Autoimmune Hemolytic Anemia

Autoimmune MONDO:0020108 Pathograph 62 Show in embeddings browser Autoimmune Disease Hematologic Disease

An acquired immune hemolytic disorder in which autoantibodies shorten red-cell survival through Fc-receptor-mediated phagocytosis and/or complement activation. Warm AIHA, cold agglutinin disease or secondary cold agglutinin syndrome, mixed AIHA and paroxysmal cold hemoglobinuria differ in antibody properties, sites of destruction and treatment response. Disease severity also depends on marrow compensation. A positive direct antiglobulin test requires accompanying evidence of hemolysis; a negative standard test does not exclude AIHA. The disorder may be primary or associated with another disease.

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21
Pathophys.
4
Histopath.
12
Phenotypes
62
Pathograph
31
Medical Actions
5
Subtypes
3
Differentials
3
Datasets
26
Trials
9
References
2
Deep Research
🏷

Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY IMMUNE RHEUMATOLOGIC
◆

Subtypes

5
Warm AIHA MONDO:0019532
Usually IgG-mediated hemolysis at body temperature, predominantly through splenic Fc-receptor-mediated clearance. Complement can contribute; IgA and warm IgM forms are uncommon.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The primary antibody isotype involved with wAIHA is IgG, but IgA and IgM may be infrequently seen"
The quote establishes IgG as the usual warm antibody and preserves uncommon IgA and IgM exceptions.
Cold agglutinin disease MONDO:0018922
Chronic clonal B-cell disease producing a pathogenic cold-reactive monoclonal antibody, usually IgM. Complement-mediated hepatic clearance and agglutination-related circulatory symptoms are distinct consequences. Also covered in the dedicated Cold Agglutinin Disease entry.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"CAD is an established clonal B-cell lymphoproliferative disorder of the bone marrow (MYD88 L265P negative)"
The review identifies the marrow B-cell clone, supporting the distinction between primary CAD and a secondary cold agglutinin syndrome.
Secondary cold agglutinin syndrome
Cold-antibody hemolysis associated with another condition, including infection or overt lymphoproliferative disease, rather than the characteristic primary CAD clone. Its course depends on the underlying disorder; not every secondary case is transient or polyclonal.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"As for other AIHAs secondary forms (identified as cold agglutinin syndrome or secondary CAD) should be carefully investigated, as the association with infections, lymphoproliferative disorders and tumors is particularly frequent"
The named associated conditions support investigating an underlying cause; the quote does not establish uniform transience or polyclonality.
Mixed AIHA MONDO:0019534
Coexisting warm IgG and a clinically significant cold-reactive antibody. IgG plus C3d DAT positivity alone does not establish this subtype; cold-antibody thermal amplitude and titer must also be evaluated.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"Since DAT positivity for IgG and C3d may be observed even in wAIHA, the titer of the cold agglutinin and the presence of spontaneous agglutination at 20°C are useful tools."
The quote explains why IgG/C3d DAT positivity alone is insufficient and why cold-antibody testing is needed for the mixed subtype.
Paroxysmal cold hemoglobinuria MONDO:0019533
Biphasic cold-reactive IgG, usually against the P/GLOB antigen, produces complement-mediated intravascular hemolysis on warming. The Donath-Landsteiner test establishes the serologic mechanism. Modern childhood cases are often transient after an infection.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"PCH is characterized by the presence of a cold-reactive IgG autoantibody."
Cold-reactive IgG distinguishes the Donath-Landsteiner/PCH antibody from the usual IgM cold agglutinin.
⚙

Pathophysiology

21
Anti-Erythrocyte Autoantibody Production
Autoreactive B-lineage cells produce antibodies against red-cell antigens. Warm disease generally involves polyclonal responses; CAD has a characteristic clonal B-cell source. Persistent antibody production by CD20-negative plasma cells can contribute to resistance to B-cell depletion.
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.
Downstream
Warm IgG Coating of Erythrocytes Warm-reactive IgG recognizes red-cell antigens.
Cold Agglutinin Binding Cold-reactive antibodies bind and crosslink red cells within their thermal amplitude.
Biphasic Hemolysin Binding In PCH, a cold-reactive IgG binds the P/GLOB antigen.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"In warm AIHA, persistent autoantibody production is driven by autoreactive plasmablasts and plasma cells, with circulating plasmablasts indicating ongoing B-cell activation"
Review synthesis of the antibody-producing compartment; persistence mechanisms are not identical in all AIHA subtypes.
Clonal B-Cell Expansion in CAD
A characteristic marrow B-cell clone supplies the pathogenic monoclonal cold agglutinin in primary CAD. This is distinct from overt lymphoma-associated secondary cold agglutinin syndrome and is not a universal feature of warm AIHA.
Downstream
Anti-Erythrocyte Autoantibody Production The CAD clone produces monoclonal cold-reactive immunoglobulin.
Show evidence (1 reference)
PMID:38673882 SUPPORT Other
"Cold agglutinin disease (CAD) or primary CAD is a clonal disease whereby the lymphoproliferation of a B-cell clone produces a cold-reactive (≤30 °C) monoclonal IgM autoantibody"
Clonal source of the cold autoantibody, as synthesized in the clinical review.
Warm IgG Coating of Erythrocytes
Warm-reactive IgG coats erythrocytes at physiological temperature. Antigen specificity varies; band 3 and Rh-associated reactivity should not be treated as a single universal target.
Downstream
Fc-Gamma-Receptor-Mediated Erythrophagocytosis Fc receptors recognize IgG coating on erythrocytes.
Classical Complement Activation Complement-fixing warm IgG can also activate C1; complement involvement is variable.
Antibody-Dependent Cellular Cytotoxicity IgG-coated red cells provide a potential substrate for Fc-receptor-bearing cytotoxic effector cells.
Show evidence (1 reference)
PMID:38673882 SUPPORT Other
"IgG antibodies have a strong attraction to red blood cells when the temperature is at the normal level of the human body (37 °C)."
Warm antibody binding establishes the opsonic signal for clearance.
Fc-Gamma-Receptor-Mediated Erythrophagocytosis
Splenic red-pulp macrophages recognize and ingest IgG-opsonized erythrocytes. Isolated human red-pulp macrophages predominantly express FcγRIIa and FcγRIIIa; the primary study did not detect the inhibitory FcγRIIb found in some blood-derived macrophage preparations.
splenic red pulp macrophage CL:0000874 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves splenic red pulp macrophage (CL:0000874). CL:0000874 is a cell type from the Cell Ontology. erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Fc-gamma receptor signaling pathway involved in phagocytosis GO:0038096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096). GO:0038096 is a biological process from the Gene Ontology.
spleen UBERON:0002106 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spleen (UBERON:0002106). UBERON:0002106 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Anemia Removal of erythrocytes shortens their circulating survival.
Partial Erythrocyte Membrane Removal Macrophages can remove part of an opsonized cell membrane rather than ingest the entire cell.
Jaundice Increased erythrocyte breakdown increases unconjugated bilirubin production.
Monocyte TNF Production in Hemolytic Conditions IgG-coated erythrocytes stimulate TNF production in cultured monocytes; the systemic feedback contribution remains inferred.
Show evidence (2 references)
PMID:29692344 SUPPORT In Vitro
"Human red pulp macrophages predominantly expressed the low-affinity receptors FcγRIIa and FcγRIIIa. In contrast to blood monocyte-derived macrophages, red pulp macrophages did not express the inhibitory FcγRIIb."
Flow-cytometric characterization of macrophages isolated from human spleens; it does not establish receptor expression in every AIHA patient.
PMID:29692344 SUPPORT In Vitro
"phagocytosis of IgG-opsonized blood cells by red pulp macrophages was dependent on the same FcγRs as phagocytosis by blood monocyte-derived macrophages"
Functional study of isolated human macrophages supports the receptor-dependent clearance mechanism.
Partial Erythrocyte Membrane Removal
Partial macrophage uptake removes erythrocyte membrane, reducing deformability and producing spherocytes that are more readily retained in the spleen.
Downstream
Spherocytosis Loss of membrane relative to cell volume produces the spherical morphology.
Splenomegaly Splenic sequestration of spherocytes and opsonized cells can contribute to enlargement.
Show evidence (1 reference)
PMID:38673882 SUPPORT Other
"In wAIHA, this leads to the degradation of the RBC membrane, causing transformation into spherocytes"
Clinical review describes membrane loss as the route to spherocyte formation.
Cold Agglutinin Binding
Cold-reactive autoantibodies bind red-cell antigens within their thermal amplitude. Binding can initiate both complement activation and red-cell crosslinking; those consequences are modeled separately.
Downstream
Classical Complement Activation Erythrocyte-bound IgM activates the classical pathway.
Erythrocyte Agglutination Multivalent antibody crosslinks erythrocytes.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"The pentameric nature of IgM promotes red cell agglutination, causing RBC aggregates that impair microcirculation in acral regions"
Agglutination is a separate consequence from complement-mediated erythrocyte destruction.
Erythrocyte Agglutination
Multivalent cold agglutinins crosslink erythrocytes into aggregates that impair acral microcirculation. These symptoms can persist despite control of complement-mediated hemolysis.
Downstream
Acrocyanosis Agglutinated erythrocytes impair acral circulation.
Raynaud phenomenon Cold-associated red-cell aggregation contributes to circulatory symptoms.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"The pentameric nature of IgM promotes red cell agglutination, causing RBC aggregates that impair microcirculation in acral regions"
Agglutination is a separate consequence from complement-mediated erythrocyte destruction.
Biphasic Hemolysin Binding
The Donath-Landsteiner IgG binds red cells at lower temperatures and initiates complement fixation; warming permits terminal complement-mediated lysis.
Downstream
Classical Complement Activation Cold-bound IgG fixes early complement components, with further activation on warming.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"the Donath-Landsteiner IgG binds to its antigen at low temperatures and fixes early complement components C1, C4, and C2"
PCH differs from the IgM mechanism of CAD/CAS.
Classical Complement Activation
Erythrocyte-bound antibody activates the C1 complex and the classical complement cascade. C3 opsonization and terminal membrane injury are distinct downstream branches. Warm IgG1/IgG3 can activate complement, although this is less consistently prominent than in cold-antibody disease.
complement activation, classical pathway GO:0006958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves complement activation, classical pathway (GO:0006958). GO:0006958 is a biological process from the Gene Ontology.
Downstream
C3b Opsonization of Erythrocytes Classical-pathway C3 activation deposits opsonic fragments on red cells.
Terminal Complement-Mediated Erythrocyte Lysis Progression through terminal complement forms the membrane attack complex; especially important in PCH and acute cold-antibody exacerbations.
Show evidence (2 references)
PMID:40821796 SUPPORT Other
"IgG1 and IgG3 autoantibodies retain the capacity to activate the classical complement cascade through C1q binding"
Complement is not confined to IgM-mediated AIHA.
PMID:30559259 SUPPORT Human Clinical
"immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis."
Clinical C1s-inhibition study establishes the complement-dependent CAD context.
C3b Opsonization of Erythrocytes
C3b coating promotes complement-receptor-mediated erythrocyte clearance. Residual C3d detected by the DAT is a marker of complement sensitization, not the principal opsonin driving this clearance.
Downstream
Hepatic Clearance of Complement-Opsonized Erythrocytes Complement receptors recognize erythrocyte-bound C3 fragments.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"Opsonization of RBCs by C3b promotes their extravascular clearance, primarily mediated by hepatic macrophages"
Separates the functional C3b opsonin from C3d detected in diagnostic testing.
Hepatic Clearance of Complement-Opsonized Erythrocytes
Hepatic macrophages remove complement-coated erythrocytes. This extravascular pathway predominates in stable CAD, explaining why splenectomy is poorly effective.
Kupffer cell CL:0000091 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Kupffer cell (CL:0000091). CL:0000091 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Anemia Accelerated erythrocyte removal lowers red-cell mass when marrow compensation is insufficient.
Jaundice Increased heme catabolism generates unconjugated bilirubin.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"Opsonization of RBCs by C3b promotes their extravascular clearance, primarily mediated by hepatic macrophages"
Clinical mechanistic synthesis of the major site of complement-opsonized clearance.
Terminal Complement-Mediated Erythrocyte Lysis
Membrane attack complex formation causes intravascular hemolysis. It is prominent in PCH and can increase during CAD exacerbations; it should not replace hepatic extravascular clearance as the predominant stable-CAD mechanism.
Downstream
Anemia Intravascular destruction reduces the circulating red-cell mass.
Hemoglobinuria Released hemoglobin can exceed plasma binding and renal reabsorption capacity.
Monocyte TNF Production in Hemolytic Conditions Heme exposure stimulates cultured human monocytes; its contribution to sustained human autoimmunity is inferred.
Thromboembolism Active intravascular hemolysis is associated with thrombosis; free hemoglobin, inflammatory and complement-coagulation interactions are candidate mediators, with additional patient-specific risk factors.
Show evidence (1 reference)
PMID:40821796 SUPPORT Other
"terminal complement activation with membrane attack complex (MAC) C5b-C9 formation is generally absent during stable clinical phases and occurs predominantly during acute exacerbations or in severe disease"
The review qualifies the relative contribution of terminal complement in CAD.
Monocyte TNF Production in Hemolytic Conditions
Mechanism confidence: Provisional
Heme and IgG-coated erythrocytes increase TNF production by cultured human monocytes. This offers a possible feedback link from hemolysis to immune dysregulation, but does not prove that TNF causes clinical AIHA.
Downstream
Regulatory T-Cell Suppressive Dysfunction Patient TNF-pathway engagement correlates with reduced FOXP3 protein and Treg frequency; a causal TNF-to-Treg effect was not directly isolated in AIHA.
Show evidence (1 reference)
PMID:37534543 SUPPORT In Vitro
"In vitro, we observed that in conditions mimicking wAIHA, monocytes were the main cells producing TNF-α."
Human-cell experiments identify a potential inflammatory feedback source.
Regulatory T-Cell Suppressive Dysfunction
Mechanism confidence: Provisional
Untreated warm-AIHA patients had fewer circulating regulatory T cells and reduced suppression of effector T-cell proliferation in coculture. FOXP3 protein was reduced despite increased transcripts. Proposed phosphorylation/deacetylation mechanisms were not directly demonstrated; onset versus persistence of autoimmunity cannot be distinguished.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
Downstream
Anti-Erythrocyte Autoantibody Production Impaired peripheral regulation may sustain autoreactive immunity; this link remains inferred in humans.
Th17-Associated Immune Polarization Treg dysfunction accompanies a Th17-biased response; a causal conversion of Tregs into Th17 cells was not established.
Show evidence (2 references)
PMID:37534543 SUPPORT In Vitro
"the suppressive function of Treg was also altered in wAIHA, as shown by a decreased ability to inhibit Teff proliferation (51% vs. 73%; P=0.003"
Suppression was tested in nine patient and nine control cocultures, not all 22 enrolled patients.
PMID:37534543 SUPPORT Human Clinical
"In humans, it is impossible to determine whether Treg dysfunction precedes the onset of the disease and promotes it, or whether this deficit merely sustains the disease."
The investigators explicitly limit temporal and causal interpretation.
Th17-Associated Immune Polarization
Mechanism confidence: Provisional
Warm-AIHA cohorts show increased IL-17 production and a higher Th17/Treg ratio. Serum IL-17 correlates with LDH and bilirubin, but not hemoglobin or reticulocyte count; this association does not establish that IL-17 directly destroys red cells.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
Downstream
Anti-Erythrocyte Autoantibody Production Th17-biased immune activity is proposed to support persistent autoreactivity; direct causal proof in patients is lacking.
Show evidence (1 reference)
PMID:37534543 SUPPORT Human Clinical
"the serum concentration of IL-17 positively correlated with markers of RBC destruction, namely lactate dehydrogenase (LDH) and bilirubin"
Observational human serum association, distinct from the cell-culture cytokine assays.
Inflammatory Bone Marrow Microenvironment
Mechanism confidence: Provisional
Biopsy-selected AIHA patients showed lymphoid infiltration and abnormal erythroid morphology. Single-cell analysis in nine warm-AIHA patients found relapse-associated inflammatory programs in T cells and monocytes. Treatment exposure, a small cohort and unrelated relapse samples limit causal inference; transcriptomic cytokine signatures are not direct measurements of secreted cytokine concentrations.
Downstream
Inadequate Erythropoietic Compensation Inflammation, erythroid abnormalities and inadequate endogenous erythropoietin may limit compensation. The marrow study did not directly demonstrate immune killing of erythroblasts.
Show evidence (1 reference)
PMID:40854885 SUPPORT Human Clinical
"at relapse, an upregulation of inflammatory pathways (TNF-alpha signaling for all the three cell types and IFN pathways for monocytes only) was noted compared with diagnosis and remission"
Single-cell analysis of patient marrow T cells and monocytes; association rather than experimentally isolated cause.
Inadequate Erythropoietic Compensation
Marrow output may fail to match accelerated erythrocyte loss. Reticulocytopenia is one presentation, but an elevated absolute reticulocyte count may still be inadequate for the severity of anemia. Inadequate endogenous erythropoietin and dyserythropoiesis are associated findings rather than universal causes.
Downstream
Anemia Insufficient replacement amplifies anemia caused by peripheral destruction.
Reticulocytopenia Some patients have a low absolute reticulocyte count, although inadequate compensation can occur without frank reticulocytopenia.
Show evidence (1 reference)
PMID:40854885 SUPPORT Human Clinical
"More than half of patients (56%) displayed inadequate reticulocytosis as depicted by a BMRI < 121, and 75% of patients had inadequate endogenous erythropoietin levels."
Findings from a selected marrow-evaluated referral cohort; the percentages are not population prevalence estimates.
Follicular Helper T-Cell Expansion
Mechanism confidence: Provisional
An expanded follicular-helper compartment can support autoreactive B-cell activation. In rat-red-cell-immunized mice, Tfh expansion increased the Tfh:Tfr ratio; Tfr absolute numbers and suppressive function were not clearly reduced. Transfer accelerated autoantibody induction only in the setting of subsequent repeated immunization, rather than demonstrating spontaneous human AIHA.
T follicular helper cell CL:0002038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T follicular helper cell (CL:0002038). CL:0002038 is a cell type from the Cell Ontology.
Downstream
Anti-Erythrocyte Autoantibody Production Tfh help supports germinal-center B-cell activation and antibody production; transfer and coculture experiments support this connection in the murine model.
Show evidence (2 references)
PMID:31875006 SUPPORT Model Organism
"The function of TFH cells in the responder group was not altered compared to the non-responder group, despite the increased number of TFH cells."
The murine study supports expansion rather than greater per-cell helper activity. Human generalization remains provisional.
PMID:31875006 SUPPORT Model Organism
"The day after transfer, the mice were immunized with rat RBCs weekly for consecutive 12 weeks."
Adoptive transfer was followed by repeated antigen challenge; it was not sufficient alone to establish spontaneous disease.
Persistent Autoreactive Plasma Cells
Autoreactive plasma cells can persist in the spleen despite corticosteroid treatment and rituximab-mediated B-cell depletion. In selected rituximab-refractory warm-AIHA splenectomy samples, these cells displayed a long-lived transcriptional program, providing a potential reservoir for continuing autoantibody production.
plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
Downstream
Anti-Erythrocyte Autoantibody Production Persistent autoreactive plasma cells continue to supply anti-red-cell antibodies.
Show evidence (2 references)
PMID:26112660 SUPPORT Human Clinical
"In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive."
Selected refractory human tissue establishes persistence, not its frequency across all warm AIHA.
PMID:26112660 SUPPORT In Vitro
"Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro."
Ex-vivo secretion supports the autoantibody-producing function of persistent plasma cells.
BAFF-Rich Splenic Survival Environment
Mechanism confidence: Provisional
In selected rituximab-treated refractory warm-AIHA samples, spleen-cell culture supernatants had increased BAFF. This supports a proposed survival environment for autoreactive plasma cells after B-cell depletion; it does not establish that BAFF elevation initiates every case of AIHA.
Downstream
Persistent Autoreactive Plasma Cells BAFF and other splenic signals may support survival after B-cell depletion; the specific contribution remains incompletely established.
Show evidence (1 reference)
PMID:26112660 SUPPORT In Vitro
"an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients."
Human-derived cell cultures provide a treatment-context association; BAFF dependence is a mechanistic interpretation rather than a universal causal finding.
Antibody-Dependent Cellular Cytotoxicity
Mechanism confidence: Provisional
Cytotoxic effector cells may contribute to destruction of antibody-coated red cells. This is a proposed auxiliary mechanism; its quantitative contribution in human AIHA is less established than macrophage phagocytosis or complement-mediated clearance.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
Downstream
Anemia Additional immune destruction could shorten red-cell survival; the relative contribution remains uncertain.
Show evidence (1 reference)
DOI:10.5633/amm.2024.0108 SUPPORT Other
"Antibody- dependent cellular cytotoxicity (ADCC) involving NK cells and CD8 + T cells is also proposed as a possible mechanism of extravascular RBC destruction in the spleen and other secondary lymphoid organs."
The full-text review explicitly presents this mechanism as proposed; it is not modeled as the dominant or universally demonstrated human effector pathway.
✶

