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Harrison's Part

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MONDO

MONDO:0016450 autoimmune hemolytic anemia, cold type Not Yet Curated

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Discussions and Knowledge Gaps

2

Is reduced complement receptor 1 on the clonal B cells a driver of the hemolytic phenotype in cold agglutinin disease, or a bystander marker of the clone?

KNOWLEDGE GAP OPEN cr1_downregulation_causal_role

Attached to

pathophysiology#Downregulation of Complement Receptor 1 on Clonal B Cells

CR1 is a regulator of C3b handling, so reduced expression is mechanistically suggestive: less CR1 would mean less cofactor activity restraining C3b deposition, which is the step this entry treats as dominant. But the observation curated here is differential expression in clonal B cells, not a demonstration that it changes C3b handling on erythrocytes, and the two are different cell populations. The node is marked `mechanism_confidence: HYPOTHETICAL` for that reason; this records the open question structurally rather than leaving it as a confidence flag.

What mechanism links chronic complement-mediated hemolysis in cold agglutinin disease to its excess thromboembolic risk?

KNOWLEDGE GAP OPEN prothrombotic_mechanism_in_cad

Attached to

pathophysiology#Prothrombotic State of Chronic Complement-Mediated Hemolysis

The epidemiological association between cold agglutinin disease and venous thromboembolism is curated from cohort data, but the mechanism is not established in this disease. Candidate routes borrowed from other hemolytic states (cell-free heme and nitric oxide scavenging, complement activation on platelets and endothelium, erythrocyte-derived microvesicles) have not been shown to operate here, and CAD hemolysis is predominantly extravascular, which weakens the cell-free-hemoglobin argument that applies to intravascular hemolytic diseases. Resolving this matters clinically because it determines whether complement inhibition should be expected to reduce thrombotic risk.

⚙

Pathophysiology

14

Somatic KMT2D and CARD11 Mutation in the CAD B-Cell Clone

The bone-marrow clone that underlies CAD carries recurrent somatic lesions, most consistently loss-of-function mutation of the histone methyltransferase gene KMT2D and gain-of-function mutation of the NF-kB scaffold gene CARD11, together with trisomies of chromosomes 3, 12 and 18. These are somatic events in the neoplastic B cells, not germline predisposition alleles, and their combination is one of the features that separates the CAD clone from lymphoplasmacytic lymphoma, in which MYD88 L265P is near-universal and absent here.

Genetic context KMT2D hgnc:7133 CARD11 hgnc:16393 variant_origin: SOMATIC functional_impact: KMT2D carries loss-of-function mutations and CARD11 gain-of-function mutations; the two impacts differ, so no single functional_impact_category value describes the pair.

Recurrent somatic mutations in the clonal B cells of primary cold agglutinin disease.

Downstream

Clonal Bone Marrow B-Cell Lymphoproliferation CARD11 gain of function activates NF-kB signalling and KMT2D loss removes an epigenetic brake, driving the clonal expansion.

Show evidence (2 references)

PMID:42117133 SUPPORT Human Clinical

"Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively"

Quantifies how often each somatic lesion is found in CAD patients, establishing them as recurrent rather than anecdotal.

PMID:41994904 SUPPORT Human Clinical

"The identification of recurrent somatic mutations in the KMT2D and CARD11 genes and trisomies of chromosomes 3, 12, and 18 in a proportion of CAD patients further strengthens the notion of it being a distinct entity"

Places the somatic mutation profile alongside the recurrent trisomies and ties it to the recognition of CAD-LPD as its own entity.

Downregulation of Complement Receptor 1 on Clonal B Cells

Mechanism confidence: Hypothetical

RNA sequencing and flow cytometry of sorted clonal CAD B cells show complement receptor 1 (CR1/CD35) to be the most strongly downregulated gene relative to IgM+ memory B cells from healthy donors. CR1 is a negative regulator of B-cell activation and differentiation, so its loss is proposed to lower the activation threshold of the CAD clone and increase its antibody output. The functional consequence is inferred from CR1 biology rather than demonstrated in CAD, so this node is provisional.

clonal CAD B cell CL:0000236

Downstream

Clonal Bone Marrow B-Cell Lymphoproliferation Proposed, not demonstrated: loss of an inhibitory receptor is expected to favour proliferation and immunoglobulin secretion by the clone.

Show evidence (1 reference)

PMID:38133636 SUPPORT In Vitro

"complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells"

Quantifies the expression difference measured by RNA sequencing of sorted clonal B cells against IgM+ memory B cells from healthy controls.

