Autoimmune Hemolytic Anemia

Autoimmune MONDO:0020108 Show in embeddings browser Autoimmune Disease Hematologic Disease

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.

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3
Pathophys.
4
Phenotypes
4
Medical Actions
3
Datasets
9
References
2
Deep Research
🏷

Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY IMMUNE RHEUMATOLOGIC
⚙

Pathophysiology

3
Warm Autoantibody-Mediated Hemolysis
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.
Macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. Red Blood Cell CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Red Blood Cell, annotated with erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Phagocytosis GO:0006909 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Phagocytosis (GO:0006909). GO:0006909 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:38673882 SUPPORT
"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."
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.
PMID:29692344 SUPPORT
"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)"
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.
Cold Agglutinin-Mediated Hemolysis
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.
Complement Activation GO:0006956 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Complement Activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:38673882 SUPPORT
"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..."
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.
PMID:30559259 SUPPORT
"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."
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.
PMID:32176765 SUPPORT
"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."
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.
B Cell Dysregulation
Loss of B cell tolerance allows production of anti-RBC autoantibodies. In secondary AIHA, underlying conditions (lymphoma, CLL, SLE) drive autoantibody production.
B Cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B Cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Immunoglobulin Production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Immunoglobulin Production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:39371250 SUPPORT
"Therapy is quite different, as steroids and rituximab are effective in the former, but have a lower response rate and duration in the latter."
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.
PMID:38673882 SUPPORT
"Treatment involves glucocorticoids and steroid-sparing agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q."
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

4
Blood 1
Anemia VERY_FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Can be severe with rapid onset
Show evidence (1 reference)
PMID:30146455 SUPPORT Human Clinical
"At the time of diagnosis, hemoglobin level was 3-10.5 g/dL."
Every patient in this consecutive primary-AIHA series presented anemic, with hemoglobin values reaching as low as 3 g/dL. The cohort is pediatric (21 children), so it establishes the presence and potential severity of anemia rather than an adult frequency estimate.
Cardiovascular 1
Splenomegaly FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Site of extravascular hemolysis
Show evidence (1 reference)
PMID:30146455 SUPPORT Human Clinical
"icterus and hepatomegaly /splenomegaly was the most common physical findings"
Splenomegaly is reported among the most common physical findings in this consecutive primary-AIHA series (pediatric, n=21). The source reports hepatomegaly and splenomegaly together, so it does not separate the two.
Digestive 1
Jaundice FREQUENT HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Due to bilirubin from hemolysis
Show evidence (1 reference)
PMID:30146455 SUPPORT Human Clinical
"Pallor and jaundice were the common complaints and icterus and hepatomegaly /splenomegaly was the most common physical findings."
Jaundice was among the most common presenting complaints, and icterus among the most common physical findings, in this consecutive primary-AIHA series (pediatric, n=21).
Constitutional 1
Fatigue VERY_FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40728672 SUPPORT Human Clinical
"All participants described fatigue as the most prominent or most bothersome symptom, with substantial impacts on daily functioning, family and social life, and emotional well-being."
Fatigue was reported by every participant in two qualitative interview studies of adults with warm AIHA (n=20 combined) and was the dominant patient-reported symptom. The sample is small and warm-AIHA-specific.
💊

Medical Actions

4
Corticosteroids
Action: corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is corticosteroid therapy, annotated with Systemic Corticosteroid Therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. Ontology label: Systemic Corticosteroid Therapy NCIT:C122080
First-line for warm AIHA.
Show evidence (1 reference)
PMID:25271314 SUPPORT Human Clinical
"The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients"
This review establishes corticosteroids as first-line therapy with 70-85% efficacy.
Rituximab
Action: rituximab therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is rituximab therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Second-line, high response rates.
Show evidence (1 reference)
PMID:25271314 SUPPORT Human Clinical
"rituximab (effective in approx. 80-90% of cases)"
Rituximab demonstrates 80-90% efficacy as second-line therapy.
Splenectomy
Action: splenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is splenectomy (NCIT:C15328). NCIT:C15328 is a clinical intervention from the NCI Thesaurus. Ontology label: Splenectomy NCIT:C15328
For refractory warm AIHA.
Show evidence (1 reference)
PMID:25271314 SUPPORT Human Clinical
"splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%)"
Splenectomy is effective in approximately 2/3 of cases with up to 20% cure rate.
Complement Inhibitors
Action: complement inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is complement inhibitor therapy, annotated with Biological Therapy (NCIT:C15187). NCIT:C15187 is a clinical intervention from the NCI Thesaurus. Ontology label: Biological Therapy NCIT:C15187
Sutimlimab for cold agglutinin disease.
Show evidence (1 reference)
PMID:33826820 SUPPORT Human Clinical
"selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue"
The CARDINAL trial demonstrated sutimlimab's efficacy in halting complement-mediated hemolysis in cold agglutinin disease.
🔬

