Autoimmune hemolytic anemia (AIHA) is a rare immune-mediated disorder caused by autoantibodies directed against red blood cell antigens. Mixed-type AIHA, characterized by the coexistence of warm-reactive IgG and cold-reactive complement-fixing antibodies, is uncommon and often diagnostically challenging due to overlapping serologic features and transfusion incompatibility. We report the case of a 40-year-old woman who presented with an acute onset of breathlessness, palpitations, and severe fatigability. She was found to have severe anemia (hemoglobin 2.7 g/dL), reticulocytosis, indirect hyperbilirubinemia, and red cell agglutination on peripheral smear. Both direct and indirect Coombs tests were strongly positive, while antibody screening demonstrated panreactivity with positive autocontrol. The monospecific direct antiglobulin test confirmed positivity for IgG and C3d, establishing the diagnosis of mixed-type AIHA. In view of hemodynamic instability, transfusion with the least-incompatible packed red cells was performed under warming precautions, alongside high-dose intravenous corticosteroids. The patient improved symptomatically, with hemoglobin rising to 8.8 g/dL. Autoimmune workup revealed high-titer antinuclear antibody and anti-SSA positivity, suggesting an evolving systemic autoimmune disorder. Mixed-type AIHA accounts for less than 10% of cases but is associated with significant morbidity due to combined extravascular and complement-mediated hemolysis, often necessitating cautious transfusion of least-incompatible blood in life-threatening anemia and escalation to rituximab or other immunosuppressive agents. This case highlights the diagnostic complexity, therapeutic challenges, and need for long-term autoimmune surveillance in patients with mixed-type AIHA.

Autoimmune hemolytic anemia (AIHA) is uncommon in the pediatric population, particularly when it manifests as severe anemia. AIHA is characterized by a positive direct antiglobulin test (DAT) and immune-mediated red blood cell (RBC) destruction. AIHA is subclassified on the basis of the thermal characteristics of autoantibody into warm, cold, and mixed. Mixed AIHA shows both the common types and characteristics of warm and cold types. A 14-year-old male, born of nonconsanguineous marriage, admitted with complaints of dizziness and hematuria. It was not associated with decreased urine output and abdominal pain. The child had a similar type of history 2 years back for that, he was treated with a 3-unit-packed RBC transfusion. On examination marked pallor, icterus and mild splenomegaly were present. Diagnosis of mixed AIHA was done on the basis of a DAT and was 4+ positive against Ig G and C3d. In cold, an agglutination test was done which was > 1:64 in titer. In peripheral blood smear, at below 37°C, it denoted the clumping of RBC with polychromasia, which is not reversed at room temperature. The child was treated with broad spectrum antibiotics, multiple-packed RBC transfusion, and injection methyl prednisolone. In follow-up, the child's clinically improved but DAT for immunoglobulin G remained positive and prednisolone was tapered to a maintenance dose of 0.5 mg/kg on alternate days. Mixed AIHA in pediatrics is an extremely rare disease, especially when presenting with severe anemia. It is very difficult to diagnose and treat. Hence, detailed clinical and extensive laboratory workup is required to diagnose the case. Clinical presentation of mixed AIHA, other than acute hemolysis, may manifest as blood group cross-match incompatibility, which is challenging for pathologists and awareness of this occurrence is essential for clinicians. A case of mixed AIHA should be treated with steroids immediately along with supportive care of packed RBC transfusion with the least incompatibility and long-term follow-up is required to improve outcome. RésuméL’anémie hémolytique auto-immune (AHAI) est rare chez les enfants, en particulier lorsqu’elle se manifeste par une anémie sévère. L’AHAI se caractérise par un test direct à l’antiglobuline (TDA) positif et une destruction des globules rouges (GR) à médiation immunitaire. L’AHAI est classée selon les caractéristiques thermiques des auto-anticorps : chaude, froide et mixte. L’AHAI mixte présente les types courants et les caractéristiques des types chaud et froid. Un garçon de 14 ans, né d’un mariage non consanguin, a été admis pour des vertiges et une hématurie. Ces symptômes n’étaient pas associés à une diminution du débit urinaire ni à des douleurs abdominales. L’enfant avait présenté des antécédents similaires deux ans auparavant, et avait donc été traité par une transfusion de 3 unités de GR. À l’examen, une pâleur marquée, un ictère et une légère splénomégalie étaient présents. Le diagnostic d’AHAI mixte a été posé sur la base d’un TDA et la positivité était de 4+ pour les Ig G et C3d. À froid, un test d’agglutination a été réalisé, dont le titre était supérieur à 1:64. Un frottis sanguin périphérique, à moins de 37 °C, a révélé une agglutination des globules rouges avec polychromasie, irréversible à température ambiante. L’enfant a été traité par antibiotiques à large spectre, transfusion de globules rouges concentrés et injection de méthylprednisolone. Lors du suivi, l’état clinique de l’enfant s’est amélioré, mais le test d’immunoglobuline G (TDA) est resté positif et la prednisolone a été réduite progressivement à une dose d’entretien de 0,5 mg/kg un jour sur deux. L’AHAI mixte en pédiatrie est une maladie extrêmement rare, surtout en cas d’anémie sévère. Son diagnostic et son traitement sont très difficiles. Par conséquent, un bilan clinique détaillé et des analyses de laboratoire approfondies sont nécessaires pour diagnostiquer ce cas. Le tableau clinique d’une AHAI mixte, autre qu’une hémolyse aiguë, peut se manifester par une incompatibilité de groupe sanguin, ce qui représente un défi pour les pathologistes et la connaissance de cette éventualité est essentielle pour les cliniciens. Un cas d’AIHA mixte doit être traité immédiatement avec des stéroïdes, accompagné de soins de soutien par transfusion de globules rouges concentrés, avec la moindre incompatibilité et un suivi à long terme est nécessaire pour améliorer le résultat.