Histopathology

4
Bone marrow hypercellularity
Found in 63/97 biopsy-selected patients. The referral cohort overrepresented cold AIHA; this is not a population prevalence estimate.
Show evidence (1 reference)
PMID:40854885 SUPPORT Human Clinical
"Hypercellularity, present in the majority of patients (65%), was associated with higher hemolytic features"
Found in 63/97 biopsy-selected patients. The referral cohort overrepresented cold AIHA; this is not a population prevalence estimate.
Bone marrow dyserythropoiesis
Results and Table 1 identify dyserythropoiesis in 74/97 patients. The abstract/discussion reverse the dyserythropoiesis and fibrosis percentages; the tabulated counts support this assignment.
Show evidence (1 reference)
PMID:40854885 SUPPORT Human Clinical
"Reticulin fibrosis (MF-1) was observed in 29% of cases, and dyserythropoiesis in 76%"
Results and Table 1 identify dyserythropoiesis in 74/97 patients. The abstract/discussion reverse the dyserythropoiesis and fibrosis percentages; the tabulated counts support this assignment.
Mild bone marrow reticulin fibrosis
Grade MF-1 in 28/97 biopsy-selected patients, based on the results and Table 1 rather than the reversed abstract percentages.
Show evidence (1 reference)
PMID:40854885 SUPPORT Human Clinical
"Reticulin fibrosis (MF-1) was observed in 29% of cases, and dyserythropoiesis in 76%"
Grade MF-1 in 28/97 biopsy-selected patients, based on the results and Table 1 rather than the reversed abstract percentages.
Bone marrow lymphoid infiltration
Table 2 separates T-cell, B-cell and mixed infiltrates. Associations with anemia, erythropoietin adequacy and treatment response do not establish direct cytotoxicity against erythroid precursors.
Show evidence (1 reference)
PMID:40854885 SUPPORT Human Clinical
"a lymphoid infiltrate was documented in 85% of patients"
Table 2 separates T-cell, B-cell and mixed infiltrates. Associations with anemia, erythropoietin adequacy and treatment response do not establish direct cytotoxicity against erythroid precursors.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autoimmune Hemolytic Anemia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Blood 4
Anemia 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
Sequelae: Fatigue Dyspnea Pallor
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.
Spherocytosis HP:0004444 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spherocytosis (HP:0004444). HP:0004444 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38673882 SUPPORT Other
"In wAIHA, this leads to the degradation of the RBC membrane, causing transformation into spherocytes"
The quoted mechanism connects erythrocyte membrane removal to spherocyte formation in warm AIHA.
Reticulocytopenia HP:0001896 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reticulocytopenia (HP:0001896). HP:0001896 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26819490 SUPPORT Human Clinical
"Reticulocytopenia occurs in 20-40% of autoimmune hemolytic anemia cases and is a poor prognostic factor."
The source establishes reticulocytopenia as a recognized poor-prognosis presentation. Its review-level percentage is not promoted to a population frequency for every subtype.
Thromboembolism HP:0001907 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thromboembolism (HP:0001907). HP:0001907 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35555857 SUPPORT Human Clinical
"Thirty-three AIHA patients (11.4%) experienced thrombosis, 70% of whom hospitalized."
The cohort included multiple AIHA subtypes and associated conditions; most events were venous, particularly pulmonary embolism.
Cardiovascular 2
Splenomegaly 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.
Raynaud phenomenon HP:0030880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Raynaud phenomenon (HP:0030880). HP:0030880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The development of acrocyanosis and Raynaud phenomenon in CAS/CAD may culminate rarely with gangrene"
The source identifies Raynaud phenomenon in CAD/CAS, supporting a cold-circulatory phenotype rather than a universal warm-AIHA finding.
Digestive 1
Jaundice 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).
Genitourinary 1
Hemoglobinuria HP:0003641 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemoglobinuria (HP:0003641). HP:0003641 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"Historically, PCH manifested primarily in patients having syphilis, and exposure to cold resulted in paroxysms of hemoglobinuria."
The historical PCH observation supports hemoglobinuria during intravascular hemolysis; it does not imply that modern PCH cases are usually syphilitic.
Integument 2
Pallor HP:0000980 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pallor (HP:0000980). HP:0000980 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The symptoms may include dyspnea, fatigue, headache, muscular weakness, pallor and/or jaundice"
The clinical review explicitly includes pallor among AIHA manifestations without quantifying its frequency.
Acrocyanosis HP:0001063 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acrocyanosis (HP:0001063). HP:0001063 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The development of acrocyanosis and Raynaud phenomenon in CAS/CAD may culminate rarely with gangrene"
The source localizes acrocyanosis to cold-antibody disease and syndrome; the rare gangrene complication is not assigned to every AIHA subtype.
Respiratory 1
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The symptoms may include dyspnea, fatigue, headache, muscular weakness, pallor and/or jaundice"
The clinical review explicitly lists dyspnea among AIHA symptoms; it does not supply a population frequency.
Constitutional 1
Fatigue 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 (2 references)
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.
PMID:40728672 SUPPORT Human Clinical
"Study participation was limited to individuals who reported having experienced fatigue due to wAIHA."
The full-text inclusion criterion prevents using 20/20 interviews as an unbiased frequency estimate.
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Medical Actions