Biochemical Markers

5
Direct Antiglobulin Test (DAT) (Positive)
Context: Diagnostic; IgG and/or C3d positive
Show evidence (2 references)
PMID:31839434 SUPPORT Human Clinical
"Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup"
The First International Consensus Meeting makes the monospecific DAT a mandatory part of the AIHA diagnostic workup, which is what distinguishes immune from non-immune hemolysis.
PMID:26819490 SUPPORT Human Clinical
"The direct antiglobulin test is the cornerstone of autoimmune forms"
Identifies the DAT as the defining laboratory marker separating autoimmune from other hemolytic anemias.
Reticulocytes (Elevated)
Context: Compensatory marrow response
Show evidence (2 references)
PMID:26819490 SUPPORT Human Clinical
"increased reticulocytes, an indicator of marrow compensatory response"
Reticulocytosis is listed as a hemolytic marker reflecting the compensatory marrow response, which is the interpretation recorded in this entry's context field.
PMID:26819490 SUPPORT Human Clinical
"Reticulocytopenia occurs in 20-40% of autoimmune hemolytic anemia cases and is a poor prognostic factor."
Qualifies the marker: in AIHA specifically, the expected reticulocytosis is absent in a substantial minority of cases, so a normal or low reticulocyte count does not exclude the diagnosis.
LDH (Elevated)
Context: Marker of hemolysis
Show evidence (1 reference)
PMID:26819490 SUPPORT Human Clinical
"elevated lactate dehydrogenase, a marker of intravascular hemolysis"
Establishes elevated LDH as a hemolytic marker, and specifies that it indexes the intravascular component in particular.
Haptoglobin (Decreased)
Context: Consumed by free hemoglobin
Show evidence (1 reference)
PMID:26819490 SUPPORT Human Clinical
"elevated lactate dehydrogenase, a marker of intravascular hemolysis, reduced haptoglobin"
Reduced haptoglobin is enumerated among the standard laboratory markers of hemolysis.
Indirect Bilirubin (Elevated)
Context: From RBC breakdown
Show evidence (1 reference)
PMID:26819490 SUPPORT Human Clinical
"reduced haptoglobin, and unconjugated hyperbilirubinemia"
Unconjugated (indirect) hyperbilirubinemia is enumerated among the standard laboratory markers of hemolysis.
📊

Related Datasets

3
Comprehensive evaluation of bone marrow microenvironment in patients with autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing. geo:GSE301528
Here we investigated bone marrow (BM) features in a large cohort of 97 patients with autoimmune hemolytic anemia (AIHA) and observed a high prevalence of hypercellularity, dyserythropoiesis, reticulin fibrosis, and T-cell infiltration (65%, 29%, 76%, and 69% of patients, respectively). These findings were associated with inadequate bone marrow compensation, more severe anemia at onset, and need of multiple treatments. In a subset of warm type AIHA patients we investigated BM microenvironment by single-cell RNA sequencing. We found distinct immune cell profiles across disease stages (diagnosis, remission, relapse).
human SINGLE CELL RNA SEQ n=18
PMID:40854885
Identified by GEO DataSets index search for Autoimmune Hemolytic Anemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Transcriptional modifications between Treg from healthy donors (HD) and Treg from patients suffering from warm autoimmune hemolytic anemia (wAIHA) geo:GSE195791
We assessed Next Generation RNA Sequencing of circulating Treg from PBMC of HD or wAIHA patients and our results showed that Treg have an activated profile with sustained transcriptional and translational activity, as well as strong engagement of the TCR and TNF-a signaling pathway during wAIHA.
human BULK RNA SEQ n=9
PMID:37534543
Identified by GEO DataSets index search for Autoimmune Hemolytic Anemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Early-onset autoimmune hemolytic anemia study ega:EGAS00001003618
human WES
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Autoimmune Hemolytic Anemia"); description-level mentions were not accepted. EGA study_type: Exome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
{ }