Clonal Bone Marrow B-Cell Lymphoproliferation

A small, low-grade clonal B-cell population sits in the bone marrow as circumscribed intraparenchymatous nodules of monotonous CD20+, surface IgM+, IgD+, CD27+, CD23-negative B cells, with a limited number of monotypic IgM+ plasma cells scattered diffusely outside the nodules. It lacks plasmacytoid cytology, the plasma-cell transcription factors MUM1, XBP1 and BLIMP1, and the MYD88 L265P mutation, which is what distinguishes CAD-associated lymphoproliferative disorder from lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia. The WHO fifth edition recognises it as a distinct entity. This clone is the source of the pathogenic cold agglutinin and the target of B-cell-directed therapy.

clonal CD20+ IgM+ CD27+ marrow B cell CL:0000236 monotypic IgM+ kappa plasma cell CL:0000786

clonal B cell proliferation in the bone marrow GO:0042100 ↑ INCREASED

Downstream

Monoclonal IgM Cold Agglutinin Production The clone and its associated monotypic plasma cells secrete the monoclonal IgM that is the pathogenic autoantibody.

Show evidence (4 references)

PMID:24143001 SUPPORT Human Clinical

"Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype."

The defining histology and immunophenotype of the CAD marrow clone in the 54-patient Nordic pathology series.

PMID:24143001 SUPPORT Human Clinical

"Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases)."

Absence of MYD88 L265P in every tested case is the negative finding that separates this clone from lymphoplasmacytic lymphoma.

PMID:42696222 SUPPORT Other

"The 2022 World Health Organization classification formally recognized CAD-associated lymphoproliferative disease as a distinct entity from lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinemia (WM)"

Records the nosological status of the clone as a WHO-recognised entity, not merely an autoantibody-producing cell population.

+ 1 more reference

Monoclonal IgM Cold Agglutinin Production

The secreted paraprotein is a monoclonal IgM, kappa-restricted in about 94% of patients and encoded by IGHV4-34 with somatic hypermutation, whose variable region recognises the carbohydrate blood-group antigen I on the erythrocyte surface. Binding is temperature-dependent: affinity is maximal well below 37 degrees Celsius, and the thermal amplitude — the highest temperature at which the antibody still agglutinates — rather than the titre alone determines whether an individual cold agglutinin is pathogenic in vivo.

monoclonal IgM production by the CAD clone GO:0002377 ↑ INCREASED

cold-dependent binding of IgM to the erythrocyte I antigen GO:0003823

Downstream

Cold-Dependent Erythrocyte Agglutination Pentameric IgM has ten binding sites and can bridge adjacent red cells once bound at low temperature.

Show evidence (4 references)

PMID:24143001 SUPPORT Human Clinical

"Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I."

Establishes both the IGHV4-34 gene usage and the anti-I specificity of the pathogenic antibody.

PMID:16585012 SUPPORT Human Clinical

"Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%."

Quantifies the isotype and light-chain restriction across an unselected national cohort, supporting "almost always IgM-kappa".

PMID:10530415 SUPPORT Human Clinical

"All patients had V(H)4-34 encoded IgM kappa cold agglutinins (CA) in high titre."

An independent clinical-immunology series in which every patient's cold agglutinin was VH4-34-encoded IgM kappa.

+ 1 more reference

Cold-Dependent Erythrocyte Agglutination

In the cooler acral circulation — fingers, toes, ears, nose — the monoclonal IgM binds the I antigen and cross-links red cells into agglutinates. This step is purely antibody-mediated and requires no complement: it is the origin of the cold-induced circulatory symptoms, and it is reversible, since the agglutinates disperse as the blood is rewarmed centrally.

erythrocyte CL:0000232

IgM-mediated erythrocyte-erythrocyte adhesion GO:0007155 ↑ INCREASED

Downstream

Classical Complement Pathway Activation on the Erythrocyte Surface The bound antigen-IgM complex is the trigger that recruits C1 to the red cell surface.

Acral Microcirculatory Obstruction The same agglutinates physically impede flow through acral capillaries, independently of any complement activation.

Show evidence (2 references)

PMID:35687757 SUPPORT Human Clinical

"In CAD, immunoglobulin M (IgM) autoantibodies (cold agglutinins) preferentially bind to the “I” antigen on erythrocytes at temperatures ≤37°C and may result in erythrocyte agglutination."

States the temperature dependence of binding and that agglutination is its direct consequence.

PMID:41994904 SUPPORT Human Clinical

"Most cold agglutinins are immunoglobulin heavy chain (IGH) gene V4‐34 encoded immunoglobulin M kappa (IgMκ), with optimal binding below body temperatures."