31
Corticosteroids
Action: Systemic Corticosteroid TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Systemic Corticosteroid Therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. NCIT:C122080
Platform: Small molecule
First-line treatment for warm AIHA, with tapering after response and substantial relapse and cumulative toxicity concerns. This role does not extend to primary CAD, where steroid responses are poor.
Mechanism Target:
INHIBITS Fc-Gamma-Receptor-Mediated Erythrophagocytosis — Reduces immune-mediated red-cell clearance in warm AIHA.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"Despite a slow steroid tapering in 4–6 months, 1/3 of patients relapse and require a further therapy line."
The review distinguishes initial warm-AIHA response from sustained steroid-free remission.
Rituximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-CD20 B-cell depletion is a preferred second-line treatment for warm AIHA and may be introduced earlier in severe disease. It also targets the pathogenic B-cell clone in CAD, as monotherapy or combined with bendamustine in suitable patients; response magnitude and durability differ by subtype.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Depletes CD20-positive B cells contributing to autoantibody production; long-lived CD20-negative plasma cells can persist.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"The anti-CD20 monoclonal antibody rituximab has become the preferred 2nd line being able to induce 70–80% of responses."
The response estimate applies to warm AIHA in this clinical review, not every AIHA subtype.
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. NCIT:C15328
Platform: Surgery
A later-line option for selected fit patients with refractory warm AIHA, after accounting for lifelong infection and thrombotic risks. It is generally ineffective in CAD because complement-opsonized cells are cleared predominantly in the liver.
Mechanism Target:
INHIBITS Fc-Gamma-Receptor-Mediated Erythrophagocytosis — Removes a major site of IgG-mediated erythrocyte clearance.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"It may be considered in young low comorbid patients after vaccination against capsulated organisms, and accounting for a life-long increase in infectious and thrombotic risk."
The clinical review limits this intervention to suitable warm-AIHA patients.
Sutimlimab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Sutimlimab NCIT:C153093 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Sutimlimab (NCIT:C153093). NCIT:C153093 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
C1s inhibition for CAD rapidly controls complement-mediated hemolysis and improves anemia and fatigue. Continued dosing is usually needed; it does not remove the B-cell clone or directly treat agglutination-mediated acrocyanosis and Raynaud symptoms.
Mechanism Target:
INHIBITS Classical Complement Activation — Selective C1s blockade prevents classical-pathway activation and downstream C3b opsonization.
Show evidence (2 references)
PMID:39091672 SUPPORT Human Clinical
"Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels."
CADENZA Part B followed 39 patients, 32 of whom completed the extension, for a median treatment duration of 99 weeks. The extension was open label and descriptive.
PMID:39091672 SUPPORT Human Clinical
"The mechanism of action of sutimlimab means that it affects the complement-mediated symptoms of CAD, such as haemolysis, anaemia, and fatigue, rather than the cold-induced, agglutination-mediated circulatory symptoms, such as acrocyanosis and Raynaud's phenomenon."
Explains the mechanistic boundary of treatment response.
Red-cell transfusion support
Action: Packed Red Blood Cell TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Packed Red Blood Cell Transfusion (NCIT:C15409). NCIT:C15409 is a clinical intervention from the NCI Thesaurus. NCIT:C15409
Platform: Other
Transfusion supports patients with severe or symptomatic anemia while disease-directed therapy takes effect. Selection depends on symptoms and comorbidity as well as hemoglobin; alloantibody investigation and close transfusion-service coordination are essential. Physiologically necessary transfusion should not be withheld solely because an autoantibody makes serologic compatibility difficult.
Mechanism Target:
BYPASSES Anemia — Replaces circulating red cells without suppressing the underlying autoimmune process.
Show evidence (2 references)
PMID:39371250 SUPPORT Human Clinical
"Therefore, a careful matching is recommended along with a close collaboration with transfusion medicine experts"
Supportive care requires attention to clinically significant alloantibodies.
PMID:38673882 SUPPORT Human Clinical
"Transfusion if necessary; do not withhold transfusion if physiologically required"
The source stresses clinical necessity while retaining investigation and matching for underlying alloantibodies.
Epoetin alfa
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Epoetin Alfa NCIT:C2695 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Epoetin Alfa (NCIT:C2695). NCIT:C2695 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
An adjunct for selected AIHA patients with inadequate reticulocyte compensation and inappropriately low endogenous erythropoietin. A prospective 47-patient cohort found an early hemoglobin and transfusion benefit, but treatment was not randomized and most patients received concomitant immunosuppression.
Mechanism Target:
RESTORES Inadequate Erythropoietic Compensation — Stimulates erythropoiesis when endogenous compensation is insufficient.
Show evidence (2 references)
PMID:38029356 SUPPORT Human Clinical
"Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months."
Response rates use time-specific evaluable denominators; Figure 1A gives 25 complete responses, six partial responses and three nonresponses at day 360, yielding 31/34; this is not 91% of all 47 enrolled patients. This is add-on evidence for inadequate marrow compensation.
PMID:38029356 SUPPORT Human Clinical
"the contribution of concomitant medication to response cannot be excluded"
The nonrandomized comparison does not isolate epoetin efficacy. Two thromboses occurred among treated patients, both with additional risk factors.
Fostamatinib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Fostamatinib NCIT:C95222 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Fostamatinib (NCIT:C95222). NCIT:C95222 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Investigational/off-label SYK inhibition for refractory warm AIHA. The 90-patient randomized FORWARD trial did not meet its primary durable-hemoglobin-response endpoint (35.6% versus 26.7%; P=0.398). Favorable post-hoc analyses and subsequent retrospective responses are hypothesis-generating, rather than a positive primary trial result.
Mechanism Target:
INHIBITS Fc-Gamma-Receptor-Mediated Erythrophagocytosis — SYK blockade interrupts Fc-receptor signaling involved in phagocytosis of antibody-coated red cells.
Show evidence (3 references)
PMID:37929318 SUPPORT Human Clinical
"Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo (p = .398)."
The prespecified phase III primary comparison was not statistically significant; regional and rescue-adjusted analyses were post hoc.
PMID:41846299 SUPPORT Human Clinical
"Regarding efficacy, 14 of 22 patients (64%) responded to fostamatinib (9 wAIHA and 5 ES)."
The 2026 retrospective cohort included 13 isolated warm-AIHA and nine Evans-syndrome patients; 10/22 had a six-month durable response, and 11 required steroid rescue. It does not overturn the randomized primary result.
PMID:41846299 SUPPORT Human Clinical
"The lack of baseline data precludes definitive conclusions."
The eight-patient molecular substudy measured post-treatment correlates, not validated pretreatment predictors or proven causal determinants of response.
Sovleplenib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Sovleplenib NCIT:C123912 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Sovleplenib (NCIT:C123912). NCIT:C123912 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Investigational SYK inhibitor evaluated in a Chinese phase II/III study. The published phase II component randomized 21 patients (16 active, five placebo) for eight weeks, followed by open-label treatment for everyone. The 24-week overall response of 14/21 (67%) therefore includes crossover and is not a maintained placebo-controlled comparison.
Mechanism Target:
INHIBITS Fc-Gamma-Receptor-Mediated Erythrophagocytosis — Targets SYK-dependent Fc-receptor signaling.
Show evidence (2 references)
PMID:39799953 SUPPORT Human Clinical
"All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period."
The study design limits interpretation of the combined 24-week response rate.
PMID:39799953 SUPPORT Human Clinical
"The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24."
These are pooled phase II results after crossover, not results from the phase III component.
Parsaclisib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Parsaclisib NCIT:C113434 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Parsaclisib (NCIT:C113434). NCIT:C113434 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Investigational PI3K-delta inhibition targeting B-cell signaling. In a 25-patient open-label phase II study spanning warm, cold and mixed AIHA, 16/25 achieved a hemoglobin response at weeks 6-12. Grade 3 or worse adverse events occurred in 13/25 and six discontinued for an adverse event.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — PI3K-delta inhibition modulates B-cell activation and survival; clinical effects on individual autoimmune cell populations remain incompletely resolved.
Show evidence (2 references)
PMID:39435908 SUPPORT Human Clinical
"Among 25 enrolled patients (median age, 63 y), 16 (64%) achieved a partial or complete Hgb response during weeks 6-12."
A small uncontrolled study; warm-AIHA responses were more frequent than those in the pooled cold/mixed group.
PMID:39435908 SUPPORT Human Clinical
"Grade ≥3 TEAEs occurred in 13 patients (52.0%)."
The adverse-event burden should accompany the efficacy summary.
Pegcetacoplan
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Pegcetacoplan NCIT:C121135 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Pegcetacoplan (NCIT:C121135). NCIT:C121135 is a therapeutic agent from the NCI Thesaurus.
Platform: Peptide
Investigational C3 inhibition in CAD and warm AIHA. An open-label phase II study randomized doses, not treatment versus placebo, in 13 CAD and 11 warm-AIHA patients. At week 48 the median hemoglobin change was 2.4 g/dL in CAD and 1.7 g/dL in warm AIHA, with a wide warm-AIHA interquartile range crossing zero.
Mechanism Target:
INHIBITS C3b Opsonization of Erythrocytes — Blocks C3 activation and downstream complement-mediated opsonization and lysis.
Show evidence (2 references)
PMID:39486046 SUPPORT Human Clinical
"In each cohort, patients were randomly assigned to receive pegcetacoplan 270 mg/d or 360 mg/d for up to 48 weeks."
Dose randomization does not supply a placebo comparator. The reported outcomes are preliminary and subtype-specific.
PMID:39486046 SUPPORT Human Clinical
"at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90-3.00) and 1.7 g/dL (-1.40 to 2.90), respectively"
The primary report supports separate CAD and warm-AIHA effect estimates.
Daratumumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Daratumumab NCIT:C74007 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Daratumumab (NCIT:C74007). NCIT:C74007 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Off-label anti-CD38 therapy for heavily pretreated refractory AIHA. A retrospective series reported hemoglobin responses in 6/12 warm and 4/7 cold cases, with improvement of acrocyanosis in 4/6 assessed cold cases. Most patients also received other immunosuppression; infections, variable schedules and lack of a control group limit inference.
Mechanism Target:
INHIBITS Persistent Autoreactive Plasma Cells — Targets CD38-positive antibody-producing cells, including plasma cells that can persist after anti-CD20 therapy; additional T-cell effects are exploratory.
Show evidence (2 references)
PMID:38507742 SUPPORT Human Clinical
"we cannot exclude late responses to the comedication given before initiation of daratumumab treatment"
The 19-patient study cannot isolate a daratumumab-specific effect. Its title refers to monotherapy, but 13 patients had concomitant immunosuppressive treatment.
PMID:38507742 SUPPORT Human Clinical
"In our cohort, infections were reported in 4 of 19 patients (21%), including 3 of grade 3 and 1 of grade 1."
Attribution was uncertain in heavily pretreated patients, but infection risk is material.
Eculizumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Eculizumab NCIT:C48386 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Eculizumab (NCIT:C48386). NCIT:C48386 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Off-label terminal complement inhibition studied in 12 CAD patients and one acute secondary cold-agglutinin case in the nonrandomized phase II DECADE trial. Hemolysis and transfusion needs improved, but the median hemoglobin increase was modest and cold-induced circulatory symptoms persisted. C5 blockade leaves upstream C3b-mediated hepatic clearance intact.
Mechanism Target:
INHIBITS Terminal Complement-Mediated Erythrocyte Lysis — C5 blockade limits terminal complement-mediated lysis without blocking C3b opsonization.
Show evidence (2 references)
PMID:30291112 SUPPORT Human Clinical
"Twelve patients with chronic CAD and 1 patient with an acute cold agglutinin syndrome were included."
Preserves the primary study population rather than labeling all 13 participants as CAD.
PMID:30291112 SUPPORT Human Clinical
"In contrast to hemolysis, cold-induced circulatory symptoms remained unaffected."
C5 inhibition does not directly prevent cold-antibody agglutination.
Conventional immunosuppressants
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Mycophenolate Mofetil NCIT:C1468 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Mycophenolate Mofetil (NCIT:C1468). NCIT:C1468 is a therapeutic agent from the NCI Thesaurus. Azathioprine NCIT:C290 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Azathioprine (NCIT:C290). NCIT:C290 is a therapeutic agent from the NCI Thesaurus. Cyclophosphamide NCIT:C405 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Cyclophosphamide (NCIT:C405). NCIT:C405 is a therapeutic agent from the NCI Thesaurus. Cyclosporine NCIT:C406 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Cyclosporine (NCIT:C406). NCIT:C406 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Azathioprine, cyclophosphamide, mycophenolate mofetil and cyclosporine are later-line options for selected refractory warm-AIHA patients, particularly with associated systemic autoimmune disease. Comparative evidence is limited and cumulative toxicity influences selection.
Mechanism Target:
MODULATES Anti-Erythrocyte Autoantibody Production — Suppresses lymphocyte-mediated autoimmunity through agent-specific mechanisms.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"For patients who are refractory to or relapsing after rituximab and not candidate for splenectomy, cytotoxic immunosuppressants, such as azathioprine, cyclophosphamide, mycophenolate mofetil, and cyclosporine may be a therapeutic option"
These are alternative agents, not a combined regimen.
Thromboprophylaxis during active hemolysis
Action: Anticoagulation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticoagulation Therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. NCIT:C63341
Platform: Other
Consider anticoagulant prophylaxis according to active hemolysis, hospitalization, additional thrombosis risks and bleeding risk. In a nonrandomized prospective subset with LDH at least 1.5 times the upper limit of normal, no thromboses occurred in 17 heparin-treated patients versus five events among 16 untreated patients. Optimal selection and duration remain uncertain.
Mechanism Target:
INHIBITS Thromboembolism — Reduces coagulation-mediated thrombotic complications without correcting autoimmune red-cell destruction.
Show evidence (1 reference)
PMID:35555857 SUPPORT Human Clinical
"In those receiving prophylaxis no thrombotic complications occurred, whereas five thrombotic episodes were registered in the remaining 16 cases."
Physician-selected prophylaxis in a small observational comparison supports risk assessment, not a definitive randomized treatment effect.
Rilzabrutinib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Rilzabrutinib NCIT:C174769 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Rilzabrutinib (NCIT:C174769). NCIT:C174769 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Investigational BTK inhibition for warm AIHA in the phase II LUMINA 2 study. Early open-label findings require confirmation; the ongoing extension does not establish an approved AIHA indication.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
Show evidence (2 references)
clinicaltrials:NCT05002777 SUPPORT Human Clinical
"All participants will receive rilzabrutinib orally. The screening period is up to 28 days, followed by a treatment period of 24 weeks for Part A. Participants who complete Part A and are deemed eligible for Part B can continue in the Core Part B period followed by an Extended Part B period for..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:40821796 SUPPORT Other
"Rilzabrutinib, a reversible covalent BTK inhibitor, has been evaluated in a multicentric open-label phase 2b trial"
Identifies the molecular target; the registry separately establishes the study population and design.
Nipocalimab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Nipocalimab NCIT:C170891 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Nipocalimab (NCIT:C170891). NCIT:C170891 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Investigational FcRn blockade intended to accelerate IgG catabolism and reduce pathogenic warm autoantibodies; evaluated in the ENERGY phase II/III trial.
Mechanism Target:
INHIBITS Warm IgG Coating of Erythrocytes — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
Show evidence (2 references)
clinicaltrials:NCT04119050 SUPPORT Human Clinical
"The main purpose of this study is to evaluate the efficacy and safety of M281 in participants with warm autoimmune hemolytic anemia (wAIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:39371250 SUPPORT Other
"blocking the neonatal Fc receptor (FcRn) by MoAbs such as nipocalimab is an interesting strategy to dampen IgG recycling, thus increasing the clearance of pathogenic autoantibodies."
Supports the proposed autoantibody-clearance mechanism, independently of trial registration.
Ianalumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Ianalumab NCIT:C116788 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Ianalumab (NCIT:C116788). NCIT:C116788 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Investigational BAFF-receptor-targeting B-cell depletion in previously treated warm AIHA; being evaluated in the phase III VAYHIA study.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
Show evidence (2 references)
clinicaltrials:NCT05648968 SUPPORT Human Clinical
"The purpose of this study is to evaluate efficacy and safety of ianalumab compared to placebo in patients with warm autoimmune hemolytic anemia, who failed at least one line of treatment."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:40821796 SUPPORT Other
"Ianalumab (VAY736), an IgG1κ monoclonal antibody targeting BAFF-R, promotes B-cell depletion via ADCC and apoptosis."
Identifies BAFF-R targeting and B-cell depletion; does not establish depletion of mature long-lived plasma cells.
Obexelimab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Obexelimab NCIT:C170236 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Obexelimab (NCIT:C170236). NCIT:C170236 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Investigational CD19/Fc-gamma-RIIb co-engagement to suppress B-cell activation without conventional B-cell depletion. The SApHiAre registry currently describes a phase III warm-AIHA study.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
Show evidence (2 references)
clinicaltrials:NCT05786573 SUPPORT Human Clinical
"This study aims to examine the efficacy and safety of obexelimab in participants with Warm Autoimmune Hemolytic Anemia (wAIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:39371250 SUPPORT Other
"the bispeciphic Moab obexelimab, which simultaneously binds CD19 and FcγRIIb"
Supports the two molecular binding targets; preserves the source spelling in the exact quotation.
Povetacicept
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Povetacicept NCIT:C190436 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Povetacicept (NCIT:C190436). NCIT:C190436 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Investigational dual BAFF/APRIL blockade intended to suppress autoreactive B-cell and plasma-cell survival. The phase I/II RUBY-4 autoimmune-cytopenia study is completed; registry completion alone does not demonstrate clinical benefit.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
INHIBITS BAFF-Rich Splenic Survival Environment — Targets BAFF-mediated survival signaling; clinical efficacy against this proposed persistence mechanism remains under study.
Show evidence (2 references)
clinicaltrials:NCT05757570 SUPPORT Human Clinical
"The goal of this clinical study is to evaluate povetacicept in adults with autoimmune cytopenias of immune thrombocytopenia, autoimmune hemolytic anemia, and cold agglutinin disease to determine if povetacicept is safe and potentially beneficial in treating these diseases. During the study..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:40821796 SUPPORT Other
"Povetacicept (ALPN-303) is a next-generation fusion protein designed to inhibit both BAFF and APRIL"
Supports the dual ligand-blockade rationale, without treating preclinical effects as proven clinical efficacy.
Riliprubart
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Riliprubart NCIT:C199103 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Riliprubart (NCIT:C199103). NCIT:C199103 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Investigational long-acting inhibitor of activated C1s in CAD. An early single-dose study was completed, while the subsequent repeat-dose study NCT04802057 is terminated in the current registry.
Mechanism Target:
INHIBITS Classical Complement Activation — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
Show evidence (2 references)
clinicaltrials:NCT04269551 SUPPORT Human Clinical
"To assess the safety and tolerability in participants with cold agglutinin disease (CAD), after a single dose of intravenous (IV) BIVV020"
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:39371250 SUPPORT Other
"the second-generation active C1s inhibitor riliprubart (formerly SAR445088, BIVV020), characterized by a prolonged half-life and thus a longer dosing interval than that of sutimlimab"
Supports activated-C1s inhibition and the long-acting development rationale.
Iptacopan
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Iptacopan NCIT:C156691 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Iptacopan (NCIT:C156691). NCIT:C156691 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Investigational factor B inhibition to suppress alternative-pathway complement amplification in CAD. Its phase II basket study was terminated for a business decision; it is not presented as established AIHA treatment.
Show evidence (2 references)
clinicaltrials:NCT05086744 SUPPORT Human Clinical
"The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:39371250 SUPPORT Other
"the orally available factor B inhibitor iptacopan is currently being evaluated in a trial including CAD and immune thrombocytopenia (NCT05086744)."
Identifies the factor B target. The historical trial-status wording is superseded by the current registry status recorded in clinical_trials.
Ibrutinib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Ibrutinib NCIT:C81934 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Ibrutinib (NCIT:C81934). NCIT:C81934 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
BTK inhibition has been investigated in cold-antibody disease and CLL-associated autoimmune cytopenias. The registered ibrutinib/rituximab phase II study specifically requires underlying CLL, so its rationale should not be generalized to all primary AIHA.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
Show evidence (2 references)
clinicaltrials:NCT03827603 SUPPORT Human Clinical
"This is an open-labeled, single arm, Phase II, two staged study of combination of ibrutinib and rituximab in patients with autoimmune cytopenia and underlying CLL. In stage I (remission induction) patients will receive ibrutinib and rituximab for 6 months; in stage II (maintenance) - only..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
PMID:39371250 SUPPORT Other
"the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been investigated in 15 patients with CAD primary or secondary CAD"
Supports BTK inhibition and distinguishes the cold-antibody observational population from the separate CLL-associated trial.
CD19 CAR T-cell therapy
Action: Chimeric Antigen Receptor T-Cell TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Chimeric Antigen Receptor T-Cell Therapy (NCIT:C126102). NCIT:C126102 is a clinical intervention from the NCI Thesaurus. NCIT:C126102
Platform: Cell therapy
Investigational therapy for primary multirefractory AIHA. A 2026 report combined five compassionate-use and six phase I patients; all 11 achieved complete response, with median follow-up 12.2 months. Nine had grade 1-2 cytokine-release syndrome, one grade 1 neurotoxicity, seven had infections and one grade 3 hematotoxicity. Small size, mixed enrollment and lack of a control group limit efficacy and safety generalization.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Profound CD19-positive B-cell depletion can interrupt autoreactive B-cell activity. Persistent plasma-cell niches may permit relapse.
Show evidence (3 references)
PMID:41534043 SUPPORT Human Clinical
"CD19 CAR T cells were administered to 11 patients - 5 in the compassionate-use program and 6 in the phase 1 study."
Preserves the actual study design rather than describing an eleven-patient randomized trial.
PMID:41534043 SUPPORT Human Clinical
"All patients had a complete response; the median time to a complete response was 45 days (range, 21 to 153)."
An early clinical signal in a selected cohort, not proof of universal durable cure.
PMID:41534043 SUPPORT Human Clinical
"A total of 15 infections occurred among 7 patients, with no infections of grade 4 or higher."
Infection burden is material despite the absence of grade 4 infection in this small series.
Folate and deficiency replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Folic Acid CHEBI:27470 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses Folic Acid (CHEBI:27470). CHEBI:27470 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Support increased erythropoietic demand with folate; replace vitamin B12 or iron when deficient. Nutritional support complements assessment and treatment of the immune process.
Mechanism Target:
RESTORES Inadequate Erythropoietic Compensation — Support increased erythropoietic demand with folate; replace vitamin B12 or iron when deficient. Nutritional support complements assessment and treatment of the immune process.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9821065/ SUPPORT Human Clinical
"All patients should be supplemented with folic acid of at least 0.4 mg/d"
Clinical review supports folate and correction of documented deficiencies, rather than routine iron in every patient.
Intravenous immunoglobulin
Action: Intravenous Immunoglobulin TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intravenous Immunoglobulin Therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. NCIT:C121331
Platform: Other
An adjunct in selected severe warm-AIHA situations, with limited evidence and often transient responses. It does not provide a reliable durable substitute for disease-directed therapy.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9821065/ SUPPORT Human Clinical
"A 2-g/dL Hgb rise in 2 weeks was seen in 25 of 62 (40%), and a Hgb rise over 2 g/dL in 2 weeks with a Hgb higher than 10 g/dL was seen in 9 of 61 (15%) patients. The treatment response was short-lived."
The response depends strongly on the endpoint definition; these historical data should not be described as a consistent durable response.
Cold avoidance and thermal protection
Platform: Behavioral / lifestyle
Supportive management for cold-antibody hemolysis and circulatory symptoms. Keep the patient and transfused blood warm when appropriate; thermal protection does not eradicate the autoantibody-producing clone.
Mechanism Target:
INHIBITS Cold Agglutinin Binding — Reduces cold-triggered antibody binding and agglutination; it does not suppress antibody production.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"Treatment of CAD is based on supportive measures (cold avoidance, folic acid, transfusions)"
Supportive measures specific to cold-antibody disease.
Rituximab plus bendamustine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus. Bendamustine NCIT:C73261 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Bendamustine (NCIT:C73261). NCIT:C73261 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Clone-directed combination used in suitable CAD patients who require treatment. It can produce deeper and more durable responses than rituximab alone but adds cytotoxic and infectious risks, particularly relevant in frail patients.
Mechanism Target:
INHIBITS Clonal B-Cell Expansion in CAD — Targets the marrow B-cell clone supplying the pathogenic cold agglutinin.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"the combination of rituximab plus bendamustine resulted in increased response rate (78%, with complete responses in 53%), and long response duration (more than 7 years)"
Clinical review of CAD combination studies; these results should not be generalized to warm AIHA.
Bortezomib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Bortezomib NCIT:C1851 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Bortezomib (NCIT:C1851). NCIT:C1851 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Off-label proteasome inhibition targeting antibody-producing cells in refractory warm or cold AIHA. The primary CAD phase II report enrolled 21 patients, with 6/19 evaluable responders; two early discontinuations were excluded from that efficacy denominator. Warm-AIHA evidence also includes small combination series, which cannot isolate the bortezomib effect.
Mechanism Target:
INHIBITS Persistent Autoreactive Plasma Cells — Off-label proteasome inhibition targeting antibody-producing cells in refractory warm or cold AIHA. The primary CAD phase II report enrolled 21 patients, with 6/19 evaluable responders; two early discontinuations were excluded from that efficacy denominator. Warm-AIHA evidence also includes small combination series, which cannot isolate the bortezomib effect.
Show evidence (2 references)
url:https://air.unimi.it/retrieve/dfa8b9a3-2887-748b-e053-3a05fe0a3a96/blood835413.pdf SUPPORT Human Clinical
"Among the 19 evaluable patients, 3 achieved a complete response (15.8%) and 3 achieved a partial response (15.8%), for an overall response rate of 31.6%"
Full-text primary report, pages 548-549: 21 enrolled and 19 evaluable. Early pulmonary embolism and headache led to the two exclusions; one excluded patient nevertheless became transfusion independent.
PMID:34795889 SUPPORT Human Clinical
"The frequency of responses is difficult to evaluate, since bortezomib has been often used in combination with other treatments, particularly steroids."
The full-text review explicitly limits inference from combination treatment and response-biased case reports.
Isatuximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Isatuximab NCIT:C90578 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Isatuximab (NCIT:C90578). NCIT:C90578 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Investigational anti-CD38 therapy for warm AIHA. The registered study was terminated for a strategic sponsor decision, not a reported safety concern; efficacy remains unestablished.
Mechanism Target:
INHIBITS Persistent Autoreactive Plasma Cells — Investigational anti-CD38 therapy for warm AIHA. The registered study was terminated for a strategic sponsor decision, not a reported safety concern; efficacy remains unestablished.
Show evidence (1 reference)
PMID:40821796 SUPPORT Human Clinical
"A phase 1b/2 trial investigating its use in warm AIHA was initiated but was prematurely discontinued due to sponsor-driven strategic decisions"
This source and the current NCT04661033 registry agree that the program stopped.
Zanubrutinib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Zanubrutinib NCIT:C141428 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Zanubrutinib (NCIT:C141428). NCIT:C141428 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Investigational BTK inhibition being evaluated separately in relapsed/refractory warm AIHA and primary CAD. The two registered populations should not be pooled as established efficacy evidence.
Mechanism Target:
INHIBITS Anti-Erythrocyte Autoantibody Production — Investigational BTK inhibition being evaluated separately in relapsed/refractory warm AIHA and primary CAD. The two registered populations should not be pooled as established efficacy evidence.
Show evidence (1 reference)
PMID:40821796 SUPPORT Human Clinical
"zanubrutinib, a next-generation, irreversible BTK inhibitor, is under investigation in a phase 2 trial (NCT05922839) for patients with warm AIHA and in a separate phase 2 trial involving CAD (NCT06067048)."
Mechanistic and study rationale; current recruitment status is recorded separately in clinical_trials.
ANX005
Action: ANX005 pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ANX005 pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Platform: Monoclonal antibody
Investigational anti-C1q monoclonal antibody evaluated in warm AIHA with complement activation or mixed forms. The completed phase II registry does not itself establish clinical efficacy.
Mechanism Target:
INHIBITS Classical Complement Activation — C1q blockade inhibits initiation of the classical complement cascade.
Show evidence (1 reference)
PMID:40821796 SUPPORT REVIEW SYNTHESIS Other
"In this regard, results are awaited from a phase 2 study (NCT04691570) evaluating subjects with warm AIHA showing evidence of complement activation or mixed forms, treated with ANX005, a recombinant anti-C1q IgG4 humanized MoAb."
The review describes the C1q target and study population while awaiting results. This supports investigational use, not clinical efficacy; the current completed registry status was checked separately.
🔬

Biochemical Markers

5
Direct Antiglobulin Test (DAT) (Often positive; standard DAT-negative cases occur)
Context: Interpret IgG/complement findings with biochemical hemolysis and clinical context; positive DAT alone is insufficient
Show evidence (4 references)
PMID:31839434 SUPPORT Human Clinical
"Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup"
DAT is a central investigation of immune hemolysis, but neither a positive result without hemolysis nor a negative standard assay alone establishes or excludes AIHA.
PMID:26819490 SUPPORT Human Clinical
"The direct antiglobulin test is the cornerstone of autoimmune forms"
DAT is a central investigation of immune hemolysis, but neither a positive result without hemolysis nor a negative standard assay alone establishes or excludes AIHA.
PMID:38673882 SUPPORT Human Clinical
"Importantly, a positive DAT does not automatically indicate AIHA."
The DAT detects red-cell sensitization, not hemolysis itself.
+ 1 more reference
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.
🔬

Diagnosis

4
Demonstrate hemolysis and characterize red-cell sensitization
Combine anemia/hemolysis markers with polyspecific and monospecific DAT testing. Determine IgG and complement reactivity and investigate secondary causes. A positive DAT without hemolysis is insufficient.
Show evidence (2 references)
PMID:39371250 SUPPORT Human Clinical
"The DAT is neither 100% specific nor sensitive, and several technical issues should be considered for a proper interpretation."
Test limitations require integrated clinical and laboratory interpretation.
PMID:31839434 SUPPORT Human Clinical
"Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup"
Consensus diagnostic recommendation; the cached landing page contains the abstract, not the full consensus paper.
Cold-antibody titer and thermal-amplitude assessment
Use cold-agglutinin studies to distinguish CAD/CAS from warm disease with complement involvement and mixed AIHA. IgG+C3d DAT positivity alone is not sufficient for mixed AIHA.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"Since DAT positivity for IgG and C3d may be observed even in wAIHA, the titer of the cold agglutinin and the presence of spontaneous agglutination at 20°C are useful tools."
Additional serology is required for subtype assignment.
Donath-Landsteiner testing
Detect the biphasic hemolysin when PCH is suspected; C3d DAT positivity alone does not distinguish PCH from other cold-antibody forms.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The diagnosis is made in the laboratory using the Donath–Landsteiner test (D–L test)"
PCH-specific serologic investigation.
Extended evaluation of suspected DAT-negative AIHA
Exclude nonimmune hemolysis and use a reference laboratory for more sensitive DAT methods, low-affinity antibody evaluation and IgA/IgM-specific reagents when indicated.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"The diagnosis of DAT-neg AIHA mostly relies on the method of excluding other possible causes"
A diagnosis of exclusion supported by specialized immune testing, not simply a negative routine DAT.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autoimmune Hemolytic Anemia:

Passenger lymphocyte syndrome
Overlapping Features Post-transplant alloimmune hemolysis can mimic AIHA.
Distinguishing Features
  • Donor lymphocytes produce antibodies against recipient red-cell antigens absent from the donor. The transplant history and antibody specificity distinguish this alloimmune process.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"It is feasible for donor lymphocytes that have been transferred to produce antibodies that are specific to RBC antigens in the recipient’s body but not present on the donor’s own red cells"
This is a mechanistic boundary despite some review taxonomies listing PLS alongside AIHA.
Drug-dependent immune hemolytic anemia
Overlapping Features A medication-dependent antibody reaction can cause immune hemolysis without a spontaneous red-cell autoantibody.
Distinguishing Features
  • Review temporal drug exposure and perform reference-laboratory testing for drug dependence. Drug-independent autoantibodies induced by medication can instead resemble warm AIHA.
Show evidence (1 reference)
PMID:39371250 SUPPORT Human Clinical
"drug-dependent antibodies that activate an immune response in the presence of the drug only"
Drug dependence distinguishes one drug-associated immune mechanism from autonomous autoantibody activity.
Nonimmune inherited or acquired hemolysis
Overlapping Features Red-cell membrane defects, enzymopathies, hemoglobinopathies and mechanical hemolysis can produce anemia, jaundice and reticulocytosis.
Distinguishing Features
  • Use personal and family history, blood-film findings and targeted membrane, enzyme or hemoglobin testing. Spherocytes alone do not establish autoimmune destruction.
Show evidence (1 reference)
PMID:38673882 SUPPORT Human Clinical
"Congenital reasons for the anemia need to be ruled out, from enzymopathies"
The diagnostic workup must exclude nonimmune causes, especially when standard DAT is negative.
📊

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
Bone marrow histology and clinical data from 97 selected AIHA patients, with single-cell RNA/TCR analysis in nine warm-AIHA patients across diagnosis, remission and relapse. Results and Table 1 report hypercellularity in 63/97, dyserythropoiesis in 74/97 and grade-1 reticulin fibrosis in 28/97; the abstract reverses the latter two percentages. The single-cell study used 12 patient specimens from nine individuals and three healthy donors, with treatment and cross-sectional relapse comparisons limiting causal interpretation. GEO sample_count denotes repository sample records rather than independent participants.
human SINGLE CELL RNA SEQ n=18
PMID:40854885
Accession verified against GEO. The publication methods describe nine patients, with three repeat remission samples; diagnosis samples were collected after 2-5 days of steroids, and relapse samples followed prior therapies. The GEO record count is retained separately from the clinical participant count.
Transcriptional modifications between Treg from healthy donors (HD) and Treg from patients suffering from warm autoimmune hemolytic anemia (wAIHA) geo:GSE195791
RNA sequencing of sorted circulating regulatory T cells in untreated warm AIHA and healthy controls. The publication reports four patients and four matched controls in the main transcriptomic comparison; the GEO sample_count is the repository record count. TCR and TNF pathway engagement was associated with reduced Treg suppression and reduced FOXP3 protein despite increased FOXP3 transcript levels; causality and post-translational mechanisms remain incompletely established.
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.
🔬

