Autoimmune Hemolytic Anemia

name: Autoimmune Hemolytic Anemia
creation_date: '2025-12-19T01:12:52Z'
updated_date: '2026-03-13T12:00:00Z'
category: Autoimmune
parents:
- Autoimmune Disease
- Hematologic Disease
disease_term:
  preferred_term: Autoimmune Hemolytic Anemia
  term:
    id: MONDO:0020108
    label: autoimmune hemolytic anemia
description: >-
  An acquired hemolytic anemia caused by autoantibodies against red blood cell
  surface antigens. Classified as warm (IgG, 70-80%) or cold (IgM, cold agglutinin
  disease) based on antibody thermal amplitude. May be primary or secondary to
  underlying disease.
pathophysiology:
- name: Warm Autoantibody-Mediated Hemolysis
  description: >-
    IgG autoantibodies coat red blood cells and are recognized by Fc receptors
    on splenic macrophages, leading to extravascular hemolysis through
    phagocytosis. Partial phagocytosis creates spherocytes with reduced
    membrane.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Red Blood Cell
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: Phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: PARTIAL
    snippet: "Warm-antibody AIHA (wAIHA) exhibits a pan-reactive IgG autoantibody
      recognizing a portion of band 3 (wherein the DAT may be positive with IgG, C3d
      or both). Treatment involves glucocorticoids and steroid-sparing agents and
      may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q."
    explanation: >-
      This comprehensive 2024 review confirms that warm AIHA is mediated by IgG autoantibodies
      that recognize RBC antigens like band 3, consistent with the FcR-mediated phagocytosis
      mechanism.
  - reference: PMID:29692344
    reference_title: "Red pulp macrophages in the human spleen are a distinct cell population with a unique expression of Fc-γ receptors."
    supports: SUPPORT
    snippet: "Tissue-resident macrophages in the spleen play a major role in the clearance
      of immunoglobulin G (IgG)-opsonized blood cells, as occurs in immune thrombocytopenia
      (ITP) and autoimmune hemolytic anemia (AIHA). Blood cells are phagocytosed via
      the Fc-γ receptors (FcγRs)"
    explanation: >-
      This study demonstrates that splenic red pulp macrophages express FcγRIIa and
      FcγRIIIa receptors
      and are responsible for phagocytosis of IgG-opsonized RBCs in AIHA, directly
      supporting the
      mechanism of extravascular hemolysis in warm AIHA.
- name: Cold Agglutinin-Mediated Hemolysis
  description: >-
    IgM autoantibodies bind RBCs at low temperatures and activate complement.
    C3b-coated cells undergo extravascular hemolysis in the liver, or MAC
    formation causes intravascular hemolysis.
  biological_processes:
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: PARTIAL
    snippet: "Cold-antibody AIHA due to IgMs range from cold agglutinin syndrome (CAS)
      to cold agglutin disease (CAD). These are typically specific to the Ii blood
      group system, with the former (CAS) being polyclonal and the latter (CAD) being
      a more severe and monoclonal entity. The DAT in either case is positive only
      with C3d."
    explanation: >-
      This comprehensive review confirms that cold AIHA is mediated by IgM autoantibodies
      that
      activate the complement cascade, resulting in C3d deposition on RBCs and complement-mediated
      hemolysis.
  - reference: PMID:30559259
    reference_title: "Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial."
    supports: SUPPORT
    snippet: "Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic
      anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement,
      resulting in predominantly extravascular hemolysis."
    explanation: >-
      This first-in-human trial of C1s inhibition confirms the central role of classical
      complement
      pathway activation in cold agglutinin disease, where IgM binding triggers complement
      fixation
      leading to C3b opsonization and extravascular hemolysis.
  - reference: PMID:32176765
    reference_title: "Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program."
    supports: SUPPORT
    snippet: "Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis
      and anemia via complement activation. Sutimlimab is a novel humanized monoclonal
      antibody directed against classical pathway complement factor C1s."
    explanation: >-
      This clinical study demonstrates that blocking C1s (the serine protease in the
      C1 complex)
      effectively stops complement-mediated hemolysis in CAD, confirming that classical
      pathway
      activation via C1s is the key mechanism driving RBC destruction in cold agglutinin
      disease.
- name: B Cell Dysregulation
  description: >-
    Loss of B cell tolerance allows production of anti-RBC autoantibodies.