Confirms that optimal binding occurs below core body temperature, which is what confines agglutination to the acral circulation.

Classical Complement Pathway Activation on the Erythrocyte Surface

IgM is the most efficient physiological activator of the classical pathway. The surface-bound antigen-IgM complex recruits C1, C1s cleaves C4 and C2, and the assembled C4b2a C3 convertase cleaves C3. Because complement activation proceeds at core temperature once the antibody has bound in the periphery, hemolysis in CAD continues year-round even though the antibody binding step is cold-dependent. Chronic low-grade consumption of C3 and C4 is measurable in the serum of many patients.

classical complement pathway activation on the red cell surface GO:0006958 ↑ INCREASED

Downstream

C3b Opsonization of Erythrocytes C3 convertase activity deposits C3b covalently on the erythrocyte membrane.

Show evidence (2 references)

PMID:27913484 SUPPORT Other

"The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b."

States that hemolysis in CAD is wholly complement-dependent and runs through the classical pathway, which is the claim of this node.

PMID:10530415 SUPPORT Human Clinical

"Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50. Such data indicate that patients with CAD experience a continuous low-grade complement consumption."

Measured C3/C4 depletion is the in-vivo footprint of continuous classical pathway consumption asserted by this node.

Acute-Phase Complement Repletion During Febrile Illness

Mechanism confidence: Provisional

Complement components are acute-phase reactants. During infection or other febrile illness their production rises, restoring the substrate that chronic low-grade consumption had depleted and transiently increasing the hemolytic capacity of an unchanged cold agglutinin. This is the mechanistic explanation for the characteristic paradox that CAD hemolysis worsens during fever rather than improving with the higher body temperature.

Downstream

Classical Complement Pathway Activation on the Erythrocyte Surface Increased availability of complement components raises the achievable rate of classical-pathway activation on already-sensitized red cells.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%."

Establishes that febrile exacerbation is common (74%) and therefore a real feature of the disease, not an anecdote.

C3b Opsonization of Erythrocytes

C3b is deposited covalently on the erythrocyte surface. When the cell circulates back to core temperature the IgM dissociates, but the covalently bound C3b does not — which is why the direct antiglobulin test in CAD is strongly positive for C3d (the degradation remnant of C3b) and negative or only weakly positive for IgG. The opsonized cell is now marked for phagocytic clearance and, if the cascade continues, for terminal-pathway lysis.

C3b opsonization of the erythrocyte membrane GO:0008228 ↑ INCREASED

Downstream

Hepatic Extravascular Hemolysis C3b-opsonized red cells are recognised and phagocytosed by hepatic macrophages, the dominant route of destruction.

Terminal Complement Pathway Assembly and Membrane Attack Complex Formation Dense C3b deposition builds C5 convertase and drives the cascade on to C5b-9; this is the minority route and occurs mainly during exacerbations.

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"Diagnosis rests on evidence of hemolysis, a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG), a cold agglutinin titer ≥ 1:64, and bone marrow evaluation; thermal amplitude can predict clinical severity better than titer alone."

The C3d-positive, IgG-negative serological signature is the direct clinical readout of C3b deposition without persistent IgG coating.

Hepatic Extravascular Hemolysis

Kupffer cells, the resident macrophages of the liver sinusoids, express complement receptors that bind C3b-opsonized erythrocytes and phagocytose them. This hepatic, complement-receptor-driven clearance is the dominant mechanism of red cell destruction in CAD, and it is the reason splenectomy fails: unlike warm autoimmune hemolytic anemia, where IgG-coated cells are removed by Fc-receptor-bearing splenic red-pulp macrophages, the effector organ here is the liver.

Kupffer cell CL:0000091 C3b-opsonized erythrocyte CL:0000232

erythrophagocytosis by hepatic macrophages GO:0006909 ↑ INCREASED hepatic clearance of opsonized erythrocytes GO:0034102 ↑ INCREASED

Downstream

Chronic Hemolytic Anemia

Prothrombotic State of Chronic Complement-Mediated Hemolysis Chronic complement activation and hemolysis are associated with excess venous and arterial thrombosis; the intermediate steps are not established.

Show evidence (2 references)

PMID:35687757 SUPPORT Human Clinical

"C3b deposition on erythrocytes results in extravascular hemolysis in the liver, the predominant mechanism of erythrocyte destruction in CAD."

Identifies hepatic extravascular hemolysis as the predominant destruction mechanism, which is the claim of this node.