Clinical Trials

26
NCT03764618 PHASE_III COMPLETED
FORWARD: randomized phase III fostamatinib versus placebo in previously treated warm AIHA. The published primary durable hemoglobin endpoint was not met; favorable reanalyses were post hoc.
Show evidence (1 reference)
clinicaltrials:NCT03764618 SUPPORT Human Clinical
"The primary objective of this study is to assess the efficacy of fostamatinib in subjects with warm antibody autoimmune hemolytic anemia (wAIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT02612558 PHASE_II COMPLETED
Open-label phase II fostamatinib study in warm AIHA; precursor to the randomized FORWARD study.
Show evidence (1 reference)
clinicaltrials:NCT02612558 SUPPORT Human Clinical
"The purpose of this study is to evaluate whether fostamatinib is safe and effective in the treatment of Warm Antibody Autoimmune Hemolytic Anemia (AIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05535933 PHASE_III ACTIVE_NOT_RECRUITING
Phase II/III sovleplenib study in primary or secondary warm AIHA. Published phase II results comprise 21 patients, with placebo crossover after eight weeks; these are not phase III efficacy results.
Show evidence (1 reference)
clinicaltrials:NCT05535933 SUPPORT Human Clinical
"Phase II Study: To evaluate the safety and preliminary efficacy of HMPL-523 in adult patients with wAIHA."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT03538041 PHASE_II COMPLETED
Open-label phase II parsaclisib study in warm, cold and mixed AIHA; 25 patients were included in the published efficacy report.
Show evidence (1 reference)
clinicaltrials:NCT03538041 SUPPORT Human Clinical
"The purpose of this study is to evaluate the safety and efficacy of parsaclisib administered orally to participants with autoimmune hemolytic anemia (AIHA) who have decreased hemoglobin and evidence of ongoing hemolysis that requires treatment intervention."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05073458 PHASE_III TERMINATED
Randomized phase III parsaclisib versus placebo in primary warm AIHA. Enrollment was discontinued for a business decision, with no safety concerns cited by the sponsor.
Show evidence (1 reference)
clinicaltrials:NCT05073458 SUPPORT Human Clinical
"The purpose of this study is to evaluate the efficacy and safety of parsaclisib compared with placebo in participants with Primary Warm Autoimmune Hemolytic Anemia (wAIHA),"
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT03226678 PHASE_II COMPLETED
PLAUDIT: open-label phase II pegcetacoplan study with CAD and warm-AIHA cohorts; randomization compared two doses rather than active treatment against placebo.
Show evidence (1 reference)
clinicaltrials:NCT03226678 SUPPORT Human Clinical
"This study is to assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of APL-2 in subjects with warm Autoimmune Hemolytic Anemia (wAIHA) or Cold Agglutinin Disease (CAD)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05096403 PHASE_III COMPLETED
CASCADE: phase III placebo-controlled pegcetacoplan study in primary CAD. The current registry lists it as completed; a completed status alone does not establish efficacy.
Show evidence (1 reference)
clinicaltrials:NCT05096403 SUPPORT Human Clinical
"The purpose of the study is to determine the efficacy of pegcetacoplan administration compared to placebo in increasing hemoglobin (Hgb) level from baseline and avoiding transfusion in participants with primary cold agglutinin disease (CAD)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT03347422 PHASE_III COMPLETED
CADENZA: randomized phase III sutimlimab versus placebo in CAD without recent transfusion, followed by an open-label extension and washout. Continuing C1s inhibition sustained benefit; hemolysis returned after withdrawal.
Show evidence (1 reference)
clinicaltrials:NCT03347422 SUPPORT Human Clinical
"The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=)1.5 grams per deciliter (g/dL) increase in hemoglobin (Hgb) level and avoidance of transfusion in participants with primary cold agglutinin disease (CAD) without a recent history..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT03347396 PHASE_III COMPLETED
CARDINAL: phase III sutimlimab study in CAD with recent transfusion, followed by a long-term extension.
Show evidence (1 reference)
clinicaltrials:NCT03347396 SUPPORT Human Clinical
"The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=) 2 grams per deciliter (g/dL) increase in hemoglobin (Hgb) levels or increased Hgb to \>= 12 g/dL and obviated the need for blood transfusion during treatment in participants with..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05002777 PHASE_II ACTIVE_NOT_RECRUITING
LUMINA 2: phase II rilzabrutinib study in warm AIHA, with a 24-week initial treatment period and extension. The registry describes an active extension, not ongoing recruitment.
Show evidence (1 reference)
clinicaltrials:NCT05002777 SUPPORT Human Clinical
"All participants will receive rilzabrutinib orally. The screening period is up to 28 days, followed by a treatment period of 24 weeks for Part A. Participants who complete Part A and are deemed eligible for Part B can continue in the Core Part B period followed by an Extended Part B period for..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT04119050 PHASE_III ACTIVE_NOT_RECRUITING
ENERGY: phase II/III nipocalimab (M281) study in adults with warm AIHA, evaluating FcRn blockade.
Show evidence (1 reference)
clinicaltrials:NCT04119050 SUPPORT Human Clinical
"The main purpose of this study is to evaluate the efficacy and safety of M281 in participants with warm autoimmune hemolytic anemia (wAIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05648968 PHASE_III ACTIVE_NOT_RECRUITING
VAYHIA: phase III ianalumab versus placebo after at least one failed line of treatment for warm AIHA.
Show evidence (1 reference)
clinicaltrials:NCT05648968 SUPPORT Human Clinical
"The purpose of this study is to evaluate efficacy and safety of ianalumab compared to placebo in patients with warm autoimmune hemolytic anemia, who failed at least one line of treatment."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05786573 PHASE_III ACTIVE_NOT_RECRUITING
SApHiAre: phase III obexelimab study in warm AIHA. The current registry phase supersedes older review articles calling this registration phase II.
Show evidence (1 reference)
clinicaltrials:NCT05786573 SUPPORT Human Clinical
"This study aims to examine the efficacy and safety of obexelimab in participants with Warm Autoimmune Hemolytic Anemia (wAIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05757570 PHASE_II COMPLETED
RUBY-4: phase I/II open-label povetacicept study in autoimmune cytopenias, including warm AIHA and CAD. The study is completed in the current registry.
Show evidence (1 reference)
clinicaltrials:NCT05757570 SUPPORT Human Clinical
"The goal of this clinical study is to evaluate povetacicept in adults with autoimmune cytopenias of immune thrombocytopenia, autoimmune hemolytic anemia, and cold agglutinin disease to determine if povetacicept is safe and potentially beneficial in treating these diseases. During the study..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT04661033 PHASE_II TERMINATED
Isatuximab study in adult warm AIHA, terminated for a strategic sponsor decision rather than a cited safety concern.
Show evidence (1 reference)
clinicaltrials:NCT04661033 SUPPORT Human Clinical
"To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults with wAIHA"
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT04691570 PHASE_II COMPLETED
Phase II ANX005 anti-C1q study in warm AIHA; current registration lists completion.
Show evidence (1 reference)
clinicaltrials:NCT04691570 SUPPORT Human Clinical
"This study will evaluate the safety and tolerability of ANX005 in participants with Warm Autoimmune Hemolytic Anemia (wAIHA)."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT04269551 PHASE_I COMPLETED
Phase I riliprubart (BIVV020) single-dose study in CAD, assessing safety, hemolysis and complement inhibition.
Show evidence (1 reference)
clinicaltrials:NCT04269551 SUPPORT Human Clinical
"To assess the safety and tolerability in participants with cold agglutinin disease (CAD), after a single dose of intravenous (IV) BIVV020"
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT04802057 PHASE_I TERMINATED
Phase I repeat-dose riliprubart (SAR445088) study in CAD; current registry status is terminated.
Show evidence (1 reference)
clinicaltrials:NCT04802057 SUPPORT Human Clinical
"To assess the long-term safety and tolerability in patients with cold agglutinin disease (CAD), after multiple doses of SAR445088"
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05086744 PHASE_II TERMINATED
Phase II iptacopan basket study including primary CAD and immune thrombocytopenia, terminated for a business decision.
Show evidence (1 reference)
clinicaltrials:NCT05086744 SUPPORT Human Clinical
"The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05931718 NOT_APPLICABLE RECRUITING
CYTOPAN observational study of autoimmune cytopenias, including diagnostic markers, marrow findings and treatment outcomes. The prospective epoetin analysis was a substudy, not a randomized epoetin trial.
Show evidence (1 reference)
clinicaltrials:NCT05931718 SUPPORT Human Clinical
"The goal of this observational study is to characterize the diagnostic and therapeutic management of autoimmune cytopenias including autoimmune hemolytic anemia, immune thrombocytopenia, and chronic idiopathic/autoimmune neutropenia."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT01303952 PHASE_II COMPLETED
DECADE: nonrandomized phase II eculizumab study; the published population comprised 12 CAD patients and one acute secondary cold-agglutinin case.
Show evidence (1 reference)
clinicaltrials:NCT01303952 SUPPORT Human Clinical
"Evaluation of the efficacy and safety of eculizumab in symptomatic or transfusion-dependent patients with untreated or refractory hemolytic cold agglutinin disease(CAD)"
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT06231368 PHASE_I ACTIVE_NOT_RECRUITING
Phase I CNCT19 CD19 CAR-T study after failure of at least three lines of AIHA therapy; open-label dose escalation and expansion, not established standard care. The 2026 primary publication combines six trial participants with five compassionate-use patients; outcomes are not from a randomized comparison.
Show evidence (1 reference)
clinicaltrials:NCT06231368 SUPPORT Human Clinical
"This is a Phase 1, single-arm, open-label, dose-escalation and dose-expansion study. The main purpose is to evaluate the safety and tolerability, efficacy of CNCT19 CAR T-cell therapy in patients with autoimmune hemolytic anemia after failure of three or more lines of therapy. Participants will..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT03827603 PHASE_II UNKNOWN
Phase II ibrutinib plus rituximab in autoimmune cytopenia associated with CLL, followed by ibrutinib maintenance. This is not a trial of unselected primary AIHA; current recruitment status is unknown.
Show evidence (1 reference)
clinicaltrials:NCT03827603 SUPPORT Human Clinical
"This is an open-labeled, single arm, Phase II, two staged study of combination of ibrutinib and rituximab in patients with autoimmune cytopenia and underlying CLL. In stage I (remission induction) patients will receive ibrutinib and rituximab for 6 months; in stage II (maintenance) - only..."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT05922839 PHASE_II UNKNOWN
Exploratory phase II zanubrutinib study in relapsed or refractory warm AIHA. The current registry labels recruitment status unknown.
Show evidence (1 reference)
clinicaltrials:NCT05922839 SUPPORT Human Clinical
"The therapeutic effect of zanubrutinib on refractory warm autoimmune hemolytic anemia, is worth exploring through exploratory research."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT06067048 PHASE_II ACTIVE_NOT_RECRUITING
CaZa: phase II zanubrutinib in primary CAD, targeting the pathogenic B-cell clone rather than complement alone.
Show evidence (1 reference)
clinicaltrials:NCT06067048 SUPPORT Human Clinical
"Bruton Tyrosine Kinase inhibitors (BTKis) are effective in many B-cell lymphoproliferative disorders including the IgM producing clone of Waldenström macroglobulinemia (WM) and were very effective on both AIHA and peripheral ischemic symptoms in patients with CAD based on retrospective data."
Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
NCT01696474 PHASE_II COMPLETED
GIMEMA short-course bortezomib study in relapsed cold-antibody hemolysis. The primary report enrolled 21 patients; six of 19 evaluable patients responded. The cohort included associated B-cell disorders not requiring separate treatment.
Show evidence (1 reference)
clinicaltrials:NCT01696474 SUPPORT Human Clinical
"This multicenter, phase II, open label study will enroll patients with chronic cold agglutinin disorder. A single course of Bortezomib will be given at the dose of 1,3 mg/sqm iv on days 1, 4, 8, 11."
Registry establishes the study objective; response and exclusion counts come from the full primary report.
{ }