    In secondary AIHA, underlying conditions (lymphoma, CLL, SLE) drive
    autoantibody production.
  cell_types:
  - preferred_term: B Cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: Immunoglobulin Production
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: PARTIAL
    snippet: "Therapy is quite different, as steroids and rituximab are effective
      in the former, but have a lower response rate and duration in the latter."
    explanation: >-
      This 2024 review confirms that B cell-targeting therapy (rituximab, anti-CD20)
      is effective
      in warm AIHA, supporting the role of dysregulated B cells in autoantibody production
      against RBCs.
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: PARTIAL
    snippet: "Treatment involves glucocorticoids and steroid-sparing agents and may
      consider IVIG or monoclonal antibodies to CD20, CD38 or C1q."
    explanation: >-
      The efficacy of anti-CD20 (rituximab) and anti-CD38 (daratumumab) therapies
      demonstrates
      that B cells and plasma cells are the cellular sources of pathogenic autoantibodies
      in AIHA,
      confirming the role of B cell dysregulation in disease pathogenesis.
phenotypes:
- name: Anemia
  category: Hematological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  notes: Can be severe with rapid onset
- name: Jaundice
  category: Hepatic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  notes: Due to bilirubin from hemolysis
- name: Splenomegaly
  category: Hematological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  notes: Site of extravascular hemolysis
- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
biochemical:
- name: Direct Antiglobulin Test (DAT)
  presence: Positive
  context: Diagnostic; IgG and/or C3d positive
- name: Reticulocytes
  presence: Elevated
  context: Compensatory marrow response
- name: LDH
  presence: Elevated
  context: Marker of hemolysis
- name: Haptoglobin
  presence: Decreased
  context: Consumed by free hemoglobin
- name: Indirect Bilirubin
  presence: Elevated
  context: From RBC breakdown
treatments:
- name: Corticosteroids
  description: First-line for warm AIHA.
  treatment_term:
    preferred_term: corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
  evidence:
  - reference: PMID:25271314
    reference_title: "Treatment of autoimmune hemolytic anemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients"
    explanation: This review establishes corticosteroids as first-line therapy with 70-85% efficacy.
- name: Rituximab
  description: Second-line, high response rates.
  treatment_term:
    preferred_term: rituximab therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:25271314
    reference_title: "Treatment of autoimmune hemolytic anemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rituximab (effective in approx. 80-90% of cases)"
    explanation: Rituximab demonstrates 80-90% efficacy as second-line therapy.
- name: Splenectomy
  description: For refractory warm AIHA.
  treatment_term:
    preferred_term: splenectomy
    term:
      id: MAXO:0001077
      label: splenectomy
  evidence:
  - reference: PMID:25271314
    reference_title: "Treatment of autoimmune hemolytic anemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%)"
    explanation: Splenectomy is effective in approximately 2/3 of cases with up to 20% cure rate.
- name: Complement Inhibitors
  description: Sutimlimab for cold agglutinin disease.
  treatment_term:
    preferred_term: complement inhibitor therapy
    term:
      id: MAXO:0000015
      label: biologic therapy
  evidence:
  - reference: PMID:33826820
    reference_title: "Sutimlimab in Cold Agglutinin Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue"
    explanation: The CARDINAL trial demonstrated sutimlimab's efficacy in halting complement-mediated hemolysis in cold agglutinin disease.
classifications:
  harrisons_chapter:
  - classification_value: hematologic disorder
  - classification_value: anemia
  - classification_value: autoimmune disease
references:
- reference: DOI:10.1016/j.eclinm.2024.102733
  title: 'Long-term efficacy and safety of continued complement C1s inhibition with
    sutimlimab in cold agglutinin disease: CADENZA study Part B'
  findings: []
- reference: DOI:10.1038/s41392-025-02348-y
  title: 'Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine
    biopsy to single cell RNA sequencing'
  findings: []
- reference: DOI:10.1159/000540475
  title: 'Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy'
  findings: []
- reference: DOI:10.1182/bloodadvances.2024012585
  title: Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia
    and cold agglutinin disease
  findings: []
- reference: DOI:10.3389/fimmu.2025.1624667
  title: 'Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks,
    therapeutic advancements and open questions'
  findings: []
- reference: DOI:10.3390/ijms25084296
  title: 'Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses
    and Management'
  findings: []
- reference: DOI:10.3390/jcm9123859
  title: 'New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy'
  findings: []
- reference: DOI:10.5633/amm.2024.0108
  title: CD4+ T CELL PROFILES IN AUTOIMMUNE HEMOLYTIC ANEMIA
  findings: []
- reference: DOI:10.6004/jadpro.2024.15.6.4
  title: Sutimlimab for Cold Agglutinin Disease
  findings: []