Successful Orthotopic Heart Transplantation in a Patient with Cold Agglutinin Disease: A Structured Perioperative Management Framework

Sutimlimab is a monoclonal antibody against complement fraction C1s approved for the treatment of hemolytic anemia due to cold agglutinin disease (CAD). Here, we analyzed and report the largest international CAD cohort of sutimlimab-treated patients ever reported to highlight its safety and effectiveness in the real-world setting. We accrued a cohort of 57 CAD patients (median age 73.5 years, 56% females). At baseline, patients had severe to moderate anemia (median Hb 8.9 g/dL) and active hemolysis, with a substantial transfusion burden despite a median of 2 prior therapies, including corticosteroids and rituximab. After sutimlimab initiation, median Hb increased by 2 g/dL within 2 weeks and reached 12 g/dL in 4 weeks, remaining stable up to 24 months. This improvement was paralleled by an early and durable normalization of hemolytic markers. Objective responses were observed in most patients by week 2, with complete responses in approximately 50% by Week 4 and 55%-60% during long-term follow-up. Peripheral cold-induced symptoms did not improve and were associated with reduced response rates. Inadequate reticulocytosis also predicted poorer response and suggests the combination with recombinant erythropoietin. Sutimlimab was generally well tolerated. Infections were the most frequent adverse events (23%); severe infections predominantly occurred in previously rituximab-treated individuals. Hemolytic exacerbations occurred in 16% of cases, mostly due to infections. Thrombotic complications were rare. Overall, sutimlimab demonstrated rapid, durable effectiveness and a favorable safety profile in heavily pretreated real-world CAD patients.

Sutimlimab vs B-cell-targeted therapy in cold agglutinin disease: which is the optimal approach?

ABSTRACTBackgroundThe fifth edition of the World Health Organization (WHO) classification defines cold agglutinin disease (CAD) as a clonal B‐cell lymphoproliferative disorder occurring in the absence of overt lymphoma, whereas cases associated with lymphoma are classified as cold agglutinin syndrome (CAS). However, whether this distinction fully reflects the biological spectrum of cold agglutinin–associated disorders remains uncertain.MethodsWe performed a comprehensive pathological review, immunoglobulin gene analysis and whole‐exome sequencing in eight patients with clinically well‐characterised CAD or CAS.ResultsFive cases showed pathological findings typical of CAD, whereas two cases demonstrated lymphoma‐like bone marrow infiltrates resembling lymphoplasmacytic lymphoma (LPL). Nevertheless, no CD5‐positive or CD10‐positive clonal B‐cell population suggestive of a specific lymphoma subtype was identified by flow cytometry. Six patients showed highly restricted IGHV4‐34 usage, and mutations involving KMT2D and CARD11 were identified. No pathogenic MYD88 L265P or CXCR4 mutations were detected in any case. Notably, the two morphologically LPL‐like cases lacked the canonical genetic hallmarks of LPL and instead exhibited immunogenetic and mutational features characteristic of CAD.ConclusionThese findings demonstrate that CAD‐like genetic signatures can be present even in cases with lymphoma‐like morphology that would currently be classified as CAS under the WHO criteria. Our results highlight a clinically relevant genotype–phenotype discordance and support the integration of molecular hallmarks into diagnostic algorithms to better reflect the biological spectrum of cold agglutinin–associated disorders.Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission

Not available.

Monoclonal gammopathies of thrombotic and hemorrhagic significance: mapping into a classification schema.

Cold agglutinin disease is an autoimmune haemolytic anaemia related to a clonal B-cell disorder of the bone marrow. Haemolysis is complement-dependent, while acrocyanosis is monoclonal agglutinin-dependent. Established therapies target the clonal B cells or the classical complement pathway. Treatment can be tailored based on clinical phenotypes.

French protocol for the diagnosis and management of autoimmune hemolytic anemia in adults.