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 immune hemolytic disorder in which autoantibodies shorten red-cell survival through Fc-receptor-mediated phagocytosis and/or complement activation. Warm AIHA, cold agglutinin disease or secondary cold agglutinin syndrome, mixed AIHA and paroxysmal cold hemoglobinuria differ in antibody properties, sites of destruction and treatment response. Disease severity also depends on marrow compensation. A positive direct antiglobulin test requires accompanying evidence of hemolysis; a negative standard test does not exclude AIHA. The disorder may be primary or associated with another disease.
pathophysiology:
- name: Anti-Erythrocyte Autoantibody Production
  biological_scale: CELLULAR
  description: >-
    Autoreactive B-lineage cells produce antibodies against red-cell antigens. Warm disease generally involves polyclonal responses; CAD has a characteristic clonal B-cell source. Persistent antibody production by CD20-negative plasma cells can contribute to resistance to B-cell depletion.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In warm AIHA, persistent autoantibody production is driven by autoreactive plasmablasts and plasma cells, with circulating plasmablasts indicating ongoing B-cell activation
    explanation: >-
      Review synthesis of the antibody-producing compartment; persistence mechanisms are not identical in all AIHA subtypes.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Warm IgG Coating of Erythrocytes
    causal_link_type: DIRECT
    description: >-
      Warm-reactive IgG recognizes red-cell antigens.
  - target: Cold Agglutinin Binding
    causal_link_type: DIRECT
    description: >-
      Cold-reactive antibodies bind and crosslink red cells within their thermal amplitude.
  - target: Biphasic Hemolysin Binding
    causal_link_type: DIRECT
    description: >-
      In PCH, a cold-reactive IgG binds the P/GLOB antigen.
- name: Clonal B-Cell Expansion in CAD
  biological_scale: CELLULAR
  description: >-
    A characteristic marrow B-cell clone supplies the pathogenic monoclonal cold agglutinin in primary CAD. This is distinct from overt lymphoma-associated secondary cold agglutinin syndrome and is not a universal feature of warm AIHA.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cold agglutinin disease (CAD) or primary CAD is a clonal disease whereby the lymphoproliferation of a B-cell clone produces a cold-reactive (≤30 °C) monoclonal IgM autoantibody
    explanation: >-
      Clonal source of the cold autoantibody, as synthesized in the clinical review.
  subtypes:
  - Cold agglutinin disease
  downstream:
  - target: Anti-Erythrocyte Autoantibody Production
    causal_link_type: DIRECT
    description: >-
      The CAD clone produces monoclonal cold-reactive immunoglobulin.
- name: Warm IgG Coating of Erythrocytes
  biological_scale: MOLECULAR
  description: >-
    Warm-reactive IgG coats erythrocytes at physiological temperature. Antigen specificity varies; band 3 and Rh-associated reactivity should not be treated as a single universal target.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IgG antibodies have a strong attraction to red blood cells when the temperature is at the normal level of the human body (37 °C).
    explanation: >-
      Warm antibody binding establishes the opsonic signal for clearance.
  subtypes:
  - Warm AIHA
  - Mixed AIHA
  downstream:
  - target: Fc-Gamma-Receptor-Mediated Erythrophagocytosis
    causal_link_type: DIRECT
    description: >-
      Fc receptors recognize IgG coating on erythrocytes.
  - target: Classical Complement Activation
    causal_link_type: DIRECT
    description: >-
      Complement-fixing warm IgG can also activate C1; complement involvement is variable.
  - target: Antibody-Dependent Cellular Cytotoxicity
    causal_link_type: DIRECT
    description: >-
      IgG-coated red cells provide a potential substrate for Fc-receptor-bearing cytotoxic effector cells.
- name: Fc-Gamma-Receptor-Mediated Erythrophagocytosis
  locations:
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  biological_scale: CELLULAR
  description: >-
    Splenic red-pulp macrophages recognize and ingest IgG-opsonized erythrocytes. Isolated human red-pulp macrophages predominantly express FcγRIIa and FcγRIIIa; the primary study did not detect the inhibitory FcγRIIb found in some blood-derived macrophage preparations.
  evidence:
  - 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
    evidence_source: IN_VITRO
    snippet: >-
      Human red pulp macrophages predominantly expressed the low-affinity receptors FcγRIIa and FcγRIIIa. In contrast to blood monocyte-derived macrophages, red pulp macrophages did not express the inhibitory FcγRIIb.
    explanation: >-
      Flow-cytometric characterization of macrophages isolated from human spleens; it does not establish receptor expression in every AIHA patient.
  - 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
    evidence_source: IN_VITRO
    snippet: >-
      phagocytosis of IgG-opsonized blood cells by red pulp macrophages was dependent on the same FcγRs as phagocytosis by blood monocyte-derived macrophages
    explanation: >-
      Functional study of isolated human macrophages supports the receptor-dependent clearance mechanism.
  subtypes:
  - Warm AIHA
  - Mixed AIHA
  cell_types:
  - preferred_term: splenic red pulp macrophage
    term:
      id: CL:0000874
      label: splenic red pulp macrophage
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: Fc-gamma receptor signaling pathway involved in phagocytosis
    term:
      id: GO:0038096
      label: Fc-gamma receptor signaling pathway involved in phagocytosis
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: >-
      Removal of erythrocytes shortens their circulating survival.
  - target: Partial Erythrocyte Membrane Removal
    causal_link_type: DIRECT
    description: >-
      Macrophages can remove part of an opsonized cell membrane rather than ingest the entire cell.
  - target: Jaundice
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Increased erythrocyte breakdown increases unconjugated bilirubin production.
  - target: Monocyte TNF Production in Hemolytic Conditions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      IgG-coated erythrocytes stimulate TNF production in cultured monocytes; the systemic feedback contribution remains inferred.
- name: Partial Erythrocyte Membrane Removal
  biological_scale: CELLULAR
  description: >-
    Partial macrophage uptake removes erythrocyte membrane, reducing deformability and producing spherocytes that are more readily retained in the spleen.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In wAIHA, this leads to the degradation of the RBC membrane, causing transformation into spherocytes
    explanation: >-
      Clinical review describes membrane loss as the route to spherocyte formation.
  subtypes:
  - Warm AIHA
  downstream:
  - target: Spherocytosis
    causal_link_type: DIRECT
    description: >-
      Loss of membrane relative to cell volume produces the spherical morphology.
  - target: Splenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Splenic sequestration of spherocytes and opsonized cells can contribute to enlargement.
- name: Cold Agglutinin Binding
  biological_scale: MOLECULAR
  description: >-
    Cold-reactive autoantibodies bind red-cell antigens within their thermal amplitude. Binding can initiate both complement activation and red-cell crosslinking; those consequences are modeled separately.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pentameric nature of IgM promotes red cell agglutination, causing RBC aggregates that impair microcirculation in acral regions
    explanation: >-
      Agglutination is a separate consequence from complement-mediated erythrocyte destruction.
  subtypes:
  - Cold agglutinin disease
  - Secondary cold agglutinin syndrome
  - Mixed AIHA
  downstream:
  - target: Classical Complement Activation
    causal_link_type: DIRECT
    description: >-
      Erythrocyte-bound IgM activates the classical pathway.
  - target: Erythrocyte Agglutination
    causal_link_type: DIRECT
    description: Multivalent antibody crosslinks erythrocytes.
- name: Erythrocyte Agglutination
  biological_scale: CELLULAR
  description: >-
    Multivalent cold agglutinins crosslink erythrocytes into aggregates that impair acral microcirculation. These symptoms can persist despite control of complement-mediated hemolysis.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pentameric nature of IgM promotes red cell agglutination, causing RBC aggregates that impair microcirculation in acral regions
    explanation: >-
      Agglutination is a separate consequence from complement-mediated erythrocyte destruction.
  subtypes:
  - Cold agglutinin disease
  - Secondary cold agglutinin syndrome
  - Mixed AIHA
  downstream:
  - target: Acrocyanosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Agglutinated erythrocytes impair acral circulation.
  - target: Raynaud phenomenon
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cold-associated red-cell aggregation contributes to circulatory symptoms.
- name: Biphasic Hemolysin Binding
  biological_scale: MOLECULAR
  description: >-
    The Donath-Landsteiner IgG binds red cells at lower temperatures and initiates complement fixation; warming permits terminal complement-mediated lysis.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the Donath-Landsteiner IgG binds to its antigen at low temperatures and fixes early complement components C1, C4, and C2
    explanation: >-
      PCH differs from the IgM mechanism of CAD/CAS.
  subtypes:
  - Paroxysmal cold hemoglobinuria
  downstream:
  - target: Classical Complement Activation
    causal_link_type: DIRECT
    description: >-
      Cold-bound IgG fixes early complement components, with further activation on warming.
- name: Classical Complement Activation
  biological_scale: MOLECULAR
  description: >-
    Erythrocyte-bound antibody activates the C1 complex and the classical complement cascade. C3 opsonization and terminal membrane injury are distinct downstream branches. Warm IgG1/IgG3 can activate complement, although this is less consistently prominent than in cold-antibody disease.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IgG1 and IgG3 autoantibodies retain the capacity to activate the classical complement cascade through C1q binding
    explanation: >-
      Complement is not confined to IgM-mediated AIHA.
  - reference: PMID:30559259
    reference_title: "Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis.
    explanation: >-
      Clinical C1s-inhibition study establishes the complement-dependent CAD context.
  biological_processes:
  - preferred_term: complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
  downstream:
  - target: C3b Opsonization of Erythrocytes
    causal_link_type: DIRECT
    description: >-
      Classical-pathway C3 activation deposits opsonic fragments on red cells.
  - target: Terminal Complement-Mediated Erythrocyte Lysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progression through terminal complement forms the membrane attack complex; especially important in PCH and acute cold-antibody exacerbations.
- name: C3b Opsonization of Erythrocytes
  biological_scale: MOLECULAR
  description: >-
    C3b coating promotes complement-receptor-mediated erythrocyte clearance. Residual C3d detected by the DAT is a marker of complement sensitization, not the principal opsonin driving this clearance.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Opsonization of RBCs by C3b promotes their extravascular clearance, primarily mediated by hepatic macrophages
    explanation: >-
      Separates the functional C3b opsonin from C3d detected in diagnostic testing.
  downstream:
  - target: Hepatic Clearance of Complement-Opsonized Erythrocytes
    causal_link_type: DIRECT
    description: >-
      Complement receptors recognize erythrocyte-bound C3 fragments.
- name: Hepatic Clearance of Complement-Opsonized Erythrocytes
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  biological_scale: CELLULAR
  description: >-
    Hepatic macrophages remove complement-coated erythrocytes. This extravascular pathway predominates in stable CAD, explaining why splenectomy is poorly effective.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Opsonization of RBCs by C3b promotes their extravascular clearance, primarily mediated by hepatic macrophages
    explanation: >-
      Clinical mechanistic synthesis of the major site of complement-opsonized clearance.
  cell_types:
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: >-
      Accelerated erythrocyte removal lowers red-cell mass when marrow compensation is insufficient.
  - target: Jaundice
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Increased heme catabolism generates unconjugated bilirubin.
- name: Terminal Complement-Mediated Erythrocyte Lysis
  conforms_to: "complement_dysregulation#C5 Convertase Activation and Terminal Pathway Assembly"
  biological_scale: CELLULAR
  description: >-
    Membrane attack complex formation causes intravascular hemolysis. It is prominent in PCH and can increase during CAD exacerbations; it should not replace hepatic extravascular clearance as the predominant stable-CAD mechanism.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      terminal complement activation with membrane attack complex (MAC) C5b-C9 formation is generally absent during stable clinical phases and occurs predominantly during acute exacerbations or in severe disease
    explanation: >-
      The review qualifies the relative contribution of terminal complement in CAD.
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: >-
      Intravascular destruction reduces the circulating red-cell mass.
  - target: Hemoglobinuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Released hemoglobin can exceed plasma binding and renal reabsorption capacity.
  - target: Monocyte TNF Production in Hemolytic Conditions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Heme exposure stimulates cultured human monocytes; its contribution to sustained human autoimmunity is inferred.
  - target: Thromboembolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Active intravascular hemolysis is associated with thrombosis; free hemoglobin, inflammatory and complement-coagulation interactions are candidate mediators, with additional patient-specific risk factors.
    evidence:
    - reference: PMID:35555857
      reference_title: Intravascular hemolysis and multitreatment predict thrombosis in patients with autoimmune hemolytic anemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thrombosis was observed in about 11% of AIHA patients, mainly grade 3, and associated with intravascular hemolysis, need of transfusions, multitreatment, and infections
      explanation: >-
        Observational association supports a clinically important connection; it does not prove any one proposed molecular mediator.
- name: Monocyte TNF Production in Hemolytic Conditions
  biological_scale: CELLULAR
  description: >-
    Heme and IgG-coated erythrocytes increase TNF production by cultured human monocytes. This offers a possible feedback link from hemolysis to immune dysregulation, but does not prove that TNF causes clinical AIHA.
  evidence:
  - reference: PMID:37534543
    reference_title: Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, we observed that in conditions mimicking wAIHA, monocytes were the main cells producing TNF-α.
    explanation: >-
      Human-cell experiments identify a potential inflammatory feedback source.
  subtypes:
  - Warm AIHA
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Regulatory T-Cell Suppressive Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patient TNF-pathway engagement correlates with reduced FOXP3 protein and Treg frequency; a causal TNF-to-Treg effect was not directly isolated in AIHA.
- name: Regulatory T-Cell Suppressive Dysfunction
  biological_scale: CELLULAR
  description: >-
    Untreated warm-AIHA patients had fewer circulating regulatory T cells and reduced suppression of effector T-cell proliferation in coculture. FOXP3 protein was reduced despite increased transcripts. Proposed phosphorylation/deacetylation mechanisms were not directly demonstrated; onset versus persistence of autoimmunity cannot be distinguished.
  evidence:
  - reference: PMID:37534543
    reference_title: Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the suppressive function of Treg was also altered in wAIHA, as shown by a decreased ability to inhibit Teff proliferation (51% vs. 73%; P=0.003
    explanation: >-
      Suppression was tested in nine patient and nine control cocultures, not all 22 enrolled patients.
  - reference: PMID:37534543
    reference_title: Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, it is impossible to determine whether Treg dysfunction precedes the onset of the disease and promotes it, or whether this deficit merely sustains the disease.
    explanation: >-
      The investigators explicitly limit temporal and causal interpretation.
  subtypes:
  - Warm AIHA
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  downstream:
  - target: Anti-Erythrocyte Autoantibody Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired peripheral regulation may sustain autoreactive immunity; this link remains inferred in humans.
  - target: Th17-Associated Immune Polarization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Treg dysfunction accompanies a Th17-biased response; a causal conversion of Tregs into Th17 cells was not established.
- name: Th17-Associated Immune Polarization
  biological_scale: CELLULAR
  description: >-
    Warm-AIHA cohorts show increased IL-17 production and a higher Th17/Treg ratio. Serum IL-17 correlates with LDH and bilirubin, but not hemoglobin or reticulocyte count; this association does not establish that IL-17 directly destroys red cells.
  evidence:
  - reference: PMID:37534543
    reference_title: Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the serum concentration of IL-17 positively correlated with markers of RBC destruction, namely lactate dehydrogenase (LDH) and bilirubin
    explanation: >-
      Observational human serum association, distinct from the cell-culture cytokine assays.
  subtypes:
  - Warm AIHA
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  downstream:
  - target: Anti-Erythrocyte Autoantibody Production
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Th17-biased immune activity is proposed to support persistent autoreactivity; direct causal proof in patients is lacking.
- name: Inflammatory Bone Marrow Microenvironment
  biological_scale: TISSUE
  description: >-
    Biopsy-selected AIHA patients showed lymphoid infiltration and abnormal erythroid morphology. Single-cell analysis in nine warm-AIHA patients found relapse-associated inflammatory programs in T cells and monocytes. Treatment exposure, a small cohort and unrelated relapse samples limit causal inference; transcriptomic cytokine signatures are not direct measurements of secreted cytokine concentrations.
  evidence:
  - reference: PMID:40854885
    reference_title: "Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      at relapse, an upregulation of inflammatory pathways (TNF-alpha signaling for all the three cell types and IFN pathways for monocytes only) was noted compared with diagnosis and remission
    explanation: >-
      Single-cell analysis of patient marrow T cells and monocytes; association rather than experimentally isolated cause.
  subtypes:
  - Warm AIHA
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Inadequate Erythropoietic Compensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inflammation, erythroid abnormalities and inadequate endogenous erythropoietin may limit compensation. The marrow study did not directly demonstrate immune killing of erythroblasts.
- name: Inadequate Erythropoietic Compensation
  biological_scale: TISSUE
  description: >-
    Marrow output may fail to match accelerated erythrocyte loss. Reticulocytopenia is one presentation, but an elevated absolute reticulocyte count may still be inadequate for the severity of anemia. Inadequate endogenous erythropoietin and dyserythropoiesis are associated findings rather than universal causes.
  evidence:
  - reference: PMID:40854885
    reference_title: "Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than half of patients (56%) displayed inadequate reticulocytosis as depicted by a BMRI < 121, and 75% of patients had inadequate endogenous erythropoietin levels.
    explanation: >-
      Findings from a selected marrow-evaluated referral cohort; the percentages are not population prevalence estimates.
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: >-
      Insufficient replacement amplifies anemia caused by peripheral destruction.
  - target: Reticulocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Some patients have a low absolute reticulocyte count, although inadequate compensation can occur without frank reticulocytopenia.
- name: Follicular Helper T-Cell Expansion
  biological_scale: CELLULAR
  description: >-
    An expanded follicular-helper compartment can support autoreactive B-cell activation. In rat-red-cell-immunized mice, Tfh expansion increased the Tfh:Tfr ratio; Tfr absolute numbers and suppressive function were not clearly reduced. Transfer accelerated autoantibody induction only in the setting of subsequent repeated immunization, rather than demonstrating spontaneous human AIHA.
  evidence:
  - reference: PMID:31875006
    reference_title: The Role of T Follicular Helper Cells and T Follicular Regulatory Cells in the Pathogenesis of Autoimmune Hemolytic Anemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The function of TFH cells in the responder group was not altered compared to the non-responder group, despite the increased number of TFH cells.
    explanation: >-
      The murine study supports expansion rather than greater per-cell helper activity. Human generalization remains provisional.
  - reference: PMID:31875006
    reference_title: The Role of T Follicular Helper Cells and T Follicular Regulatory Cells in the Pathogenesis of Autoimmune Hemolytic Anemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The day after transfer, the mice were immunized with rat RBCs weekly for consecutive 12 weeks.
    explanation: >-
      Adoptive transfer was followed by repeated antigen challenge; it was not sufficient alone to establish spontaneous disease.
  downstream:
  - target: Anti-Erythrocyte Autoantibody Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Tfh help supports germinal-center B-cell activation and antibody production; transfer and coculture experiments support this connection in the murine model.
  cell_types:
  - preferred_term: T follicular helper cell
    term:
      id: CL:0002038
      label: T follicular helper cell
  notes: >-
    The cached CD4 T-cell review (DOI:10.5633/amm.2024.0108) was cross-checked against the primary murine study. The ratio change is not modeled as proven Tfr depletion or a universal human initiating lesion.
  mechanism_confidence: PROVISIONAL
- name: Persistent Autoreactive Plasma Cells
  biological_scale: CELLULAR
  description: >-
    Autoreactive plasma cells can persist in the spleen despite corticosteroid treatment and rituximab-mediated B-cell depletion. In selected rituximab-refractory warm-AIHA splenectomy samples, these cells displayed a long-lived transcriptional program, providing a potential reservoir for continuing autoantibody production.
  evidence:
  - reference: PMID:26112660
    reference_title: Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive.
    explanation: >-
      Selected refractory human tissue establishes persistence, not its frequency across all warm AIHA.
  - reference: PMID:26112660
    reference_title: Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro.
    explanation: >-
      Ex-vivo secretion supports the autoantibody-producing function of persistent plasma cells.
  downstream:
  - target: Anti-Erythrocyte Autoantibody Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Persistent autoreactive plasma cells continue to supply anti-red-cell antibodies.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  subtypes:
  - Warm AIHA
- name: BAFF-Rich Splenic Survival Environment
  biological_scale: CELLULAR
  description: >-
    In selected rituximab-treated refractory warm-AIHA samples, spleen-cell culture supernatants had increased BAFF. This supports a proposed survival environment for autoreactive plasma cells after B-cell depletion; it does not establish that BAFF elevation initiates every case of AIHA.
  evidence:
  - reference: PMID:26112660
    reference_title: Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients.
    explanation: >-
      Human-derived cell cultures provide a treatment-context association; BAFF dependence is a mechanistic interpretation rather than a universal causal finding.
  downstream:
  - target: Persistent Autoreactive Plasma Cells
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      BAFF and other splenic signals may support survival after B-cell depletion; the specific contribution remains incompletely established.
  subtypes:
  - Warm AIHA
  mechanism_confidence: PROVISIONAL
- name: Antibody-Dependent Cellular Cytotoxicity
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Cytotoxic effector cells may contribute to destruction of antibody-coated red cells. This is a proposed auxiliary mechanism; its quantitative contribution in human AIHA is less established than macrophage phagocytosis or complement-mediated clearance.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: DOI:10.5633/amm.2024.0108
    reference_title: CD4+ T CELL PROFILES IN AUTOIMMUNE HEMOLYTIC ANEMIA
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Antibody- dependent cellular cytotoxicity (ADCC) involving NK cells and CD8 + T cells is also proposed as a possible mechanism of extravascular RBC destruction in the spleen and other secondary lymphoid organs.
    explanation: >-
      The full-text review explicitly presents this mechanism as proposed; it is not modeled as the dominant or universally demonstrated human effector pathway.
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: >-
      Additional immune destruction could shorten red-cell survival; the relative contribution remains uncertain.
phenotypes:
- name: Anemia
  category: Hematological
  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.
  sequelae:
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced oxygen-carrying capacity contributes to this manifestation.
  - target: Dyspnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced oxygen-carrying capacity contributes to this manifestation.
  - target: Pallor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced circulating hemoglobin contributes to pallor.
- name: Jaundice
  category: Hepatic
  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
  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
  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.
  - 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: >-
      Study participation was limited to individuals who reported having experienced fatigue due to wAIHA.
    explanation: >-
      The full-text inclusion criterion prevents using 20/20 interviews as an unbiased frequency estimate.
  description: >-