Source YAML

click to show 
name: Autoimmune Hemolytic Anemia
creation_date: '2025-12-19T01:12:52Z'
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: SUPPORT
    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: SUPPORT
    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: SUPPORT
    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: SUPPORT
    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
  evidence:
  - reference: PMID:30146455
    reference_title: "Clinical features and treatment of primary autoimmune hemolytic anemia in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of diagnosis, hemoglobin level was 3-10.5 g/dL."
    explanation: >-
      Every patient in this consecutive primary-AIHA series presented anemic,
      with hemoglobin values reaching as low as 3 g/dL. The cohort is pediatric
      (21 children), so it establishes the presence and potential severity of
      anemia rather than an adult frequency estimate.
- name: Jaundice
  category: Hepatic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  notes: Due to bilirubin from hemolysis
  evidence:
  - reference: PMID:30146455
    reference_title: "Clinical features and treatment of primary autoimmune hemolytic anemia in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pallor and jaundice were the common complaints and icterus and hepatomegaly /splenomegaly was the most common physical findings."
    explanation: >-
      Jaundice was among the most common presenting complaints, and icterus
      among the most common physical findings, in this consecutive primary-AIHA
      series (pediatric, n=21).
- name: Splenomegaly
  category: Hematological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  notes: Site of extravascular hemolysis
  evidence:
  - reference: PMID:30146455
    reference_title: "Clinical features and treatment of primary autoimmune hemolytic anemia in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "icterus and hepatomegaly /splenomegaly was the most common physical findings"
    explanation: >-
      Splenomegaly is reported among the most common physical findings in this
      consecutive primary-AIHA series (pediatric, n=21). The source reports
      hepatomegaly and splenomegaly together, so it does not separate the two.
- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:40728672
    reference_title: "Content validity and meaningful change for the FACIT-Fatigue scale in warm autoimmune hemolytic anemia: results from qualitative interview studies with patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All participants described fatigue as the most prominent or most bothersome symptom, with substantial impacts on daily functioning, family and social life, and emotional well-being."
    explanation: >-
      Fatigue was reported by every participant in two qualitative interview
      studies of adults with warm AIHA (n=20 combined) and was the dominant
      patient-reported symptom. The sample is small and warm-AIHA-specific.
biochemical:
- name: Direct Antiglobulin Test (DAT)
  presence: Positive
  context: Diagnostic; IgG and/or C3d positive
  evidence:
  - reference: PMID:31839434
    reference_title: "Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup"
    explanation: >-
      The First International Consensus Meeting makes the monospecific DAT a
      mandatory part of the AIHA diagnostic workup, which is what distinguishes
      immune from non-immune hemolysis.
  - reference: PMID:26819490
    reference_title: "Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The direct antiglobulin test is the cornerstone of autoimmune forms"
    explanation: >-
      Identifies the DAT as the defining laboratory marker separating autoimmune
      from other hemolytic anemias.
- name: Reticulocytes
  presence: Elevated
  context: Compensatory marrow response
  evidence:
  - reference: PMID:26819490
    reference_title: "Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased reticulocytes, an indicator of marrow compensatory response"
    explanation: >-
      Reticulocytosis is listed as a hemolytic marker reflecting the
      compensatory marrow response, which is the interpretation recorded in
      this entry's context field.
  - reference: PMID:26819490
    reference_title: "Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reticulocytopenia occurs in 20-40% of autoimmune hemolytic anemia cases and is a poor prognostic factor."
    explanation: >-
      Qualifies the marker: in AIHA specifically, the expected reticulocytosis
      is absent in a substantial minority of cases, so a normal or low
      reticulocyte count does not exclude the diagnosis.
- name: LDH
  presence: Elevated
  context: Marker of hemolysis
  evidence:
  - reference: PMID:26819490
    reference_title: "Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated lactate dehydrogenase, a marker of intravascular hemolysis"
    explanation: >-
      Establishes elevated LDH as a hemolytic marker, and specifies that it
      indexes the intravascular component in particular.
- name: Haptoglobin
  presence: Decreased
  context: Consumed by free hemoglobin
  evidence:
  - reference: PMID:26819490
    reference_title: "Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated lactate dehydrogenase, a marker of intravascular hemolysis, reduced haptoglobin"
    explanation: >-
      Reduced haptoglobin is enumerated among the standard laboratory markers of
      hemolysis.
- name: Indirect Bilirubin
  presence: Elevated
  context: From RBC breakdown
  evidence:
  - reference: PMID:26819490
    reference_title: "Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduced haptoglobin, and unconjugated hyperbilirubinemia"
    explanation: >-
      Unconjugated (indirect) hyperbilirubinemia is enumerated among the
      standard laboratory markers of hemolysis.
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: NCIT:C15986
      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: NCIT:C15328
      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: NCIT:C15187
      label: Biological 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: ONCOLOGY_HEMATOLOGY
  - classification_value: IMMUNE_RHEUMATOLOGIC
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: []
datasets:
- accession: geo:GSE301528
  title: 'Comprehensive evaluation of bone marrow microenvironment in patients with autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing.'
  description: Here we investigated bone marrow (BM) features in a large cohort of 97 patients with autoimmune hemolytic anemia (AIHA) and observed a high prevalence of hypercellularity, dyserythropoiesis, reticulin fibrosis, and T-cell infiltration (65%, 29%, 76%, and 69% of patients, respectively). These findings were associated with inadequate bone marrow compensation, more severe anemia at onset, and need of multiple treatments. In a subset of warm type AIHA patients we investigated BM microenvironment by single-cell RNA sequencing. We found distinct immune cell profiles across disease stages (diagnosis, remission, relapse).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 18
  publication: PMID:40854885
  notes: Identified by GEO DataSets index search for Autoimmune Hemolytic Anemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE195791
  title: Transcriptional modifications between Treg from healthy donors (HD) and Treg from patients suffering from warm autoimmune hemolytic anemia (wAIHA)
  description: We assessed Next Generation RNA Sequencing of circulating Treg from PBMC of HD or wAIHA patients and our results showed that Treg have an activated profile with sustained transcriptional and translational activity, as well as strong engagement of the TCR and TNF-a signaling pathway during wAIHA.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 9
  publication: PMID:37534543
  notes: Identified by GEO DataSets index search for Autoimmune Hemolytic Anemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003618
  title: Early-onset autoimmune hemolytic anemia study
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WES
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Autoimmune Hemolytic Anemia"); description-level mentions were not accepted. EGA study_type: Exome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
📚

