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Autoimmune Hemolytic Anemia

Pathophysiology description (narrative for KB entry)

2025-12-18
Falcon MONDO:0020108 Model: Edison Scientific Literature 28 citations

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.