PMID:42696222 SUPPORT Other

"it explains why therapies effective in warm AIHA, such as corticosteroids and splenectomy, are largely ineffective in CAD, where hemolysis is complement-driven and predominantly hepatic rather than Fc-mediated and splenic"

Makes the liver-versus-spleen contrast explicit and connects it to the therapeutic consequence recorded in this entry's treatments.

Terminal Complement Pathway Assembly and Membrane Attack Complex Formation

When C3b density is high enough, C5 convertase forms and the terminal pathway proceeds to the C5b-9 membrane attack complex on the erythrocyte surface. Progression this far is limited in CAD because CD55 and CD59 remain intact on the red cell, unlike in paroxysmal nocturnal hemoglobinuria, so the terminal pathway contributes a minority of hemolysis and does so mainly during acute exacerbations. This is also why C5 inhibition alone gives only a modest hemoglobin response in CAD.

membrane attack complex assembly on the erythrocyte GO:0001905 ↑ INCREASED

Downstream

Intravascular Hemolysis Completed C5b-9 pores lyse the red cell within the circulation, releasing free hemoglobin.

Show evidence (2 references)

PMID:42696222 SUPPORT Other

"Complete progression to the membrane attack complex (C5b-9) causes intravascular hemolysis, which occurs mainly during acute exacerbations."

States both the effect of terminal-pathway completion and its restriction to exacerbations, which is what makes this the minority branch.

PMID:35687757 SUPPORT Human Clinical

"because of intact CD55- and CD59-mediated regulation in CAD"

Gives the reason terminal-pathway lysis stays limited in CAD, which is why this node is modelled as a minority branch rather than the main route.

Intravascular Hemolysis

Lysis of erythrocytes within the vasculature releases free hemoglobin, which saturates haptoglobin and appears in the urine as hemoglobinuria. In CAD this accounts for a minority of red cell loss and is most evident during cold- or infection-triggered exacerbations.

erythrocyte CL:0000232

complement-mediated lysis of erythrocytes GO:0097278 ↑ INCREASED

Downstream

Chronic Hemolytic Anemia

Hemoglobinuria

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"Patients were required to have symptomatic disease within 3 months of screening, defined as one or more of the following: symptomatic anemia, acrocyanosis, Raynaud phenomenon, hemoglobinuria, disabling circulatory symptoms, and/or major adverse vascular event, including thrombosis."

Hemoglobinuria is one of the recognised disease manifestations used to define symptomatic CAD in a phase 3 trial, which is the clinical signature of the intravascular component.

Chronic Hemolytic Anemia

Destruction of erythrocytes outstrips compensatory erythropoiesis, so hemoglobin falls. Mean hemoglobin at presentation is around 9 g/dL, but a quarter of patients are below 8 g/dL and about half require red-cell transfusion at some point. The anemia is chronic and year-round rather than purely seasonal, because the complement-mediated effector arm operates at core temperature.

erythrocyte homeostasis GO:0034101 ⚠ ABNORMAL

Downstream

Anemia

Fatigue

Jaundice

Show evidence (2 references)

PMID:32374875 SUPPORT Human Clinical

"Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL."

Quantifies the severity distribution of the anemia across 232 patients in five countries.

PMID:16585012 SUPPORT Human Clinical

"At least 51% had received red blood cell transfusions. The mean initial hemoglobin level was 9.2 g/dL (range, 4.5-15.6)"

Independent population-based confirmation of the hemoglobin level and of how often the anemia becomes transfusion-dependent.

Acral Microcirculatory Obstruction

Agglutinated red cells impede flow through the small vessels of fingers, toes, ears and nose on cold exposure, producing acrocyanosis, Raynaud-like phenomena and livedo reticularis. This branch of the mechanism is purely agglutination-driven: it does not require complement, and complement inhibitors therefore do not relieve it — a distinction with direct therapeutic consequences, since a patient whose dominant complaint is circulatory rather than hemolytic will not benefit from sutimlimab.

Downstream

Acrocyanosis

Raynaud Phenomenon

Livedo Reticularis

Show evidence (2 references)

PMID:42696222 SUPPORT Other

"Importantly, these symptoms are not complement-mediated and are therefore not addressed by complement inhibitors, a distinction with direct therapeutic relevance."

Establishes that this branch is independent of the complement chain, which is why it is modelled as a separate limb of the graph.

PMID:16585012 SUPPORT Human Clinical

"cold-induced circulatory symptoms in 91%"

Gives the frequency of this branch in an unselected national cohort.