Mixed autoimmune hemolytic anemia (AIHA) is a rare and clinically complex hematologic disorder defined by the simultaneous presence of both warm and cold autoantibodies, resulting in severe and often treatment-resistant hemolysis. Due to variability in diagnostic criteria and limited data, a comprehensive understanding of its epidemiology, clinical characteristics, and management remains incomplete. To address these gaps, we performed a systematic literature review employing stringent diagnostic criteria to evaluate epidemiologic patterns, clinical features, and therapeutic outcomes. Our analysis included 81 patients identified across 35 studies, revealing a median age of 45 years and a notable female predominance (2.25:1). Autoimmune diseases constituted the most frequent underlying etiology, followed by hematologic malignancies and infections. Patients exhibited significant anemia, with median nadir hemoglobin levels reaching 5.6 g/dL. Corticosteroids represented the most common therapeutic intervention; however, only 43% of patients achieved remission, while 37% experienced chronic hemolysis, and mortality reached 11%. Many patients required multiple lines of therapy, including rituximab and cytotoxic agents, highlighting the disease's refractory nature and management complexity. The substantial variability in diagnostic and therapeutic approaches emphasizes an urgent need for standardized diagnostic criteria, earlier integration of combination therapies, and exploration of innovative treatment modalities. Future prospective, multicenter studies are essential to refine disease recognition, optimize therapeutic strategies, and ultimately improve patient outcomes in mixed AIHA.

Autoimmune hemolytic anemia (AIHA) is an acquired condition caused by autoantibody mediated destruction of erythrocytes. AIHA is classified as warm or cold depending on whether the autoantibodies involved react optimally at or below body temperature (37°C), respectively. Mixed AIHA, with features of both, is rare and clinically more severe. We report a case of mixed AIHA that was found to be the presentation of systemic lupus erythematosus (SLE). Treatment with rituximab and prednisone resulted in good response. Although more commonly associated with warm AIHA, SLE can present with mixed AIHA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to a wide spectrum of clinical and immunological abnormalities. Hematologic abnormalities are an important manifestation of SLE. The incidence of autoimmune hemolytic anemia (AIHA) has been reported in approximately 10% of patients with SLE. Among them, mixed-type AIHA, which is caused by warm autoantibodies and cold hemagglutinin, is relatively rarely reported. We report the case of a 72-year-old woman, who was admitted to our hospital due to shortness of breath, jaundice, and severe anemia, with SLE and antiphospholipid syndrome (APS) complicated by mixed-type AIHA. Laboratory data revealed severe hemolytic anemia (low hemoglobin, high indirect bilirubin, and high lactate dehydrogenase levels), low complement levels, and the presence of antinuclear antibodies and lupus anticoagulant. Imaging results revealed pleural effusion and pulmonary embolisms, and echocardiogram revealed high estimated right ventricular pressure. She was diagnosed with SLE and APS complicated by mixed-type AIHA based on positive direct antiglobulin and cold agglutinin tests (thermal amplitude ≥30°C). As mixed-type AIHA is a severe and chronic condition, she was administered potent treatments with immunosuppressants. However, because she was a carrier of human T-cell leukemia virus type-1, only a moderate amount of prednisolone was administered. She refused to take warfarin. Fortunately, her symptoms and laboratory abnormalities improved after prednisolone administration, and no relapse occurred after tapering the prednisolone dose. Although mixed-type AIHA is characterized by fewer clinical symptoms than cold agglutinin disease, hemolytic anemia is more severe and chronic. Therefore, it is important to confirm the presence of cold agglutinins, which are active at ≥30°C in patients with SLE and warm AIHA. In addition, it is important to consider that AIHA is associated with thromboembolism, and patients with lupus anticoagulant or anticardiolipin antibodies having a history of AIHA are at a high risk of developing thrombosis.