IntroductionPropylthiouracil (PTU) is typically used as first line therapy for hyperthyroidism but is associated with a spectrum of adverse effects including vasculitis, that may lead to acute renal failure and exceptionally to pancreatitis, represents the most severe.Case descriptionHere we present the case of a 43-year-old woman with a history of Graves’ disease until recently on PTU therapy, who presented with fever and myalgia complicated by cold agglutinin disease, acute renal failure and pancreatitis. Subsequent laboratory studies and thorough physical examination excluding other causes revealed the presence of antibodies against leukocyte proteinase 3. Prompt initiation of immunosuppressive therapy and plasmapheresis led to immediate improvement of the patient’s clinical condition and laboratory tests.ConclusionClinicians should maintain a high index of suspicion for autoimmune phenomena in patients receiving PTU even after cessation of the medication. Early recognition, immediate discontinuation of the drug, and timely initiation of immunosuppressive therapy are essential to prevent irreversible organ damage.LEARNING POINTSPropylthiouracil is a well described trigger for the development of drug-induced vasculitis, seldom even long after cessation of therapy.In patients presenting with multi-organ failure the differential diagnosis should broaden to include systemic autoimmune vasculitis with atypical features.The cornerstone of therapy in drug induced autoimmune vasculitis is the immediate withdrawal of the offending agent and initiation of immunosuppressive therapy.

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA). CAD occurs in the context of a small clonal B-cell lymphoproliferation restricted to blood and/or bone marrow (BM), without overt or extramedullary lymphoma. The WHO-HAEM5 introduced a description of the CAD-associated lymphoproliferative disorder (CAD-LPD) in the BM as a desirable criterium for CAD. Still, data on BM pathology underlying CAD remain scarce. We assessed the clinical and pathologic characteristics of a large patient cohort with cold-type AIHA. A total of 85 BM biopsies of 56 patients were evaluated. In 10 patients (18%), pathology revision revealed other overt B-cell malignancies leading to a diagnosis of cold agglutinin syndrome. In the remaining 46, evidence for B-cell clonality was found in the vast majority (45; 98%), manifesting as a paraproteinemia and/or clonal B-cells or plasma cells in BM. Most of these 45 had an M-protein (89%), evidence of monoclonal B-cells and/or plasma cells in BM tissue (89%), and were MYD88 wild-type (100%). Surprisingly, while ancillary methods detected clonality in the majority (84%), only 5 (11%) of 45 CAD cases strictly fulfilled the WHO-HAEM5 morphological description for CAD-LPD. These data imply that sensitive techniques should be used in BM evaluation in CAD.