    Fatigue can impair daily activities, work, social participation and emotional well-being. In the 20-person warm-AIHA interview study, fatigue was required for eligibility, so universal reporting within that sample does not establish population prevalence.
- name: Dyspnea
  category: Clinical
  description: >-
    Reported clinical symptom associated with anemia; severity and frequency vary.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The symptoms may include dyspnea, fatigue, headache, muscular weakness, pallor and/or jaundice
    explanation: >-
      The clinical review explicitly lists dyspnea among AIHA symptoms; it does not supply a population frequency.
- name: Pallor
  category: Clinical
  description: >-
    Reported manifestation of anemia, without a population frequency estimate.
  phenotype_term:
    preferred_term: Pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The symptoms may include dyspnea, fatigue, headache, muscular weakness, pallor and/or jaundice
    explanation: >-
      The clinical review explicitly includes pallor among AIHA manifestations without quantifying its frequency.
- name: Acrocyanosis
  category: Clinical
  description: >-
    Cold-antibody agglutination can cause acral cyanosis independently of complement-mediated hemolysis. This also occurs in secondary cold agglutinin syndrome.
  phenotype_term:
    preferred_term: Acrocyanosis
    term:
      id: HP:0001063
      label: Acrocyanosis
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The development of acrocyanosis and Raynaud phenomenon in CAS/CAD may culminate rarely with gangrene
    explanation: >-
      The source localizes acrocyanosis to cold-antibody disease and syndrome; the rare gangrene complication is not assigned to every AIHA subtype.
  subtype: Cold agglutinin disease
- name: Raynaud phenomenon
  category: Clinical
  description: >-
    Cold-associated circulatory manifestation of cold-antibody disease; it is not a general feature of every AIHA subtype.
  phenotype_term:
    preferred_term: Raynaud phenomenon
    term:
      id: HP:0030880
      label: Raynaud phenomenon
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The development of acrocyanosis and Raynaud phenomenon in CAS/CAD may culminate rarely with gangrene
    explanation: >-
      The source identifies Raynaud phenomenon in CAD/CAS, supporting a cold-circulatory phenotype rather than a universal warm-AIHA finding.
  subtype: Cold agglutinin disease
- name: Spherocytosis
  category: Hematological
  description: >-
    Partial macrophage removal of antibody-coated red-cell membrane produces spherocytes; this blood-film finding is not specific for AIHA.
  phenotype_term:
    preferred_term: Spherocytosis
    term:
      id: HP:0004444
      label: Spherocytosis
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In wAIHA, this leads to the degradation of the RBC membrane, causing transformation into spherocytes
    explanation: >-
      The quoted mechanism connects erythrocyte membrane removal to spherocyte formation in warm AIHA.
  subtype: Warm AIHA
- name: Hemoglobinuria
  category: Hematological
  description: >-
    A manifestation of intravascular hemolysis, characteristic of PCH but not confined to that subtype. Modern childhood PCH commonly follows a viral illness and need not have recurrent cold-triggered attacks.
  phenotype_term:
    preferred_term: Hemoglobinuria
    term:
      id: HP:0003641
      label: Hemoglobinuria
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Historically, PCH manifested primarily in patients having syphilis, and exposure to cold resulted in paroxysms of hemoglobinuria.
    explanation: >-
      The historical PCH observation supports hemoglobinuria during intravascular hemolysis; it does not imply that modern PCH cases are usually syphilitic.
  subtype: Paroxysmal cold hemoglobinuria
- name: Reticulocytopenia
  category: Hematological
  description: >-
    A low reticulocyte count can accompany AIHA. Inadequate compensation relative to the degree of anemia is a broader concept and can occur even with a numerically elevated count.
  phenotype_term:
    preferred_term: Reticulocytopenia
    term:
      id: HP:0001896
      label: Reticulocytopenia
  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: >-
      Reticulocytopenia occurs in 20-40% of autoimmune hemolytic anemia cases and is a poor prognostic factor.
    explanation: >-
      The source establishes reticulocytopenia as a recognized poor-prognosis presentation. Its review-level percentage is not promoted to a population frequency for every subtype.
- name: Thromboembolism
  category: Cardiovascular
  description: >-
    Venous and arterial thrombosis can complicate AIHA, especially during active hemolysis. A tertiary-center cohort observed events in 33/287 patients (11.4%); this selected cohort is not a universal frequency estimate.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:35555857
    reference_title: Intravascular hemolysis and multitreatment predict thrombosis in patients with autoimmune hemolytic anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-three AIHA patients (11.4%) experienced thrombosis, 70% of whom hospitalized.
    explanation: >-
      The cohort included multiple AIHA subtypes and associated conditions; most events were venous, particularly pulmonary embolism.
biochemical:
- name: Direct Antiglobulin Test (DAT)
  presence: Often positive; standard DAT-negative cases occur
  context: Interpret IgG/complement findings with biochemical hemolysis and clinical context; positive DAT alone is insufficient
  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: >-
      DAT is a central investigation of immune hemolysis, but neither a positive result without hemolysis nor a negative standard assay alone establishes or excludes AIHA.
  - 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: >-
      DAT is a central investigation of immune hemolysis, but neither a positive result without hemolysis nor a negative standard assay alone establishes or excludes AIHA.
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, a positive DAT does not automatically indicate AIHA.
    explanation: >-
      The DAT detects red-cell sensitization, not hemolysis itself.
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 1% to 10% of people diagnosed with AIHA have a negative DAT
    explanation: >-
      Standard assays may miss low-density or low-affinity IgG and antibodies not recognized by the test reagent.
- 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
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    First-line treatment for warm AIHA, with tapering after response and substantial relapse and cumulative toxicity concerns. This role does not extend to primary CAD, where steroid responses are poor.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite a slow steroid tapering in 4–6 months, 1/3 of patients relapse and require a further therapy line.
    explanation: >-
      The review distinguishes initial warm-AIHA response from sustained steroid-free remission.
  treatment_term:
    preferred_term: Systemic Corticosteroid Therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
  target_mechanisms:
  - target: Fc-Gamma-Receptor-Mediated Erythrophagocytosis
    treatment_effect: INHIBITS
    description: >-
      Reduces immune-mediated red-cell clearance in warm AIHA.
- name: Rituximab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Anti-CD20 B-cell depletion is a preferred second-line treatment for warm AIHA and may be introduced earlier in severe disease. It also targets the pathogenic B-cell clone in CAD, as monotherapy or combined with bendamustine in suitable patients; response magnitude and durability differ by subtype.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The anti-CD20 monoclonal antibody rituximab has become the preferred 2nd line being able to induce 70–80% of responses.
    explanation: >-
      The response estimate applies to warm AIHA in this clinical review, not every AIHA subtype.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Depletes CD20-positive B cells contributing to autoantibody production; long-lived CD20-negative plasma cells can persist.
- name: Splenectomy
  therapeutic_modality: SURGERY
  description: >-
    A later-line option for selected fit patients with refractory warm AIHA, after accounting for lifelong infection and thrombotic risks. It is generally ineffective in CAD because complement-opsonized cells are cleared predominantly in the liver.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It may be considered in young low comorbid patients after vaccination against capsulated organisms, and accounting for a life-long increase in infectious and thrombotic risk.
    explanation: >-
      The clinical review limits this intervention to suitable warm-AIHA patients.
  treatment_term:
    preferred_term: Splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Fc-Gamma-Receptor-Mediated Erythrophagocytosis
    treatment_effect: INHIBITS
    description: >-
      Removes a major site of IgG-mediated erythrocyte clearance.
- name: Sutimlimab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    C1s inhibition for CAD rapidly controls complement-mediated hemolysis and improves anemia and fatigue. Continued dosing is usually needed; it does not remove the B-cell clone or directly treat agglutination-mediated acrocyanosis and Raynaud symptoms.
  evidence:
  - reference: PMID:39091672
    reference_title: "Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels.
    explanation: >-
      CADENZA Part B followed 39 patients, 32 of whom completed the extension, for a median treatment duration of 99 weeks. The extension was open label and descriptive.
  - reference: PMID:39091672
    reference_title: "Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mechanism of action of sutimlimab means that it affects the complement-mediated symptoms of CAD, such as haemolysis, anaemia, and fatigue, rather than the cold-induced, agglutination-mediated circulatory symptoms, such as acrocyanosis and Raynaud's phenomenon.
    explanation: >-
      Explains the mechanistic boundary of treatment response.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Sutimlimab
      term:
        id: NCIT:C153093
        label: Sutimlimab
  target_mechanisms:
  - target: Classical Complement Activation
    treatment_effect: INHIBITS
    description: >-
      Selective C1s blockade prevents classical-pathway activation and downstream C3b opsonization.
- name: Red-cell transfusion support
  therapeutic_modality: OTHER
  description: >-
    Transfusion supports patients with severe or symptomatic anemia while disease-directed therapy takes effect. Selection depends on symptoms and comorbidity as well as hemoglobin; alloantibody investigation and close transfusion-service coordination are essential. Physiologically necessary transfusion should not be withheld solely because an autoantibody makes serologic compatibility difficult.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, a careful matching is recommended along with a close collaboration with transfusion medicine experts
    explanation: >-
      Supportive care requires attention to clinically significant alloantibodies.
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transfusion if necessary; do not withhold transfusion if physiologically required
    explanation: >-
      The source stresses clinical necessity while retaining investigation and matching for underlying alloantibodies.
  treatment_term:
    preferred_term: Packed Red Blood Cell Transfusion
    term:
      id: NCIT:C15409
      label: Packed Red Blood Cell Transfusion
  target_mechanisms:
  - target: Anemia
    treatment_effect: BYPASSES
    description: >-
      Replaces circulating red cells without suppressing the underlying autoimmune process.
- name: Epoetin alfa
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    An adjunct for selected AIHA patients with inadequate reticulocyte compensation and inappropriately low endogenous erythropoietin. A prospective 47-patient cohort found an early hemoglobin and transfusion benefit, but treatment was not randomized and most patients received concomitant immunosuppression.
  evidence:
  - reference: PMID:38029356
    reference_title: "Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months.
    explanation: >-
      Response rates use time-specific evaluable denominators; Figure 1A gives 25 complete responses, six partial responses and three nonresponses at day 360, yielding 31/34; this is not 91% of all 47 enrolled patients. This is add-on evidence for inadequate marrow compensation.
  - reference: PMID:38029356
    reference_title: "Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the contribution of concomitant medication to response cannot be excluded
    explanation: >-
      The nonrandomized comparison does not isolate epoetin efficacy. Two thromboses occurred among treated patients, both with additional risk factors.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Epoetin Alfa
      term:
        id: NCIT:C2695
        label: Epoetin Alfa
  target_mechanisms:
  - target: Inadequate Erythropoietic Compensation
    treatment_effect: RESTORES
    description: >-
      Stimulates erythropoiesis when endogenous compensation is insufficient.
- name: Fostamatinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational/off-label SYK inhibition for refractory warm AIHA. The 90-patient randomized FORWARD trial did not meet its primary durable-hemoglobin-response endpoint (35.6% versus 26.7%; P=0.398). Favorable post-hoc analyses and subsequent retrospective responses are hypothesis-generating, rather than a positive primary trial result.
  evidence:
  - reference: PMID:37929318
    reference_title: "Fostamatinib for warm antibody autoimmune hemolytic anemia: Phase 3, randomized, double-blind, placebo-controlled, global study (FORWARD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo (p = .398).
    explanation: >-
      The prespecified phase III primary comparison was not statistically significant; regional and rescue-adjusted analyses were post hoc.
  - reference: PMID:41846299
    reference_title: "A multicentre analysis of efficacy, safety and molecular response correlates of fostamatinib in warm autoimmune haemolytic anaemia and Evans syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regarding efficacy, 14 of 22 patients (64%) responded to fostamatinib (9 wAIHA and 5 ES).
    explanation: >-
      The 2026 retrospective cohort included 13 isolated warm-AIHA and nine Evans-syndrome patients; 10/22 had a six-month durable response, and 11 required steroid rescue. It does not overturn the randomized primary result.
  - reference: PMID:41846299
    reference_title: "A multicentre analysis of efficacy, safety and molecular response correlates of fostamatinib in warm autoimmune haemolytic anaemia and Evans syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lack of baseline data precludes definitive conclusions.
    explanation: >-
      The eight-patient molecular substudy measured post-treatment correlates, not validated pretreatment predictors or proven causal determinants of response.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Fostamatinib
      term:
        id: NCIT:C95222
        label: Fostamatinib
  target_mechanisms:
  - target: Fc-Gamma-Receptor-Mediated Erythrophagocytosis
    treatment_effect: INHIBITS
    description: >-
      SYK blockade interrupts Fc-receptor signaling involved in phagocytosis of antibody-coated red cells.
- name: Sovleplenib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational SYK inhibitor evaluated in a Chinese phase II/III study. The published phase II component randomized 21 patients (16 active, five placebo) for eight weeks, followed by open-label treatment for everyone. The 24-week overall response of 14/21 (67%) therefore includes crossover and is not a maintained placebo-controlled comparison.
  evidence:
  - reference: PMID:39799953
    reference_title: "Sovleplenib in patients with primary or secondary warm autoimmune haemolytic anaemia: results from phase 2 of a randomised, double-blind, placebo-controlled, phase 2/3 study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period.
    explanation: >-
      The study design limits interpretation of the combined 24-week response rate.
  - reference: PMID:39799953
    reference_title: "Sovleplenib in patients with primary or secondary warm autoimmune haemolytic anaemia: results from phase 2 of a randomised, double-blind, placebo-controlled, phase 2/3 study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24.
    explanation: >-
      These are pooled phase II results after crossover, not results from the phase III component.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Sovleplenib
      term:
        id: NCIT:C123912
        label: Sovleplenib
  target_mechanisms:
  - target: Fc-Gamma-Receptor-Mediated Erythrophagocytosis
    treatment_effect: INHIBITS
    description: >-
      Targets SYK-dependent Fc-receptor signaling.
- name: Parsaclisib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational PI3K-delta inhibition targeting B-cell signaling. In a 25-patient open-label phase II study spanning warm, cold and mixed AIHA, 16/25 achieved a hemoglobin response at weeks 6-12. Grade 3 or worse adverse events occurred in 13/25 and six discontinued for an adverse event.
  evidence:
  - reference: PMID:39435908
    reference_title: "Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 25 enrolled patients (median age, 63 y), 16 (64%) achieved a partial or complete Hgb response during weeks 6-12.
    explanation: >-
      A small uncontrolled study; warm-AIHA responses were more frequent than those in the pooled cold/mixed group.
  - reference: PMID:39435908
    reference_title: "Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Grade ≥3 TEAEs occurred in 13 patients (52.0%).
    explanation: >-
      The adverse-event burden should accompany the efficacy summary.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Parsaclisib
      term:
        id: NCIT:C113434
        label: Parsaclisib
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      PI3K-delta inhibition modulates B-cell activation and survival; clinical effects on individual autoimmune cell populations remain incompletely resolved.
  notes: >-
    The phase III NCT05073458 study was terminated for a business decision; the registry states that safety concerns did not contribute. Status verified 2026-09-27.
- name: Pegcetacoplan
  therapeutic_modality: PEPTIDE
  description: >-
    Investigational C3 inhibition in CAD and warm AIHA. An open-label phase II study randomized doses, not treatment versus placebo, in 13 CAD and 11 warm-AIHA patients. At week 48 the median hemoglobin change was 2.4 g/dL in CAD and 1.7 g/dL in warm AIHA, with a wide warm-AIHA interquartile range crossing zero.
  evidence:
  - reference: PMID:39486046
    reference_title: Safety and efficacy of pegcetacoplan treatment for cold agglutinin disease and warm antibody autoimmune hemolytic anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In each cohort, patients were randomly assigned to receive pegcetacoplan 270 mg/d or 360 mg/d for up to 48 weeks.
    explanation: >-
      Dose randomization does not supply a placebo comparator. The reported outcomes are preliminary and subtype-specific.
  - reference: PMID:39486046
    reference_title: Safety and efficacy of pegcetacoplan treatment for cold agglutinin disease and warm antibody autoimmune hemolytic anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90-3.00) and 1.7 g/dL (-1.40 to 2.90), respectively
    explanation: >-
      The primary report supports separate CAD and warm-AIHA effect estimates.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Pegcetacoplan
      term:
        id: NCIT:C121135
        label: Pegcetacoplan
  target_mechanisms:
  - target: C3b Opsonization of Erythrocytes
    treatment_effect: INHIBITS
    description: >-
      Blocks C3 activation and downstream complement-mediated opsonization and lysis.
- name: Daratumumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Off-label anti-CD38 therapy for heavily pretreated refractory AIHA. A retrospective series reported hemoglobin responses in 6/12 warm and 4/7 cold cases, with improvement of acrocyanosis in 4/6 assessed cold cases. Most patients also received other immunosuppression; infections, variable schedules and lack of a control group limit inference.
  evidence:
  - reference: PMID:38507742
    reference_title: Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we cannot exclude late responses to the comedication given before initiation of daratumumab treatment
    explanation: >-
      The 19-patient study cannot isolate a daratumumab-specific effect. Its title refers to monotherapy, but 13 patients had concomitant immunosuppressive treatment.
  - reference: PMID:38507742
    reference_title: Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort, infections were reported in 4 of 19 patients (21%), including 3 of grade 3 and 1 of grade 1.
    explanation: >-
      Attribution was uncertain in heavily pretreated patients, but infection risk is material.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Daratumumab
      term:
        id: NCIT:C74007
        label: Daratumumab
  target_mechanisms:
  - target: Persistent Autoreactive Plasma Cells
    treatment_effect: INHIBITS
    description: >-
      Targets CD38-positive antibody-producing cells, including plasma cells that can persist after anti-CD20 therapy; additional T-cell effects are exploratory.
- name: Eculizumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Off-label terminal complement inhibition studied in 12 CAD patients and one acute secondary cold-agglutinin case in the nonrandomized phase II DECADE trial. Hemolysis and transfusion needs improved, but the median hemoglobin increase was modest and cold-induced circulatory symptoms persisted. C5 blockade leaves upstream C3b-mediated hepatic clearance intact.
  evidence:
  - reference: PMID:30291112
    reference_title: "Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve patients with chronic CAD and 1 patient with an acute cold agglutinin syndrome were included.
    explanation: >-
      Preserves the primary study population rather than labeling all 13 participants as CAD.
  - reference: PMID:30291112
    reference_title: "Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to hemolysis, cold-induced circulatory symptoms remained unaffected.
    explanation: >-
      C5 inhibition does not directly prevent cold-antibody agglutination.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Eculizumab
      term:
        id: NCIT:C48386
        label: Eculizumab
  target_mechanisms:
  - target: Terminal Complement-Mediated Erythrocyte Lysis
    treatment_effect: INHIBITS
    description: >-
      C5 blockade limits terminal complement-mediated lysis without blocking C3b opsonization.
- name: Conventional immunosuppressants
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Azathioprine, cyclophosphamide, mycophenolate mofetil and cyclosporine are later-line options for selected refractory warm-AIHA patients, particularly with associated systemic autoimmune disease. Comparative evidence is limited and cumulative toxicity influences selection.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For patients who are refractory to or relapsing after rituximab and not candidate for splenectomy, cytotoxic immunosuppressants, such as azathioprine, cyclophosphamide, mycophenolate mofetil, and cyclosporine may be a therapeutic option
    explanation: >-
      These are alternative agents, not a combined regimen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Mycophenolate Mofetil
      term:
        id: NCIT:C1468
        label: Mycophenolate Mofetil
    - preferred_term: Azathioprine
      term:
        id: NCIT:C290
        label: Azathioprine
    - preferred_term: Cyclophosphamide
      term:
        id: NCIT:C405
        label: Cyclophosphamide
    - preferred_term: Cyclosporine
      term:
        id: NCIT:C406
        label: Cyclosporine
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: MODULATES
    description: >-
      Suppresses lymphocyte-mediated autoimmunity through agent-specific mechanisms.
- name: Thromboprophylaxis during active hemolysis
  therapeutic_modality: OTHER
  description: >-
    Consider anticoagulant prophylaxis according to active hemolysis, hospitalization, additional thrombosis risks and bleeding risk. In a nonrandomized prospective subset with LDH at least 1.5 times the upper limit of normal, no thromboses occurred in 17 heparin-treated patients versus five events among 16 untreated patients. Optimal selection and duration remain uncertain.
  evidence:
  - reference: PMID:35555857
    reference_title: Intravascular hemolysis and multitreatment predict thrombosis in patients with autoimmune hemolytic anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In those receiving prophylaxis no thrombotic complications occurred, whereas five thrombotic episodes were registered in the remaining 16 cases.
    explanation: >-
      Physician-selected prophylaxis in a small observational comparison supports risk assessment, not a definitive randomized treatment effect.
  treatment_term:
    preferred_term: Anticoagulation Therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
  target_mechanisms:
  - target: Thromboembolism
    treatment_effect: INHIBITS
    description: >-
      Reduces coagulation-mediated thrombotic complications without correcting autoimmune red-cell destruction.
- name: Rilzabrutinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational BTK inhibition for warm AIHA in the phase II LUMINA 2 study. Early open-label findings require confirmation; the ongoing extension does not establish an approved AIHA indication.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rilzabrutinib
      term:
        id: NCIT:C174769
        label: Rilzabrutinib
  evidence:
  - reference: clinicaltrials:NCT05002777
    reference_title: "A Multicenter, Open-label, Phase IIb Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Rilzabrutinib in Patients With Warm Autoimmune Hemolytic Anemia (LUMINA 2)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All participants will receive rilzabrutinib orally. The screening period is up to 28 days, followed by a treatment period of 24 weeks for Part A. Participants who complete Part A and are deemed eligible for Part B can continue in the Core Part B period followed by an Extended Part B period for up to 253 weeks.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rilzabrutinib, a reversible covalent BTK inhibitor, has been evaluated in a multicentric open-label phase 2b trial
    explanation: >-
      Identifies the molecular target; the registry separately establishes the study population and design.
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
- name: Nipocalimab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Investigational FcRn blockade intended to accelerate IgG catabolism and reduce pathogenic warm autoantibodies; evaluated in the ENERGY phase II/III trial.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Nipocalimab
      term:
        id: NCIT:C170891
        label: Nipocalimab
  evidence:
  - reference: clinicaltrials:NCT04119050