References & Deep Research

References

9
DOI:10.1016/j.eclinm.2024.102733
Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B
No top-level findings curated for this source.
DOI:10.1038/s41392-025-02348-y
Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing
No top-level findings curated for this source.
DOI:10.1159/000540475
Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy
No top-level findings curated for this source.
DOI:10.1182/bloodadvances.2024012585
Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease
No top-level findings curated for this source.
DOI:10.3389/fimmu.2025.1624667
Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions
No top-level findings curated for this source.
DOI:10.3390/ijms25084296
Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management
No top-level findings curated for this source.
DOI:10.3390/jcm9123859
New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy
No top-level findings curated for this source.
DOI:10.5633/amm.2024.0108
CD4+ T CELL PROFILES IN AUTOIMMUNE HEMOLYTIC ANEMIA
No top-level findings curated for this source.
DOI:10.6004/jadpro.2024.15.6.4
Sutimlimab for Cold Agglutinin Disease
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Autoimmune Hemolytic Anemia
  • Category: Autoimmune
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 16

Key Pathophysiology Nodes

  • Warm Autoantibody-Mediated Hemolysis
  • Cold Agglutinin-Mediated Hemolysis
  • B Cell Dysregulation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.eclinm.2024.102733
  • DOI:10.1038/s41392-025-02348-y
  • DOI:10.1159/000540475
  • DOI:10.1182/bloodadvances.2024012585
  • DOI:10.3389/fimmu.2025.1624667
  • DOI:10.3390/ijms25084296
  • DOI:10.3390/jcm9123859
  • DOI:10.5633/amm.2024.0108
  • DOI:10.6004/jadpro.2024.15.6.4
Falcon ▸
Pathophysiology description (narrative for KB entry)
Edison Scientific Literature 28 citations 2025-12-18T09:55:23.467538