The GCNT2 gene encodes β-1,6-acetylglucosaminyltransferase (IGnT), the enzyme responsible for converting i antigen to I antigen on red blood cells (RBCs). However, mutations in GCNT2 disrupt poly-N-acetyllactosamine branching, preventing this conversion and resulting in adult i or weak I phenotypes.1 Mutations in exon 1C can inactivate IGnT, while those in exons 2 or 3 affect other transcripts, potentially causing abnormal I antigen expression and congenital cataracts.2, 3 Adult RBCs express high levels of I antigen, whereas fetal and neonatal RBCs express the i antigen. Physiologically, the i antigen gradually converts to the I antigen, reaching adult levels by age two. Anti-I was originally identified as a high-titer cold agglutinin in a patient with hemolytic anemia. Notably, anti-I antibodies can bind complement at 37°C, leading to the shortened survival of I-antigen-positive RBCs.4 We report a novel GCNT2 variant, c.869C>A (p.Ser290Tyr), identified in a 69-year-old Chinese male with weak I antigen expression and anti-I antibody formation following transfusion. I antigen phenotyping was performed using the standard tube method following AABB guidelines. A mouse monoclonal anti-human I IgM antibody (Lot No. 20240801, clone: I4C4; Changchun Boxun Biotechnology Co., Ltd.) was utilized. Two drops of anti-I reagent were added to tubes labeled 1–4 (Cord Blood), 5–7 (Adult), and 8 (Patient), respectively. One drop of a 3% RBC saline suspension was added to each tube. Mixtures were centrifuged at 1000 × g for 15 s and observed. Genomic DNA was extracted from peripheral blood (Maxwell® RSC Whole Blood DNA Kit, Promega). Exons 1C, 2, and 3 of GCNT2 were sequenced by the Sanger method and compared with the reference sequence (GCNT2, NG_007469.3). Variants were annotated using the RefSeqGene database. Serologic and genetic findings are summarized in Table 1. The proband, diagnosed with a B-cell lymphoproliferative disorder (blood type O, RhD positive), developed anti-I antibodies after multiple transfusions. Due to the absence of i-antigen-negative donors, repeated transfusions of I-positive RBCs yielded limited efficacy. Serologic testing showed negative reactivity with cord RBCs and strong positivity (4+) with adult RBCs. The patient's RBCs demonstrated weaker than 4+ agglutination, indicating reduced I antigen expression. As illustrated in Figure 1, the anti-I serum reacted differentially with O-type RBCS from umbilical cord (tubes 1–4), adult (tubes 5–7), and the proband (tube 8). Sequencing identified a novel GCNT2 mutation in exon 1C (c.869C>A, p.Ser290Tyr), with no variation in exons 2 or 3. This novel sequence has been deposited in GenBank (BankIt:PX363474). The expression of I and i antigens is regulated by the sequential action of multiple glycosyltransferases. The heterozygous mutation (c.869C>A) identified in exon 1C results in the substitution of serine with tyrosine at position 290. Ser290 is located within a characteristic peptide sequence of the GCNT2 protein; this region is likely a critical functional domain. The mutation may interfere with protein function, leading to structural changes in the I antigen, and provoke alloimmune responses to I-positive blood, resulting in hemolytic reactions.5 This likely contributed to weakened I antigen expression and anti-I antibody formation, leading to suboptimal transfusion outcomes. Whether the variant contributes to the patient's lymphoproliferative disorder requires further investigation. A limitation of this study is that the enzymatic activity of the mutant GCNT2 was not assessed in a mammalian cell expression system. Future studies are needed to directly verify the structural characteristics and enzymatic activity of the variant. A novel GCNT2 variant, c.869C>A (p.Ser290Tyr), was identified in a patient with weak I antigen expression. This expands the allelic spectrum of GCNT2 and underscores the need for molecular testing in patients with atypical I antigen phenotypes. This work was supported by the Sanming Project of Medicine in Shenzhen (No. SZSM202311032). This work was supported by the Sanming Project of Medicine in Shenzhen (No. SZSM202311032). The authors declare no conflicts of interest. The data that support the findings of this study are openly available in GenBank: PX363474.1 at https://www.ncbi.nlm.nih.gov/nuccore/PX363474.1.

Autoimmune hemolytic anemia: New frontiers in diagnosis and therapy.

Case seriesPatients: Female, 45-year-old • Male, 62-year-oldFinal Diagnosis: Non-infectious type II cryoglobulinaemiaSymptoms: Arthralgia • fatigue • glomerulonephritis • polyneuropathy • proteinuria • purpura • Raynaud’s phenomenonClinical Procedure: —Specialty: HematologyObjective: Rare diseaseBackgroundCryoglobulinemia is a rare disease with a prevalence of <5 cases per 10 000. In many cases there is significant diagnostic delay, leading to years of morbidity. There are no randomized trials on non-infectious type II cryoglobulinemia, and choice of therapy is based on clinical expertise and observational data. Therapy based on the monoclonal anti-CD20 antibody rituximab in combination with glucocorticosteroids is the preferred choice in many centers. This strategy induces clinical remission in two-thirds of patients. However, one-third of the initially-responding patients experience relapse within the first year. As such, many patients will not achieve sustained remission.Case ReportsWe describe the clinical course of 2 patients with non-infectious type II cryoglobulinemia. They were initially treated according to standard clinical practice, without lasting symptom relief. A novel treatment strategy was attempted, targeting the underlying B-cell clone responsible for the production of disease-inducing monoclonal immunoglobulins. These protocols, initially developed for treatment of chronic cold agglutinin disease, contain rituximab in combination with fludarabine or bendamustine. Sustained clinical, immunological, and hematological remissions were achieved in both patients, and the treatment was well tolerated with no need for hospitalization or other supportive measures.ConclusionsTreating patients with type II cryoglobulinemia using chemo-immune therapy in the same regimens as used in cold agglutinin disease could be considered as a therapeutic option. Based on our observations in the 2 patients described in this case series, this approach seems feasible and well tolerated. Deep sustained remissions may be possible.