    reference_title: "Efficacy and Safety of M281 in Adults With Warm Autoimmune Hemolytic Anemia: A Multicenter, Randomized, Double-blind, Placebo-controlled Study With a Long-term Open-label Extension"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main purpose of this study is to evaluate the efficacy and safety of M281 in participants with warm autoimmune hemolytic anemia (wAIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      blocking the neonatal Fc receptor (FcRn) by MoAbs such as nipocalimab is an interesting strategy to dampen IgG recycling, thus increasing the clearance of pathogenic autoantibodies.
    explanation: >-
      Supports the proposed autoantibody-clearance mechanism, independently of trial registration.
  target_mechanisms:
  - target: Warm IgG Coating of Erythrocytes
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
- name: Ianalumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Investigational BAFF-receptor-targeting B-cell depletion in previously treated warm AIHA; being evaluated in the phase III VAYHIA study.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Ianalumab
      term:
        id: NCIT:C116788
        label: Ianalumab
  evidence:
  - reference: clinicaltrials:NCT05648968
    reference_title: "A Phase 3, Randomized, Double-blind, Study to Assess Efficacy and Safety of Ianalumab (VAY736) Versus Placebo in Warm Autoimmune Hemolytic Anemia (wAIHA) Patients Who Failed at Least One Line of Treatment"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate efficacy and safety of ianalumab compared to placebo in patients with warm autoimmune hemolytic anemia, who failed at least one line of treatment.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ianalumab (VAY736), an IgG1κ monoclonal antibody targeting BAFF-R, promotes B-cell depletion via ADCC and apoptosis.
    explanation: >-
      Identifies BAFF-R targeting and B-cell depletion; does not establish depletion of mature long-lived plasma cells.
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
- name: Obexelimab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Investigational CD19/Fc-gamma-RIIb co-engagement to suppress B-cell activation without conventional B-cell depletion. The SApHiAre registry currently describes a phase III warm-AIHA study.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Obexelimab
      term:
        id: NCIT:C170236
        label: Obexelimab
  evidence:
  - reference: clinicaltrials:NCT05786573
    reference_title: "A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With An Open Label Safety and Dose Confirmation Run-In Period, To Evaluate the Efficacy and Safety of Obexelimab in Patients With Warm Autoimmune Hemolytic Anemia (SApHiAre)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study aims to examine the efficacy and safety of obexelimab in participants with Warm Autoimmune Hemolytic Anemia (wAIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the bispeciphic Moab obexelimab, which simultaneously binds CD19 and FcγRIIb
    explanation: >-
      Supports the two molecular binding targets; preserves the source spelling in the exact quotation.
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
- name: Povetacicept
  therapeutic_modality: OTHER
  description: >-
    Investigational dual BAFF/APRIL blockade intended to suppress autoreactive B-cell and plasma-cell survival. The phase I/II RUBY-4 autoimmune-cytopenia study is completed; registry completion alone does not demonstrate clinical benefit.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Povetacicept
      term:
        id: NCIT:C190436
        label: Povetacicept
  evidence:
  - reference: clinicaltrials:NCT05757570
    reference_title: "Open-Label Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Povetacicept in Subjects With Autoimmune Cytopenias (RUBY-4)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this clinical study is to evaluate povetacicept in adults with autoimmune cytopenias of immune thrombocytopenia, autoimmune hemolytic anemia, and cold agglutinin disease to determine if povetacicept is safe and potentially beneficial in treating these diseases. During the study treatment period participants will receive povetacicept approximately every 4 weeks for 6 months, with the possibility of participating in a 6-month study treatment extension period.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Povetacicept (ALPN-303) is a next-generation fusion protein designed to inhibit both BAFF and APRIL
    explanation: >-
      Supports the dual ligand-blockade rationale, without treating preclinical effects as proven clinical efficacy.
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
  - target: BAFF-Rich Splenic Survival Environment
    treatment_effect: INHIBITS
    description: >-
      Targets BAFF-mediated survival signaling; clinical efficacy against this proposed persistence mechanism remains under study.
- name: Riliprubart
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Investigational long-acting inhibitor of activated C1s in CAD. An early single-dose study was completed, while the subsequent repeat-dose study NCT04802057 is terminated in the current registry.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Riliprubart
      term:
        id: NCIT:C199103
        label: Riliprubart
  evidence:
  - reference: clinicaltrials:NCT04269551
    reference_title: "A Multicenter, Phase 1b, Open Label, Nonrandomized, Single Dose Study Evaluating the Safety, Tolerability and Activity of BIVV020 in Adults With Cold Agglutinin Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To assess the safety and tolerability in participants with cold agglutinin disease (CAD), after a single dose of intravenous (IV) BIVV020
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the second-generation active C1s inhibitor riliprubart (formerly SAR445088, BIVV020), characterized by a prolonged half-life and thus a longer dosing interval than that of sutimlimab
    explanation: >-
      Supports activated-C1s inhibition and the long-acting development rationale.
  target_mechanisms:
  - target: Classical Complement Activation
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
- name: Iptacopan
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational factor B inhibition to suppress alternative-pathway complement amplification in CAD. Its phase II basket study was terminated for a business decision; it is not presented as established AIHA treatment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Iptacopan
      term:
        id: NCIT:C156691
        label: Iptacopan
  evidence:
  - reference: clinicaltrials:NCT05086744
    reference_title: "An Open-label, Multi-center, Phase 2 Basket Study to Assess Efficacy, Safety and Pharmacokinetics of Iptacopan (LNP023) in Participants With Autoimmune Benign Hematological Disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the orally available factor B inhibitor iptacopan is currently being evaluated in a trial including CAD and immune thrombocytopenia (NCT05086744).
    explanation: >-
      Identifies the factor B target. The historical trial-status wording is superseded by the current registry status recorded in clinical_trials.
- name: Ibrutinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    BTK inhibition has been investigated in cold-antibody disease and CLL-associated autoimmune cytopenias. The registered ibrutinib/rituximab phase II study specifically requires underlying CLL, so its rationale should not be generalized to all primary AIHA.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Ibrutinib
      term:
        id: NCIT:C81934
        label: Ibrutinib
  evidence:
  - reference: clinicaltrials:NCT03827603
    reference_title: "Ibrutinib in Steroid Refractory Autoimmune Hemolytic Anemia: ELaboration of Treatment Approach"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is an open-labeled, single arm, Phase II, two staged study of combination of ibrutinib and rituximab in patients with autoimmune cytopenia and underlying CLL. In stage I (remission induction) patients will receive ibrutinib and rituximab for 6 months; in stage II (maintenance) - only ibrutinib until relapse, progression or unacceptable toxicity. A total of 50 patients will be enrolled into the trial. The results will be compared to historical control, efficacy of rituximab as monotherapy or in combination with chemotherapy in patients with AIC and underlying CLL.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been investigated in 15 patients with CAD primary or secondary CAD
    explanation: >-
      Supports BTK inhibition and distinguishes the cold-antibody observational population from the separate CLL-associated trial.
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Proposed therapeutic target; clinical study registration alone does not establish treatment efficacy.
- name: CD19 CAR T-cell therapy
  therapeutic_modality: CELL_THERAPY
  description: >-
    Investigational therapy for primary multirefractory AIHA. A 2026 report combined five compassionate-use and six phase I patients; all 11 achieved complete response, with median follow-up 12.2 months. Nine had grade 1-2 cytokine-release syndrome, one grade 1 neurotoxicity, seven had infections and one grade 3 hematotoxicity. Small size, mixed enrollment and lack of a control group limit efficacy and safety generalization.
  evidence:
  - reference: PMID:41534043
    reference_title: CD19 CAR T-Cell Therapy for Autoimmune Hemolytic Anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CD19 CAR T cells were administered to 11 patients - 5 in the compassionate-use program and 6 in the phase 1 study.
    explanation: >-
      Preserves the actual study design rather than describing an eleven-patient randomized trial.
  - reference: PMID:41534043
    reference_title: CD19 CAR T-Cell Therapy for Autoimmune Hemolytic Anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had a complete response; the median time to a complete response was 45 days (range, 21 to 153).
    explanation: >-
      An early clinical signal in a selected cohort, not proof of universal durable cure.
  - reference: PMID:41534043
    reference_title: CD19 CAR T-Cell Therapy for Autoimmune Hemolytic Anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 15 infections occurred among 7 patients, with no infections of grade 4 or higher.
    explanation: >-
      Infection burden is material despite the absence of grade 4 infection in this small series.
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Profound CD19-positive B-cell depletion can interrupt autoreactive B-cell activity. Persistent plasma-cell niches may permit relapse.
  treatment_term:
    preferred_term: Chimeric Antigen Receptor T-Cell Therapy
    term:
      id: NCIT:C126102
      label: Chimeric Antigen Receptor T-Cell Therapy
- name: Folate and deficiency replacement
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Support increased erythropoietic demand with folate; replace vitamin B12 or iron when deficient. Nutritional support complements assessment and treatment of the immune process.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9821065/
    reference_title: Warm autoimmune hemolytic anemia and the best treatment strategies - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients should be supplemented with folic acid of at least 0.4 mg/d
    explanation: >-
      Clinical review supports folate and correction of documented deficiencies, rather than routine iron in every patient.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Folic Acid
      term:
        id: CHEBI:27470
        label: folic acid
  target_mechanisms:
  - target: Inadequate Erythropoietic Compensation
    treatment_effect: RESTORES
    description: >-
      Support increased erythropoietic demand with folate; replace vitamin B12 or iron when deficient. Nutritional support complements assessment and treatment of the immune process.
- name: Intravenous immunoglobulin
  therapeutic_modality: OTHER
  description: >-
    An adjunct in selected severe warm-AIHA situations, with limited evidence and often transient responses. It does not provide a reliable durable substitute for disease-directed therapy.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9821065/
    reference_title: Warm autoimmune hemolytic anemia and the best treatment strategies - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 2-g/dL Hgb rise in 2 weeks was seen in 25 of 62 (40%), and a Hgb rise over 2 g/dL in 2 weeks with a Hgb higher than 10 g/dL was seen in 9 of 61 (15%) patients. The treatment response was short-lived.
    explanation: >-
      The response depends strongly on the endpoint definition; these historical data should not be described as a consistent durable response.
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
- name: Cold avoidance and thermal protection
  review_notes: >-
    OLS NCIT search for cold avoidance returned no applicable intervention term;
    the unrelated cold-contaminant-free radiopharmaceutical result was rejected.
    BEHAVIORAL records the modality without inventing a specific ontology binding.
  therapeutic_modality: BEHAVIORAL
  description: >-
    Supportive management for cold-antibody hemolysis and circulatory symptoms. Keep the patient and transfused blood warm when appropriate; thermal protection does not eradicate the autoantibody-producing clone.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of CAD is based on supportive measures (cold avoidance, folic acid, transfusions)
    explanation: >-
      Supportive measures specific to cold-antibody disease.
  target_mechanisms:
  - target: Cold Agglutinin Binding
    treatment_effect: INHIBITS
    description: >-
      Reduces cold-triggered antibody binding and agglutination; it does not suppress antibody production.
- name: Rituximab plus bendamustine
  therapeutic_modality: OTHER
  description: >-
    Clone-directed combination used in suitable CAD patients who require treatment. It can produce deeper and more durable responses than rituximab alone but adds cytotoxic and infectious risks, particularly relevant in frail patients.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the combination of rituximab plus bendamustine resulted in increased response rate (78%, with complete responses in 53%), and long response duration (more than 7 years)
    explanation: >-
      Clinical review of CAD combination studies; these results should not be generalized to warm AIHA.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
    - preferred_term: Bendamustine
      term:
        id: NCIT:C73261
        label: Bendamustine
  target_mechanisms:
  - target: Clonal B-Cell Expansion in CAD
    treatment_effect: INHIBITS
    description: >-
      Targets the marrow B-cell clone supplying the pathogenic cold agglutinin.
- name: Bortezomib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Off-label proteasome inhibition targeting antibody-producing cells in refractory warm or cold AIHA. The primary CAD phase II report enrolled 21 patients, with 6/19 evaluable responders; two early discontinuations were excluded from that efficacy denominator. Warm-AIHA evidence also includes small combination series, which cannot isolate the bortezomib effect.
  evidence:
  - reference: url:https://air.unimi.it/retrieve/dfa8b9a3-2887-748b-e053-3a05fe0a3a96/blood835413.pdf
    reference_title: "https://air.unimi.it/retrieve/dfa8b9a3-2887-748b-e053-3a05fe0a3a96/blood835413.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 19 evaluable patients, 3 achieved a complete response (15.8%) and 3 achieved a partial response (15.8%), for an overall response rate of 31.6%
    explanation: >-
      Full-text primary report, pages 548-549: 21 enrolled and 19 evaluable. Early pulmonary embolism and headache led to the two exclusions; one excluded patient nevertheless became transfusion independent.
  - reference: PMID:34795889
    reference_title: Bortezomib in autoimmune hemolytic anemia and beyond.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of responses is difficult to evaluate, since bortezomib has been often used in combination with other treatments, particularly steroids.
    explanation: >-
      The full-text review explicitly limits inference from combination treatment and response-biased case reports.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Bortezomib
      term:
        id: NCIT:C1851
        label: Bortezomib
  target_mechanisms:
  - target: Persistent Autoreactive Plasma Cells
    treatment_effect: INHIBITS
    description: >-
      Off-label proteasome inhibition targeting antibody-producing cells in refractory warm or cold AIHA. The primary CAD phase II report enrolled 21 patients, with 6/19 evaluable responders; two early discontinuations were excluded from that efficacy denominator. Warm-AIHA evidence also includes small combination series, which cannot isolate the bortezomib effect.
- name: Isatuximab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Investigational anti-CD38 therapy for warm AIHA. The registered study was terminated for a strategic sponsor decision, not a reported safety concern; efficacy remains unestablished.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A phase 1b/2 trial investigating its use in warm AIHA was initiated but was prematurely discontinued due to sponsor-driven strategic decisions
    explanation: >-
      This source and the current NCT04661033 registry agree that the program stopped.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Isatuximab
      term:
        id: NCIT:C90578
        label: Isatuximab
  target_mechanisms:
  - target: Persistent Autoreactive Plasma Cells
    treatment_effect: INHIBITS
    description: >-
      Investigational anti-CD38 therapy for warm AIHA. The registered study was terminated for a strategic sponsor decision, not a reported safety concern; efficacy remains unestablished.
- name: Zanubrutinib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Investigational BTK inhibition being evaluated separately in relapsed/refractory warm AIHA and primary CAD. The two registered populations should not be pooled as established efficacy evidence.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      zanubrutinib, a next-generation, irreversible BTK inhibitor, is under investigation in a phase 2 trial (NCT05922839) for patients with warm AIHA and in a separate phase 2 trial involving CAD (NCT06067048).
    explanation: >-
      Mechanistic and study rationale; current recruitment status is recorded separately in clinical_trials.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Zanubrutinib
      term:
        id: NCIT:C141428
        label: Zanubrutinib
  target_mechanisms:
  - target: Anti-Erythrocyte Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Investigational BTK inhibition being evaluated separately in relapsed/refractory warm AIHA and primary CAD. The two registered populations should not be pooled as established efficacy evidence.
- name: ANX005
  treatment_term:
    preferred_term: ANX005 pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  review_notes: >-
    OLS NCIT search for ANX005 found no specific agent term. The pharmacotherapy
    action is bound; the drug identity and anti-C1q target remain explicit in prose.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Investigational anti-C1q monoclonal antibody evaluated in warm AIHA with complement activation or mixed forms. The completed phase II registry does not itself establish clinical efficacy.
  evidence:
  - reference: PMID:40821796
    reference_title: "Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In this regard, results are awaited from a phase 2 study (NCT04691570) evaluating subjects with warm AIHA showing evidence of complement activation or mixed forms, treated with ANX005, a recombinant anti-C1q IgG4 humanized MoAb.
    explanation: >-
      The review describes the C1q target and study population while awaiting results. This supports investigational use, not clinical efficacy; the current completed registry status was checked separately.
  target_mechanisms:
  - target: Classical Complement Activation
    treatment_effect: INHIBITS
    description: >-
      C1q blockade inhibits initiation of the classical complement cascade.
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: >-
    Bone marrow histology and clinical data from 97 selected AIHA patients, with single-cell RNA/TCR analysis in nine warm-AIHA patients across diagnosis, remission and relapse. Results and Table 1 report hypercellularity in 63/97, dyserythropoiesis in 74/97 and grade-1 reticulin fibrosis in 28/97; the abstract reverses the latter two percentages. The single-cell study used 12 patient specimens from nine individuals and three healthy donors, with treatment and cross-sectional relapse comparisons limiting causal interpretation. GEO sample_count denotes repository sample records rather than independent participants.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 18
  publication: PMID:40854885
  notes: >-
    Accession verified against GEO. The publication methods describe nine patients, with three repeat remission samples; diagnosis samples were collected after 2-5 days of steroids, and relapse samples followed prior therapies. The GEO record count is retained separately from the clinical participant count.
- accession: geo:GSE195791
  title: Transcriptional modifications between Treg from healthy donors (HD) and Treg from patients suffering from warm autoimmune hemolytic anemia (wAIHA)
  description: >-
    RNA sequencing of sorted circulating regulatory T cells in untreated warm AIHA and healthy controls. The publication reports four patients and four matched controls in the main transcriptomic comparison; the GEO sample_count is the repository record count. TCR and TNF pathway engagement was associated with reduced Treg suppression and reduced FOXP3 protein despite increased FOXP3 transcript levels; causality and post-translational mechanisms remain incompletely established.
  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.'
has_subtypes:
- name: Warm AIHA
  description: >-
    Usually IgG-mediated hemolysis at body temperature, predominantly through splenic Fc-receptor-mediated clearance. Complement can contribute; IgA and warm IgM forms are uncommon.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary antibody isotype involved with wAIHA is IgG, but IgA and IgM may be infrequently seen
    explanation: >-
      The quote establishes IgG as the usual warm antibody and preserves uncommon IgA and IgM exceptions.
  subtype_term:
    preferred_term: autoimmune hemolytic anemia, warm type
    term:
      id: MONDO:0019532
      label: autoimmune hemolytic anemia, warm type
- name: Cold agglutinin disease
  description: >-
    Chronic clonal B-cell disease producing a pathogenic cold-reactive monoclonal antibody, usually IgM. Complement-mediated hepatic clearance and agglutination-related circulatory symptoms are distinct consequences. Also covered in the dedicated Cold Agglutinin Disease entry.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CAD is an established clonal B-cell lymphoproliferative disorder of the bone marrow (MYD88 L265P negative)
    explanation: >-
      The review identifies the marrow B-cell clone, supporting the distinction between primary CAD and a secondary cold agglutinin syndrome.
  subtype_term:
    preferred_term: cold agglutinin disease
    term:
      id: MONDO:0018922
      label: cold agglutinin disease
- name: Secondary cold agglutinin syndrome
  review_notes: >-
    OLS MONDO searches for secondary cold agglutinin syndrome and cold agglutinin
    found no term specific to the secondary syndrome. MONDO:0016450, autoimmune
    hemolytic anemia, cold type, also encompasses primary CAD and is too broad
    for this subtype distinction.
  description: >-
    Cold-antibody hemolysis associated with another condition, including infection or overt lymphoproliferative disease, rather than the characteristic primary CAD clone. Its course depends on the underlying disorder; not every secondary case is transient or polyclonal.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As for other AIHAs secondary forms (identified as cold agglutinin syndrome or secondary CAD) should be carefully investigated, as the association with infections, lymphoproliferative disorders and tumors is particularly frequent
    explanation: >-
      The named associated conditions support investigating an underlying cause; the quote does not establish uniform transience or polyclonality.
- name: Mixed AIHA
  subtype_term:
    preferred_term: mixed-type autoimmune hemolytic anemia
    term:
      id: MONDO:0019534
      label: mixed-type autoimmune hemolytic anemia
  description: >-
    Coexisting warm IgG and a clinically significant cold-reactive antibody. IgG plus C3d DAT positivity alone does not establish this subtype; cold-antibody thermal amplitude and titer must also be evaluated.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since DAT positivity for IgG and C3d may be observed even in wAIHA, the titer of the cold agglutinin and the presence of spontaneous agglutination at 20°C are useful tools.
    explanation: >-
      The quote explains why IgG/C3d DAT positivity alone is insufficient and why cold-antibody testing is needed for the mixed subtype.
- name: Paroxysmal cold hemoglobinuria
  description: >-
    Biphasic cold-reactive IgG, usually against the P/GLOB antigen, produces complement-mediated intravascular hemolysis on warming. The Donath-Landsteiner test establishes the serologic mechanism. Modern childhood cases are often transient after an infection.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PCH is characterized by the presence of a cold-reactive IgG autoantibody.
    explanation: >-
      Cold-reactive IgG distinguishes the Donath-Landsteiner/PCH antibody from the usual IgM cold agglutinin.
  subtype_term:
    preferred_term: paroxysmal cold hemoglobinuria
    term:
      id: MONDO:0019533
      label: paroxysmal cold hemoglobinuria
diagnosis:
- name: Demonstrate hemolysis and characterize red-cell sensitization
  description: >-
    Combine anemia/hemolysis markers with polyspecific and monospecific DAT testing. Determine IgG and complement reactivity and investigate secondary causes. A positive DAT without hemolysis is insufficient.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The DAT is neither 100% specific nor sensitive, and several technical issues should be considered for a proper interpretation.
    explanation: >-
      Test limitations require integrated clinical and laboratory interpretation.
  - 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: >-
      Consensus diagnostic recommendation; the cached landing page contains the abstract, not the full consensus paper.
- name: Cold-antibody titer and thermal-amplitude assessment
  description: >-
    Use cold-agglutinin studies to distinguish CAD/CAS from warm disease with complement involvement and mixed AIHA. IgG+C3d DAT positivity alone is not sufficient for mixed AIHA.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since DAT positivity for IgG and C3d may be observed even in wAIHA, the titer of the cold agglutinin and the presence of spontaneous agglutination at 20°C are useful tools.
    explanation: >-
      Additional serology is required for subtype assignment.
- name: Donath-Landsteiner testing
  description: >-
    Detect the biphasic hemolysin when PCH is suspected; C3d DAT positivity alone does not distinguish PCH from other cold-antibody forms.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis is made in the laboratory using the Donath–Landsteiner test (D–L test)