Pathophysiology description (narrative for KB entry) AIHA results from immune recognition of self-RBC antigens with autoantibodies (IgG or IgM) that initiate FcγR-mediated erythrophagocytosis in the spleen or classical complement activation with C3 opsonization and occasional MAC-mediated lysis. Warm IgG autoantibodies (often anti-band 3/Rh) at 37°C engage FcγR-bearing splenic macrophages (extravascular hemolysis), with complement contributing variably. Cold IgM autoantibodies in CAD agglutinate RBCs and drive C1q/C1s-dependent C3b deposition, favoring hepatic Kupffer cell clearance and sometimes intravascular hemolysis; mixed AIHA combines both mechanisms; PCH features a biphasic IgG (Donath–Landsteiner) that fixes complement on rewarming to cause intravascular hemolysis. A breakdown in immune tolerance involving Tfh/Treg and B-cell survival signals sustains autoantibody production. Clinical severity depends on effector balance (extravascular vs intravascular), degree of complement activation, and marrow compensation. Mechanism-based therapies target B cells (rituximab), plasma cells (daratumumab), FcγR signaling (SYK), BCR signaling (BTK/PI3K), IgG recycling (FcRn), and complement (C1s, C5) (barcellini2024autoimmunehemolyticanemias pages 1-2, loriamini2024autoimmunehemolyticanemiasa pages 4-5, costa2025beneaththesurface pages 2-3, costa2025beneaththesurface pages 1-2, loriamini2024autoimmunehemolyticanemiasa pages 7-8, kostic2024cd4+tcell pages 1-2).

Gene/protein annotations with ontology terms (examples) - FCGR2A (HGNC) – GO: Fcγ receptor signaling, FcγR-mediated phagocytosis; CL: splenic red pulp macrophage; UBERON: spleen; Evidence: wAIHA extravascular hemolysis (costa2025beneaththesurface pages 2-3, barcellini2024autoimmunehemolyticanemias pages 1-2). - C1S (HGNC) – GO: classical complement activation; UBERON: liver (Kupffer cell clearance) and blood (activation); CHEBI: IgM triggers; Evidence: CAD complement dependence; sutimlimab efficacy (barcellini2024autoimmunehemolyticanemias pages 1-2, costa2025beneaththesurface pages 2-3). - SLC4A1/Band 3 (HGNC) – GO: RBC membrane; target of warm autoantibodies; Evidence: warm panreactive anti-band 3 (barcellini2020newinsightsin pages 1-3, loriamini2024autoimmunehemolyticanemiasa pages 1-2).

Phenotype associations (HPO; examples) - Autoimmune hemolytic anemia (HP:0001933); Jaundice (HP:0000952); Hemoglobinuria (HP:0002904); Acrocyanosis (HP:0001063) in CAD; Elevated LDH (HP:0032456); Low haptoglobin (HP:0012394); Reticulocytosis (HP:0001923) or Reticulocytopenia (HP:0020059) (barcellini2024autoimmunehemolyticanemias pages 1-2, loriamini2024autoimmunehemolyticanemiasa pages 4-5, costa2025beneaththesurface pages 2-3).

Cell type involvement (CL; examples) - Splenic red pulp macrophages (CL:0000898) – ADCP of IgG-opsonized RBCs; Kupffer cells (CL:0000232) – complement-opsonized RBC clearance; Tfh (CL:0002323); Treg (CL:0000815); NK cells (CL:0000623) (costa2025beneaththesurface pages 2-3, barcellini2024autoimmunehemolyticanemias pages 1-2, kostic2024cd4+tcell pages 1-2).

Anatomical locations (UBERON; examples) - Spleen (UBERON:0002106); Liver (UBERON:0002107); Bone marrow (UBERON:0002371); Blood (UBERON:0000178) (barcellini2024autoimmunehemolyticanemias pages 1-2, loriamini2024autoimmunehemolyticanemiasa pages 4-5, loriamini2024autoimmunehemolyticanemiasa pages 7-8).

Chemical entities (CHEBI; examples) - IgG (CHEBI:16110); IgM (CHEBI:15996); Heme (CHEBI:17627); Bilirubin (CHEBI:16990). Drugs: rituximab, daratumumab, sutimlimab, eculizumab, fostamatinib, ibrutinib, FcRn blockers (barcellini2024autoimmunehemolyticanemias pages 1-2, loriamini2024autoimmunehemolyticanemiasa pages 7-8, costa2025beneaththesurface pages 2-3).

