used in the clinical practice or are under development in clinical trials. This has led to the accumulation of refractory/relapsed cases that often represent a clinical challenge. Moreover, the availability of several drugs acting on the different pathophysiologic mechanisms of the disease pinpoints the need to harness therapy. In particular, it is advisable to define the best choice, sequence and/or combination of drugs during the different phases of the disease. In particular relapsed/refractory cases may resemble pre-myelodysplastic or bone marrow failure syndromes, suggesting a careful use of immunosuppressants, and vice versa advising bone marrow immunomodulating/stimulating agents. A peculiar setting is AIHA after autologous and allogeneic hematopoietic stem cell transplantation, which is increasingly reported. These cases are generally severe and refractory to standard therapy, and have high mortality. AIHAs may be primary/idiopathic or secondary to infections, autoimmune diseases, malignancies, particularly lymphoproliferative disorders, and drugs, further complicating their clinical picture and management. Regarding new drugs, the false positivity of the Coombs test (direct antiglobulin test, DAT) following daratumumab adds to the list of difficult diagnosis, together with the passenger lymphocyte syndrome after solid organ transplants. Diagnosis of DAT-negative AIHAs and evaluation of disease-related risk factors for relapse and mortality, notwithstanding improvement in diagnostic approach, are still an unmet need. Finally, AIHA is increasingly described following therapy of solid cancers with inhibitors of immune checkpoint molecules. On the whole, the double-edged sword of new pathogenetic insights and therapies has changed the landscape of AIHA, both providing enthusiastic knowledge and complicating the clinical management of this disease.

Drug-induced immune hemolytic anemia (DIIHA) is a rare but serious condition, with an estimated incidence of one in 100,000 cases, associated with various antibiotics. This study reports on a case of ceftizoxime-induced hemolysis observed in a patient in China. A Chinese patient diagnosed with malignant rectal cancer underwent antimicrobial therapy after laparoscopic partial recto-sigmoid resection (L-Dixon). After receiving four doses of ceftizoxime, the patient developed symptoms including rash, itchy skin, and chest distress, followed by a rapid decline in hemoglobin levels, the presence of hemoglobin in the urine (hemoglobinuria), renal failure, and disseminated intravascular coagulation. Laboratory analysis revealed high-titer antibodies against ceftizoxime and red blood cells (RBCs) in the patient's serum, including immunoglobulin M (IgM) (1:128) antibodies and immunoglobulin G (IgG) (1:8) antibodies, with noted crossreactivity to ceftriaxone. Significant improvement in the patient's hemolytic symptoms was observed following immediate discontinuation of the drug, two plasma exchanges, and extensive RBC transfusion. This case, together with previous reports, underscores the importance of considering DIIHA in patients who exhibit unexplained decreases in hemoglobin levels following antibiotic therapy. A thorough examination of the patient's medical history can provide crucial insights for diagnosing DIIHA. The effective management of DIIHA includes immediate cessation of the implicated drug, plasma exchange, and transfusion support based on the identification of specific drug-dependent antibodies through serological testing.

Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.

Familial xerocytosis (HX) in humans is an autosomal disease that causes dehydration of red blood cells resulting in hemolytic anemia which has been traced to two individual mutations in the mechanosensitive ion channel, PIEZO1. Each mutation alters channel kinetics in ways that can explain the clinical presentation. Both mutations slowed inactivation and introduced a pronounced latency for activation. A conservative substitution of lysine for arginine (R2456K) eliminated inactivation and also slowed deactivation, indicating that this mutant’s loss of charge is not responsible for HX. Fitting the current vs. pressure data to Boltzmann distributions showed that the half-activation pressure, P ₁/₂, for M2225R was similar to that of WT, whereas mutations at position 2456 were left shifted. The absolute stress sensitivity was calibrated by cotransfection and comparison with MscL, a well-characterized mechanosensitive channel from bacteria that is driven by bilayer tension. The slope sensitivity of WT and mutant human PIEZO1 (hPIEZO1) was similar to that of MscL implying that the in-plane area increased markedly, by ∼6–20 nm ² during opening. In addition to the behavior of individual channels, groups of hPIEZO1 channels could undergo simultaneous changes in kinetics including a loss of inactivation and a long (∼200 ms), silent latency for activation. These observations suggest that hPIEZO1 exists in spatial domains whose global properties can modify channel gating. The mutations that create HX affect cation fluxes in two ways: slow inactivation increases the cation flux, and the latency decreases it. These data provide a direct link between pathology and mechanosensitive channel dysfunction in nonsensory cells.