    explanation: >-
      PCH-specific serologic investigation.
- name: Extended evaluation of suspected DAT-negative AIHA
  description: >-
    Exclude nonimmune hemolysis and use a reference laboratory for more sensitive DAT methods, low-affinity antibody evaluation and IgA/IgM-specific reagents when indicated.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of DAT-neg AIHA mostly relies on the method of excluding other possible causes
    explanation: >-
      A diagnosis of exclusion supported by specialized immune testing, not simply a negative routine DAT.
histopathology:
- name: Bone marrow hypercellularity
  description: >-
    Found in 63/97 biopsy-selected patients. The referral cohort overrepresented cold AIHA; this is not a population prevalence estimate.
  context: Retrospective cohort of 97 AIHA patients undergoing marrow assessment
  evidence:
  - reference: PMID:40854885
    reference_title: "Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypercellularity, present in the majority of patients (65%), was associated with higher hemolytic features
    explanation: >-
      Found in 63/97 biopsy-selected patients. The referral cohort overrepresented cold AIHA; this is not a population prevalence estimate.
- name: Bone marrow dyserythropoiesis
  description: >-
    Results and Table 1 identify dyserythropoiesis in 74/97 patients. The abstract/discussion reverse the dyserythropoiesis and fibrosis percentages; the tabulated counts support this assignment.
  context: Retrospective cohort of 97 AIHA patients undergoing marrow assessment
  evidence:
  - reference: PMID:40854885
    reference_title: "Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reticulin fibrosis (MF-1) was observed in 29% of cases, and dyserythropoiesis in 76%
    explanation: >-
      Results and Table 1 identify dyserythropoiesis in 74/97 patients. The abstract/discussion reverse the dyserythropoiesis and fibrosis percentages; the tabulated counts support this assignment.
- name: Mild bone marrow reticulin fibrosis
  description: >-
    Grade MF-1 in 28/97 biopsy-selected patients, based on the results and Table 1 rather than the reversed abstract percentages.
  context: Retrospective cohort of 97 AIHA patients undergoing marrow assessment
  evidence:
  - reference: PMID:40854885
    reference_title: "Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reticulin fibrosis (MF-1) was observed in 29% of cases, and dyserythropoiesis in 76%
    explanation: >-
      Grade MF-1 in 28/97 biopsy-selected patients, based on the results and Table 1 rather than the reversed abstract percentages.
- name: Bone marrow lymphoid infiltration
  description: >-
    Table 2 separates T-cell, B-cell and mixed infiltrates. Associations with anemia, erythropoietin adequacy and treatment response do not establish direct cytotoxicity against erythroid precursors.
  context: Retrospective cohort of 97 AIHA patients undergoing marrow assessment
  evidence:
  - reference: PMID:40854885
    reference_title: "Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a lymphoid infiltrate was documented in 85% of patients
    explanation: >-
      Table 2 separates T-cell, B-cell and mixed infiltrates. Associations with anemia, erythropoietin adequacy and treatment response do not establish direct cytotoxicity against erythroid precursors.
clinical_trials:
- name: NCT03764618
  description: >-
    FORWARD: randomized phase III fostamatinib versus placebo in previously treated warm AIHA. The published primary durable hemoglobin endpoint was not met; favorable reanalyses were post hoc.
  phase: PHASE_III
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT03764618
    reference_title: "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Study of Fostamatinib Disodium in the Treatment of Warm Antibody Autoimmune Hemolytic Anemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary objective of this study is to assess the efficacy of fostamatinib in subjects with warm antibody autoimmune hemolytic anemia (wAIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2023-05-25.
- name: NCT02612558
  description: >-
    Open-label phase II fostamatinib study in warm AIHA; precursor to the randomized FORWARD study.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT02612558
    reference_title: "A Phase 2, Multi-Center, Open Label, Simon Two-Stage Study to Evaluate the Safety and Efficacy of Fostamatinib Disodium in the Treatment of Warm Antibody Autoimmune Hemolytic Anemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate whether fostamatinib is safe and effective in the treatment of Warm Antibody Autoimmune Hemolytic Anemia (AIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2021-07-21.
- name: NCT05535933
  description: >-
    Phase II/III sovleplenib study in primary or secondary warm AIHA. Published phase II results comprise 21 patients, with placebo crossover after eight weeks; these are not phase III efficacy results.
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT05535933
    reference_title: "A Randomized, Double-Blind, Placebo-Controlled Phase II/III Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of HMPL-523 in the Treatment of Warm Antibody Autoimmune Hemolytic Anemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phase II Study: To evaluate the safety and preliminary efficacy of HMPL-523 in adult patients with wAIHA.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-05-18. The schema phase records the highest registered phase; the combined design is stated in the description.
- name: NCT03538041
  description: >-
    Open-label phase II parsaclisib study in warm, cold and mixed AIHA; 25 patients were included in the published efficacy report.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT03538041
    reference_title: "A Phase 2, Open-Label Study of INCB050465 in Participants With Autoimmune Hemolytic Anemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the safety and efficacy of parsaclisib administered orally to participants with autoimmune hemolytic anemia (AIHA) who have decreased hemoglobin and evidence of ongoing hemolysis that requires treatment intervention.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-07-11.
- name: NCT05073458
  description: >-
    Randomized phase III parsaclisib versus placebo in primary warm AIHA. Enrollment was discontinued for a business decision, with no safety concerns cited by the sponsor.
  phase: PHASE_III
  status: TERMINATED
  evidence:
  - reference: clinicaltrials:NCT05073458
    reference_title: "A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Parsaclisib in Participants With Primary Warm Autoimmune Hemolytic Anemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of parsaclisib compared with placebo in participants with Primary Warm Autoimmune Hemolytic Anemia (wAIHA),
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-11-03. Registry reason for stopping: A business decision was made to discontinue further enrollment. There were no safety concerns that contributed to this decision.
- name: NCT03226678
  description: >-
    PLAUDIT: open-label phase II pegcetacoplan study with CAD and warm-AIHA cohorts; randomization compared two doses rather than active treatment against placebo.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT03226678
    reference_title: "An Open Label, Prospective, Study to Assess the Safety, Tolerability, Efficacy and Pharmacokinetics of APL-2 in Patients With Warm Type Autoimmune Hemolytic Anemia (wAIHA) or Cold Agglutinin Disease (CAD)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study is to assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of APL-2 in subjects with warm Autoimmune Hemolytic Anemia (wAIHA) or Cold Agglutinin Disease (CAD).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2024-12-12.
- name: NCT05096403
  description: >-
    CASCADE: phase III placebo-controlled pegcetacoplan study in primary CAD. The current registry lists it as completed; a completed status alone does not establish efficacy.
  phase: PHASE_III
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT05096403
    reference_title: "A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With Cold Agglutinin Disease (CAD)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of the study is to determine the efficacy of pegcetacoplan administration compared to placebo in increasing hemoglobin (Hgb) level from baseline and avoiding transfusion in participants with primary cold agglutinin disease (CAD).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-10-30.
- name: NCT03347422
  description: >-
    CADENZA: randomized phase III sutimlimab versus placebo in CAD without recent transfusion, followed by an open-label extension and washout. Continuing C1s inhibition sustained benefit; hemolysis returned after withdrawal.
  phase: PHASE_III
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT03347422
    reference_title: "A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Sutimlimab in Patients With Primary Cold Agglutinin Disease Without a Recent History of Blood Transfusion"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=)1.5 grams per deciliter (g/dL) increase in hemoglobin (Hgb) level and avoidance of transfusion in participants with primary cold agglutinin disease (CAD) without a recent history of blood transfusion. The purpose of Part B was to evaluate the long-term safety and tolerability of sutimlimab in participants with primary CAD.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2022-12-23.
- name: NCT03347396
  description: >-
    CARDINAL: phase III sutimlimab study in CAD with recent transfusion, followed by a long-term extension.
  phase: PHASE_III
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT03347396
    reference_title: "A Phase 3, Pivotal, Open-label, Multicenter Study to Assess the Efficacy and Safety of Sutimlimab in Patients With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=) 2 grams per deciliter (g/dL) increase in hemoglobin (Hgb) levels or increased Hgb to \>= 12 g/dL and obviated the need for blood transfusion during treatment in participants with primary cold agglutinin disease (CAD) who had a recent history of blood transfusion. The purpose of Part B was to evaluate the long-term safety and tolerability of sutimlimab in participants with CAD.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2022-10-31.
- name: NCT05002777
  description: >-
    LUMINA 2: phase II rilzabrutinib study in warm AIHA, with a 24-week initial treatment period and extension. The registry describes an active extension, not ongoing recruitment.
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT05002777
    reference_title: "A Multicenter, Open-label, Phase IIb Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Rilzabrutinib in Patients With Warm Autoimmune Hemolytic Anemia (LUMINA 2)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All participants will receive rilzabrutinib orally. The screening period is up to 28 days, followed by a treatment period of 24 weeks for Part A. Participants who complete Part A and are deemed eligible for Part B can continue in the Core Part B period followed by an Extended Part B period for up to 253 weeks.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-06-05.
- name: NCT04119050
  description: >-
    ENERGY: phase II/III nipocalimab (M281) study in adults with warm AIHA, evaluating FcRn blockade.
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT04119050
    reference_title: "Efficacy and Safety of M281 in Adults With Warm Autoimmune Hemolytic Anemia: A Multicenter, Randomized, Double-blind, Placebo-controlled Study With a Long-term Open-label Extension"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main purpose of this study is to evaluate the efficacy and safety of M281 in participants with warm autoimmune hemolytic anemia (wAIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-08-31. The schema phase records the highest registered phase; the combined design is stated in the description.
- name: NCT05648968
  description: >-
    VAYHIA: phase III ianalumab versus placebo after at least one failed line of treatment for warm AIHA.
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT05648968
    reference_title: "A Phase 3, Randomized, Double-blind, Study to Assess Efficacy and Safety of Ianalumab (VAY736) Versus Placebo in Warm Autoimmune Hemolytic Anemia (wAIHA) Patients Who Failed at Least One Line of Treatment"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate efficacy and safety of ianalumab compared to placebo in patients with warm autoimmune hemolytic anemia, who failed at least one line of treatment.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-09-11.
- name: NCT05786573
  description: >-
    SApHiAre: phase III obexelimab study in warm AIHA. The current registry phase supersedes older review articles calling this registration phase II.
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT05786573
    reference_title: "A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With An Open Label Safety and Dose Confirmation Run-In Period, To Evaluate the Efficacy and Safety of Obexelimab in Patients With Warm Autoimmune Hemolytic Anemia (SApHiAre)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study aims to examine the efficacy and safety of obexelimab in participants with Warm Autoimmune Hemolytic Anemia (wAIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-06-25.
- name: NCT05757570
  description: >-
    RUBY-4: phase I/II open-label povetacicept study in autoimmune cytopenias, including warm AIHA and CAD. The study is completed in the current registry.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT05757570
    reference_title: "Open-Label Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Povetacicept in Subjects With Autoimmune Cytopenias (RUBY-4)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this clinical study is to evaluate povetacicept in adults with autoimmune cytopenias of immune thrombocytopenia, autoimmune hemolytic anemia, and cold agglutinin disease to determine if povetacicept is safe and potentially beneficial in treating these diseases. During the study treatment period participants will receive povetacicept approximately every 4 weeks for 6 months, with the possibility of participating in a 6-month study treatment extension period.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-09-14. The schema phase records the highest registered phase; the combined design is stated in the description.
- name: NCT04661033
  description: >-
    Isatuximab study in adult warm AIHA, terminated for a strategic sponsor decision rather than a cited safety concern.
  phase: PHASE_II
  status: TERMINATED
  evidence:
  - reference: clinicaltrials:NCT04661033
    reference_title: "A Multicenter, Open-label, Non-randomized, Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults with wAIHA
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2024-12-05. Registry reason for stopping: Study discontinuation based on strategic sponsor decision; not driven by any safety concerns.
- name: NCT04691570
  description: >-
    Phase II ANX005 anti-C1q study in warm AIHA; current registration lists completion.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT04691570
    reference_title: "A Phase 2, Open-Label, Repeat Dose Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Intravenous ANX005 in Subjects With Warm Autoimmune Hemolytic Anemia (wAIHA)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study will evaluate the safety and tolerability of ANX005 in participants with Warm Autoimmune Hemolytic Anemia (wAIHA).
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-06-30.
- name: NCT04269551
  description: >-
    Phase I riliprubart (BIVV020) single-dose study in CAD, assessing safety, hemolysis and complement inhibition.
  phase: PHASE_I
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT04269551
    reference_title: "A Multicenter, Phase 1b, Open Label, Nonrandomized, Single Dose Study Evaluating the Safety, Tolerability and Activity of BIVV020 in Adults With Cold Agglutinin Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To assess the safety and tolerability in participants with cold agglutinin disease (CAD), after a single dose of intravenous (IV) BIVV020
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-09-22.
- name: NCT04802057
  description: >-
    Phase I repeat-dose riliprubart (SAR445088) study in CAD; current registry status is terminated.
  phase: PHASE_I
  status: TERMINATED
  evidence:
  - reference: clinicaltrials:NCT04802057
    reference_title: "An Open-label, Long-term, Safety and Tolerability Study of SAR445088 in Participants With Cold Agglutinin Disease Previously Treated With SAR445088 or Never Treated With SAR445088"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To assess the long-term safety and tolerability in patients with cold agglutinin disease (CAD), after multiple doses of SAR445088
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-09-11.
- name: NCT05086744
  description: >-
    Phase II iptacopan basket study including primary CAD and immune thrombocytopenia, terminated for a business decision.
  phase: PHASE_II
  status: TERMINATED
  evidence:
  - reference: clinicaltrials:NCT05086744
    reference_title: "An Open-label, Multi-center, Phase 2 Basket Study to Assess Efficacy, Safety and Pharmacokinetics of Iptacopan (LNP023) in Participants With Autoimmune Benign Hematological Disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-10-16. Registry reason for stopping: Business decision
- name: NCT05931718
  description: >-
    CYTOPAN observational study of autoimmune cytopenias, including diagnostic markers, marrow findings and treatment outcomes. The prospective epoetin analysis was a substudy, not a randomized epoetin trial.
  phase: NOT_APPLICABLE
  status: RECRUITING
  evidence:
  - reference: clinicaltrials:NCT05931718
    reference_title: "Evaluation of the Diagnostic/Therapeutic Course of Patients With Autoimmune Cytopenias (Autoimmune Hemolytic Anemia AIHA, Immune Thrombocytopenia ITP, Chronic Idiopathic/Autoimmune Neutropenia CIN/AIN) and Identification of Predictive and Prognostic Markers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this observational study is to characterize the diagnostic and therapeutic management of autoimmune cytopenias including autoimmune hemolytic anemia, immune thrombocytopenia, and chronic idiopathic/autoimmune neutropenia.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2024-10-15.
- name: NCT01303952
  description: >-
    DECADE: nonrandomized phase II eculizumab study; the published population comprised 12 CAD patients and one acute secondary cold-agglutinin case.
  phase: PHASE_II
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT01303952
    reference_title: "Therapy for Chronic Cold Agglutinin Disease: A Prospective, Non-Randomized Multi-Center Study Demonstrating the Efficacy of Terminal Complement Inhibition in Patients With Cold Agglutinin Disease Using Eculizumab"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evaluation of the efficacy and safety of eculizumab in symptomatic or transfusion-dependent patients with untreated or refractory hemolytic cold agglutinin disease(CAD)
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2017-07-19.
- name: NCT06231368
  description: >-
    Phase I CNCT19 CD19 CAR-T study after failure of at least three lines of AIHA therapy; open-label dose escalation and expansion, not established standard care. The 2026 primary publication combines six trial participants with five compassionate-use patients; outcomes are not from a randomized comparison.
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT06231368
    reference_title: The Safety and Efficacy of CNCT19 for Patients With Autoimmune Hemolytic Anemia After Failure of Three or More Lines of Therapy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a Phase 1, single-arm, open-label, dose-escalation and dose-expansion study. The main purpose is to evaluate the safety and tolerability, efficacy of CNCT19 CAR T-cell therapy in patients with autoimmune hemolytic anemia after failure of three or more lines of therapy. Participants will receive CNCT19 cell infusion after preconditioning, and they will receive a 1-year follow-up.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2025-05-16.
- name: NCT03827603
  description: >-
    Phase II ibrutinib plus rituximab in autoimmune cytopenia associated with CLL, followed by ibrutinib maintenance. This is not a trial of unselected primary AIHA; current recruitment status is unknown.
  phase: PHASE_II
  status: UNKNOWN
  evidence:
  - reference: clinicaltrials:NCT03827603
    reference_title: "Ibrutinib in Steroid Refractory Autoimmune Hemolytic Anemia: ELaboration of Treatment Approach"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is an open-labeled, single arm, Phase II, two staged study of combination of ibrutinib and rituximab in patients with autoimmune cytopenia and underlying CLL. In stage I (remission induction) patients will receive ibrutinib and rituximab for 6 months; in stage II (maintenance) - only ibrutinib until relapse, progression or unacceptable toxicity. A total of 50 patients will be enrolled into the trial. The results will be compared to historical control, efficacy of rituximab as monotherapy or in combination with chemotherapy in patients with AIC and underlying CLL.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2020-01-10.
- name: NCT05922839
  description: >-
    Exploratory phase II zanubrutinib study in relapsed or refractory warm AIHA. The current registry labels recruitment status unknown.
  phase: PHASE_II
  status: UNKNOWN
  evidence:
  - reference: clinicaltrials:NCT05922839
    reference_title: "Zanubrutinib in Relapsed or Refractory Warm Autoimmune Hemolytic Anemia: a Prospective Cohort Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The therapeutic effect of zanubrutinib on refractory warm autoimmune hemolytic anemia, is worth exploring through exploratory research.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2024-04-26.
- name: NCT06067048
  description: >-
    CaZa: phase II zanubrutinib in primary CAD, targeting the pathogenic B-cell clone rather than complement alone.
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  evidence:
  - reference: clinicaltrials:NCT06067048
    reference_title: Phase II Trial of Zanubrutinib in Primary Cold Agglutinin Disease. CaZa Study
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bruton Tyrosine Kinase inhibitors (BTKis) are effective in many B-cell lymphoproliferative disorders including the IgM producing clone of Waldenström macroglobulinemia (WM) and were very effective on both AIHA and peripheral ischemic symptoms in patients with CAD based on retrospective data.
    explanation: >-
      Registry text establishes the study scope and rationale; it is not evidence of a successful clinical outcome.
  notes: >-
    Status and phase checked against the ClinicalTrials.gov API on 2026-09-27; last posted update 2026-03-06.
- name: NCT01696474
  phase: PHASE_II
  status: COMPLETED
  description: >-
    GIMEMA short-course bortezomib study in relapsed cold-antibody hemolysis. The primary report enrolled 21 patients; six of 19 evaluable patients responded. The cohort included associated B-cell disorders not requiring separate treatment.
  evidence:
  - reference: clinicaltrials:NCT01696474
    reference_title: Short Course of Bortezomib in Anemic Patients With Refractory Cold Agglutinin Disease
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This multicenter, phase II, open label study will enroll patients with chronic cold agglutinin disorder. A single course of Bortezomib will be given at the dose of 1,3 mg/sqm iv on days 1, 4, 8, 11.
    explanation: >-
      Registry establishes the study objective; response and exclusion counts come from the full primary report.
  notes: >-
    Status checked against ClinicalTrials.gov API on 2026-09-27; last posted update 2017-10-27.
differential_diagnoses:
- name: Passenger lymphocyte syndrome
  description: >-
    Post-transplant alloimmune hemolysis can mimic AIHA.
  distinguishing_features:
  - >-
    Donor lymphocytes produce antibodies against recipient red-cell antigens absent from the donor. The transplant history and antibody specificity distinguish this alloimmune process.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is feasible for donor lymphocytes that have been transferred to produce antibodies that are specific to RBC antigens in the recipient’s body but not present on the donor’s own red cells
    explanation: >-
      This is a mechanistic boundary despite some review taxonomies listing PLS alongside AIHA.
- name: Drug-dependent immune hemolytic anemia
  description: >-
    A medication-dependent antibody reaction can cause immune hemolysis without a spontaneous red-cell autoantibody.
  distinguishing_features:
  - >-
    Review temporal drug exposure and perform reference-laboratory testing for drug dependence. Drug-independent autoantibodies induced by medication can instead resemble warm AIHA.
  evidence:
  - reference: PMID:39371250
    reference_title: "Autoimmune Hemolytic Anemias: Challenges in Diagnosis and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      drug-dependent antibodies that activate an immune response in the presence of the drug only
    explanation: >-
      Drug dependence distinguishes one drug-associated immune mechanism from autonomous autoantibody activity.
- name: Nonimmune inherited or acquired hemolysis
  description: >-
    Red-cell membrane defects, enzymopathies, hemoglobinopathies and mechanical hemolysis can produce anemia, jaundice and reticulocytosis.
  distinguishing_features:
  - >-
    Use personal and family history, blood-film findings and targeted membrane, enzyme or hemoglobin testing. Spherocytes alone do not establish autoimmune destruction.
  evidence:
  - reference: PMID:38673882
    reference_title: "Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital reasons for the anemia need to be ruled out, from enzymopathies
    explanation: >-
      The diagnostic workup must exclude nonimmune causes, especially when standard DAT is negative.
notes: >-
  AIHA is an acquired immune phenotype, not a single Mendelian disorder. Germline immune-dysregulation syndromes and somatic CAD clones can provide underlying context; common HLA/cytokine association signals are not treated as universal causal alleles. This umbrella entry preserves mechanistic subtype distinctions; the dedicated Cold Agglutinin Disease entry provides additional clonal detail. DAT-negative status is a diagnostic category rather than a separate effector mechanism. Passenger lymphocyte syndrome is modeled as an alloimmune differential. Reference reviews contain conflicting numerical and mechanistic statements; primary-study denominators and current trial registry records take precedence. The marrow study PMID:40854885 reverses dyserythropoiesis and fibrosis percentages in its abstract/discussion, so the results and Table 1 counts are used. The daratumumab erratum PMID:39671214 corrects Figure 1 time-axis units to weeks, not months. PMID:39708374 was identified as a later rituximab/bortezomib phase II report, but the current fetch retrieved no abstract/full text; no efficacy claim is inferred from its title.
📚

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

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

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.