Mixed autoimmune hemolytic anemia can manifest with severe intra- and extravascular hemolysis, with autoagglutination contributing to vaso-occlusive microangiopathic phenomena. We present a case of mixed autoimmune haemolytic anemia with unusually severe cold agglutinin syndrome causing cutaneous, cerebral, ocular, and aural manifestations of microvasculopathy and massive intravascular haemolysis, requiring 6 double-volume whole-blood exchanges over 8 days to temporise severe hemolysis and autoagglutination while immunosuppression with high-dose steroids, rituximab, and bortezomib took effect. Whole-blood exchange permitted fluid-neutral clearance of preformed antibodies and antibody-coated red cells, with dramatic resolution of microvasculopathy and hemolysis, before discharge home on oral steroid therapy.

We present the case of a 43-year-old man who developed painless jaundice following a respiratory infection. Diagnostic workup revealed severe immune hemolytic anemia, specifically cold agglutinin syndrome (CAS), characterized by a positive direct antiglobulin test (DAT) for complement C3d and IgM antibodies. The patient's clinical course was complicated by significant hemolysis, requiring supportive care and multiple blood transfusions. Further microbiological investigation identified Mycoplasma pneumoniae as the underlying trigger for this secondary CAS.

Cold agglutinin disease is an autoimmune condition characterised by expression of self-reactive antibodies to I/i carbohydrate blood group antigens (polymers of N-acetyllactosamine or 'LacNAc' units) resulting in anaemia through the agglutination and complement-mediated destruction of red blood cells. This antibody response is dominated by antibodies of the human IGHV4-34 germline, which display a unique hydrophobic patch formed by germline-encoded tryptophan and tyrosine residues at positions 7 and 25 within framework 1 (FR1). Although the requirement for conservation of this FR1 patch for binding to the I/i carbohydrate antigen has been well established, structural insights regarding the mechanistic role of the FR1 patch have remained elusive. Intriguingly, recent papers describing IGHV4-34 antibodies bound to the glycan-adorned surface of the HIV envelope glycoprotein shed light on the utility of this FR1 surface. Rather than indirectly shaping the conformation of the conventional antigen binding site as previously proposed, the structures reveal direct interfaces between the hydrophobic FR1 patch and high mannose glycans projected by HIV. Given the stereochemical similarities between these glycans and LacNAc, these structures suggest how I/i self-antigen glycans might be similarly engaged by IGHV4-34 antibodies in a framework-centric non-CDR mode and provide a rationale for the preservation of this otherwise self-reactive antibody germline.

Monoclonal immunoglobulin and/or free light chains cause diverse complications that can affect almost all tissues or organs. Monoclonal immunoglobulin can interfere with hemostasis and cause both hypercoagulation or hemorrhagic diathesis. In patients with non-malignant gammopathy and untreated multiple myeloma, thrombotic complications are more common than hemorrhagic complications. Exceptionally, monoclonal immunoglobulin can also exhibit the properties of an autoantibody and cause diverse organ damage. Among the more common forms, there is cold agglutinin disease, neuropathy, and various forms of eye damage. In the text, less common disorders are also mentioned. All the complications described in the text may be caused by monoclonal immunoglobulin, but they can also have other causes. If it is possible to establish an etiopathogenetic connection of these problems with monoclonal immunoglobulin, then targeted treatment that suppresses its production may lead to the disappearance of the problem.

