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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.

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.

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.

Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Pyruvate kinase deficiency, the most common genetic lesion in the glycolytic pathway, leads to chronic hemolytic anemia. Mitapivat, an oral agent, can activate some mutant enzymes and restore red-cell ATP generation. In this trial, hemoglobin levels increased from baseline by 1.5 g per deciliter or more at 24 weeks in 40% of the patients with pyruvate kinase deficiency who received mitapivat.

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 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.

Abstract Background Saline agglutination tests (SATs) are widely recommended for diagnosis of immune-mediated hemolytic anemia in dogs, but there are frequent false-positive results. Objectives Specificity of SATs will improve at higher saline-to-blood ratios. Animals One hundred fifty dogs treated at a veterinary referral hospital with hematocrits ≤30%. Methods Prospective diagnostic accuracy study. Immune-mediated hemolysis (IMH) was considered present if a gel direct antiglobulin test (DAT) was positive and there was clinical evidence of hemolysis (n = 9), absent if another mechanism for anemia was identified and the DAT was negative or there was no hemolysis (n = 138), and if IMH status was unclear, dogs were excluded (n = 3). Saline agglutination tests were prepared at 1 : 1, 4 : 1, 9 : 1, and 49 : 1 saline-to-blood ratios, and microscopic agglutination was considered a positive result. Results Specificity for IMH increased from 29% (95% confidence interval 20-38) at a 1 : 1 dilution to 97% (93-99) at a 49 : 1 dilution. Sensitivity was 88% (47-100) at 1 : 1 and 4 : 1 dilutions and 67% (30-93%) at 9 : 1 and 49 : 1 dilutions. Diagnostic accuracy increased from 33% (24–42) at 1 : 1 dilution to 95% (90-98) at 49 : 1 dilution. Conclusions and Clinical Importance If performed using a 49 : 1 saline-to-blood ratio, SATs achieve high specificity for IMH. Based on a gold standard of positive DAT and evidence of hemolysis, lower saline-to-blood ratio results should not be used because false-positive results are common.