Notes on limitations - Some epidemiologic figures vary across datasets and geography; subtyping by DAT requires expert interpretation due to imperfect sensitivity/specificity; several T-cell tolerance and BAFF-centric mechanisms are derived from broader autoimmunity literature and specific AIHA-focused immunophenotyping continues to evolve (barcellini2024autoimmunehemolyticanemias pages 1-2, loriamini2024autoimmunehemolyticanemiasa pages 7-8, kostic2024cd4+tcell pages 1-2).

References

  1. (barcellini2024autoimmunehemolyticanemias pages 1-2): Wilma Barcellini and Bruno Fattizzo. Autoimmune hemolytic anemias: challenges in diagnosis and therapy. Transfusion Medicine and Hemotherapy, 51:321-331, Aug 2024. URL: https://doi.org/10.1159/000540475, doi:10.1159/000540475. This article has 18 citations and is from a peer-reviewed journal.

  2. (loriamini2024autoimmunehemolyticanemiasa pages 4-5): Melika Loriamini, Christine Cserti-Gazdewich, and Donald R. Branch. Autoimmune hemolytic anemias: classifications, pathophysiology, diagnoses and management. International Journal of Molecular Sciences, 25:4296, Apr 2024. URL: https://doi.org/10.3390/ijms25084296, doi:10.3390/ijms25084296. This article has 40 citations and is from a poor quality or predatory journal.

  3. (costa2025beneaththesurface pages 1-2): Alessandro Costa, Olga Mulas, Angela Maria Mereu, Mercede Schintu, Marianna Greco, and Giovanni Caocci. Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions. Frontiers in Immunology, Jul 2025. URL: https://doi.org/10.3389/fimmu.2025.1624667, doi:10.3389/fimmu.2025.1624667. This article has 1 citations and is from a peer-reviewed journal.

  4. (kostic2024cd4+tcell pages 1-2): Miloš Kostić, Nikola Živković, and Ana Cvetanović. Cd4+ t cell profiles in autoimmune hemolytic anemia. Acta Medica Medianae, 63:73-82, Mar 2024. URL: https://doi.org/10.5633/amm.2024.0108, doi:10.5633/amm.2024.0108. This article has 0 citations.

  5. (costa2025beneaththesurface pages 2-3): Alessandro Costa, Olga Mulas, Angela Maria Mereu, Mercede Schintu, Marianna Greco, and Giovanni Caocci. Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions. Frontiers in Immunology, Jul 2025. URL: https://doi.org/10.3389/fimmu.2025.1624667, doi:10.3389/fimmu.2025.1624667. This article has 1 citations and is from a peer-reviewed journal.

  6. (loriamini2024autoimmunehemolyticanemiasa pages 7-8): Melika Loriamini, Christine Cserti-Gazdewich, and Donald R. Branch. Autoimmune hemolytic anemias: classifications, pathophysiology, diagnoses and management. International Journal of Molecular Sciences, 25:4296, Apr 2024. URL: https://doi.org/10.3390/ijms25084296, doi:10.3390/ijms25084296. This article has 40 citations and is from a poor quality or predatory journal.

  7. (loriamini2024autoimmunehemolyticanemiasa pages 1-2): Melika Loriamini, Christine Cserti-Gazdewich, and Donald R. Branch. Autoimmune hemolytic anemias: classifications, pathophysiology, diagnoses and management. International Journal of Molecular Sciences, 25:4296, Apr 2024. URL: https://doi.org/10.3390/ijms25084296, doi:10.3390/ijms25084296. This article has 40 citations and is from a poor quality or predatory journal.

  8. (barcellini2020newinsightsin pages 1-3): Wilma Barcellini, Anna Zaninoni, Juri Alessandro Giannotta, and Bruno Fattizzo. New insights in autoimmune hemolytic anemia: from pathogenesis to therapy. Journal of Clinical Medicine, 9:3859, Nov 2020. URL: https://doi.org/10.3390/jcm9123859, doi:10.3390/jcm9123859. This article has 139 citations and is from a poor quality or predatory journal.