Complement inhibition has revolutionized the management of hemolytic diseases by targeting the underlying drivers of red blood celldestruction in disorders such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and cold agglutinin disease. Recent advances have expanded the therapeutic landscape beyond terminal C5 inhibition to proximal strategies targeting C3, factor B, and factor D. These newer agents-such as pegcetacoplan, iptacopan, and danicopan-not only control intravascular hemolysis but also address extravascular hemolysis and offer oral or subcutaneous alternatives. In cold agglutinin disease, the efficacy of the classical pathway inhibitor sutimlimab provides compelling evidence for the therapeutic value of targeting early initiating molecules of the complement cascade. For clinicians, these innovations provide personalized treatment choices based on disease phenotype, hemolysis profile, patient preference, and risk stratification. The evolving complement inhibitor arsenal enables optimized, targeted care and pathway-specific interventions in hemolytic conditions.

Cold Agglutinin Syndrome (CAS) is a rare immune-mediated hemolytic anemia in children, typically triggered by infections and characterized by red blood cell agglutination at low temperatures below 37°C due to IgM autoantibodies. Pediatric CAS often presents with anemia, jaundice, and respiratory infections. While well-documented in adults, pediatric CAS remains underreported, with limited data on hemoglobin kinetics. Here we present a case series of four pediatric patients diagnosed with post-infectious Cold Agglutinin Syndrome (CAS), a rare form of autoimmune hemolytic anemia. Three cases were triggered by confirmed Mycoplasma pneumoniae infection, while one had a probable viral etiology. Hemoglobin levels at presentation varied from severe anemia (4.3 g/dL) requiring transfusion to mild reductions (12.8 to 11.5 g/dL). Laboratory findings demonstrated RBC agglutination in three patients, elevated LDH (218–3052 IU/L), and positive cold agglutinin titers in two cases. The direct Coombs test was positive or weakly positive in three cases. Two children required blood transfusions, and all received antimicrobial therapy. Reticulocyte counts ranged from initial reticulocytopenia (0.3%) to compensatory reticulocytosis (2.3%) after treatment. Supportive care, including warmed transfusions and nutritional supplementation, led to full hematological recovery in all cases. This series highlights the transient, infection-associated nature of pediatric CAS and underscores the importance of early diagnosis and conservative management. Thus Pediatric CAS is typically self-limiting and infection-driven. Hemoglobin kinetics and lab markers like LDH and reticulocyte counts guide diagnosis and recovery monitoring. Supportive care and appropriate antibiotics are generally sufficient for management.

Abstract Background Atypical pneumonia, particularly that caused by Mycoplasma pneumoniae, presents unique diagnostic challenges due to its variable clinical course and potential for severe complications such as necrotizing pneumonia. Early identification of predictive features for disease progression is critical. We sought to evaluate the clinical, laboratory, and radiographic markers associated with necrotizing Mycoplasma pneumoniae pneumonia and assess the potential for artificial intelligence (AI) models to predict complications at initial presentation. Methods We reviewed recent literature characterizing severe and necrotizing Mycoplasma pneumonia infections. We compiled key predictive features, including clinical presentation, radiologic findings, laboratory markers, and risk factors for complications. An AI-based framework was conceptualized utilizing these features to predict progression to necrotizing disease. Results Clinical predictors included subacute onset of fever, dry cough, extrapulmonary manifestations, and rapid respiratory decline. Radiographic findings associated with complicated disease included segmental or lobar consolidation, ground-glass opacities, and early cavitation. Laboratory predictors encompassed elevated CRP, ESR, LDH, cold agglutinin positivity, and rising D-dimer levels. Risk factors for complications included delayed initiation of appropriate antibiotics, presence of bacterial co-infection, and hyperimmune responses. AI models incorporating early imaging findings, inflammatory marker kinetics, and time to appropriate therapy initiation demonstrate potential for early stratification of patients at risk for necrotizing progression. Conclusion Identifying clinical, laboratory, and imaging predictors is essential for timely diagnosis and intervention in atypical pneumonia complicated by necrotizing Mycoplasma pneumoniae. AI-driven predictive models show promise in aiding early recognition of severe disease, ultimately improving patient outcomes. Prospective validation of these AI tools is warranted. Disclosures All Authors: No reported disclosures