In this study, approximately half the patients with red-cell pyruvate kinase deficiency who were treated with mitapivat had an improvement in their hemoglobin level and decreased hemolysis that was sustained for nearly 3 years. Patients who had missense mutations that allowed for synthesis of a hypofunctioning enzyme were most likely to have a response.

Contrast medium is frequently associated with allergic reactions and kidney dysfunction. However, contrast media can induce hemolytic anemia with a broad spectrum of hemolytic manifestations. We report a 38-year-old patient with very severe immune hemolytic anemia after the application of iomeprol due to a CT of the thorax/abdomen. In this case report, we illustrate the diagnostics and treatment of life-threatening hemolytic anemia induced by a contrast medium that was successfully treated with eculizumab.

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use has been restricted in patients with preexisting autoimmune diseases due to concerns about increased risk of immune-related adverse events (irAEs). Case presentation We present a case of a patient with stage IV lung adenocarcinoma and a history of complement-mediated autoimmune hemolytic anemia in remission. After receiving a single dose of pembrolizumab, the patient experienced life-threatening recurrent hemolytic anemia, de novo thrombocytopenia, diarrhea, myocarditis, and acute kidney injury. Laboratory tests confirmed the diagnosis of Evan's syndrome, with positive PAIgG and direct antiglobulin test. Treatment with intravenous methylprednisolone at a dose of 2 mg/kg resulted in a favorable response, with resolution of symptoms and rapid recovery of kidney function. The probable cause of pre-renal hypoperfusion (evidenced by a BUN-to-creatinine ratio of 48.1) leading to acute tubular injury was attributed to pembrolizumab-induced diarrhea. Conclusions This case illustrates a life-threatening recurrence of complement-mediated autoimmune hemolytic anemia induced by ICIs. Clinicians should carefully consider the expected efficacy and potential toxicity before initiating ICIs therapy in patients with preexisting autoimmune diseases. Additionally, the occurrence of acute kidney injury during ICIs therapy adds complexity and requires careful differential diagnosis.

In recent years, the pathophysiologic framework of autoimmune hemolytic anemias (AIHAs) has evolved considerably, extending beyond the simplistic paradigm of antibody-mediated red blood cell (RBC) destruction, which is now recognized as a downstream consequence of a broader immune dysregulation. AIHA is fundamentally orchestrated by a complex interplay between innate and adaptive immune components, including autoreactive B and T lymphocytes, macrophages, and the reticuloendothelial system. Central to disease pathogenesis are two interrelated mechanisms: clonal B-cell expansion with autoantibody production and complement activation. These immunologic processes support the heterogeneity of AIHA, delineating distinct clinical entities such as warm AIHA, cold agglutinin disease/syndrome (CAD/CAS), and atypical variants, each characterized by specific therapeutic susceptibilities. Glucocorticoids remain the standard first-line therapy for warm AIHA; in contrast, CAD/CAS is increasingly managed with agents targeting B-cell function or complement activation, including rituximab and sutimlimab. However, therapeutic algorithms are rapidly shifting, particularly in the context of treatment-refractory disease. Emerging therapeutics targeting the classical complement pathway include novel anti-C1s monoclonal antibodies such as riliprubart, which exhibits an extended half-life due to enhanced affinity for the neonatal Fc receptor. Parallel strategies aim to disrupt B-cell receptor (BCR) signaling cascades, employing Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, spleen tyrosine kinase (SYK) inhibitors such as fostamatinib and sovleplenib, and phosphoinositide 3-kinase (PI3K) inhibitors such as parsaclisib. Collectively, these advances are reshaping the therapeutic landscape of AIHA toward a precision medicine model guided by mechanistic insights into disease biology. In this review, we delineate the evolving immunopathogenesis of AIHAs and examine emerging therapeutic strategies, integrating their underlying rationale, clinical data, and implications for future treatment paradigms.

Immune‐mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered secondary when it can be attributed to an underlying disease, and as primary (idiopathic) if no cause is found. Eliminating diseases that cause IMHA may attenuate or stop immune‐mediated erythrocyte destruction, and adverse consequences of long‐term immunosuppressive treatment can be avoided. Infections, cancer, drugs, vaccines, and inflammatory processes may be underlying causes of IMHA. Evidence for these comorbidities has not been systematically evaluated, rendering evidence‐based decisions difficult. We identified and extracted data from studies published in the veterinary literature and developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria for IMHA, comorbidities, and causality. Succinct evidence summary statements were written, along with screening recommendations. Statements were refined by conducting 3 iterations of Delphi review with panel and task force members. Commentary was solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted. The resulting document is intended to provide clinical guidelines for diagnosis of, and underlying disease screening for, IMHA in dogs and cats. These should be implemented with consideration of animal, owner, and geographical factors.