Prothrombotic State of Chronic Complement-Mediated Hemolysis

Mechanism confidence: Hypothetical

Patients with CAD have a higher incidence of venous thromboembolism, and of arterial events, than matched controls. Complement-driven endothelial activation is the proposed mediator, but the intermediate steps have not been established in CAD, so this node records an epidemiological association with a hypothesised mechanism rather than a demonstrated causal chain.

Downstream

Venous Thromboembolism

Show evidence (2 references)

PMID:31648316 SUPPORT Human Clinical

"Risk of TEs was higher in the CAD patient cohort than in the comparison cohort at 1 year (7.2% of CAD patients had TEs vs 1.9% of comparisons)"

Quantifies the excess thromboembolic risk against a matched general population cohort.

PMID:42696222 SUPPORT Other

"Complement-driven endothelial activation is thought to contribute to this prothrombotic state."

The proposed mechanism, stated by the source as a belief rather than an established finding, which is why this node is marked hypothetical.

✶

Histopathology

3

Nodular Clonal B-Cell Infiltrate of the Bone Marrow Present in about three quarters of CAD marrows examined in dedicated series.

The marrow lesion of CAD-associated lymphoproliferative disorder is a small, circumscribed, intraparenchymatous nodular infiltrate of monotonous monoclonal B cells, typically occupying only about a tenth of marrow cellularity. It resembles marginal zone lymphoma architecturally while lacking extramedullary disease.

Show evidence (2 references)

PMID:24143001 SUPPORT Human Clinical

"Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype."

Gives the architecture, the proportion of patients showing it, the degree of marrow involvement, and the immunophenotype, in the largest dedicated marrow series.

PMID:41994904 SUPPORT Human Clinical

"The majority (74%) displayed a small homogeneous lymphoid infiltration, characterized by nodular B‐cell aggregates strongly resembling MZL, but without extramedullary disease."

Independently reports the same nodular pattern and its frequency, and names the marginal zone lymphoma resemblance that makes CAD marrows liable to misclassification.

Monotypic Plasma Cells Outside the Lymphoid Nodules

Monoclonal IgM-positive plasma cells are present but sit outside the B-cell nodules, scattered through the marrow, and the infiltrating B cells themselves show no plasmacytoid differentiation. This spatial separation is the morphological argument that the lesion is not lymphoplasmacytic lymphoma.

Show evidence (3 references)

PMID:24143001 SUPPORT Human Clinical

"However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow."

Establishes that the plasma cells are extranodular, which is the observation that separates this lesion from the lymphoplasmacytic pattern.

PMID:24143001 SUPPORT Human Clinical

"The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different..."

The authors' own summary of the four features that make this a distinct entity, which is the claim the entry makes elsewhere about CAD-LPD.

PMID:41994904 SUPPORT Human Clinical

"The presence of monotypic plasma cells was consistent with LPL, but key morphological findings diagnostic of LPL were lacking, including paratrabecular growth and lymphoplasmacytoid cells."

Names the two LPL features that are absent, which is what the extranodular plasma-cell pattern has to be read against.

Strict WHO-HAEM5 CAD-LPD Morphology Is Met by a Minority

The WHO-HAEM5 morphological description of CAD-LPD is a desirable rather than an essential criterion, and in practice most CAD marrows do not meet it in full even when clonality is demonstrable by other means. Treating the strict morphological picture as a diagnostic requirement would therefore misclassify the majority of genuine cases, which is why sensitive ancillary techniques are recommended alongside morphology.

Show evidence (1 reference)

PMID:41994904 SUPPORT Human Clinical

"Surprisingly, while ancillary methods detected clonality in the majority (84%), only 5 (11%) of 45 CAD cases strictly fulfilled the WHO-HAEM5 morphological description for CAD-LPD."

Quantifies the gap between demonstrable clonality and strict WHO-HAEM5 morphology, which is the reason this section records the morphology as characteristic rather than as a diagnostic requirement.

⬡

Pathograph

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Phenotypes

8

Blood 2

Anemia VERY_FREQUENT Hemolytic anemia HP:0001878

Show evidence (1 reference)

PMID:32374875 SUPPORT Human Clinical

"Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL."

Anemia was present in every patient of this 232-patient multinational cohort, with the quoted distribution of severity.

Venous Thromboembolism OCCASIONAL Venous thrombosis HP:0004936

Show evidence (2 references)

PMID:31648316 SUPPORT Human Clinical

"Risk of TEs was higher in the CAD patient cohort than in the comparison cohort at 1 year (7.2% of CAD patients had TEs vs 1.9% of comparisons)"

Supplies both the presence of the phenotype and the quantitative excess over a matched comparison cohort, which is what the OCCASIONAL band records.

PMID:32374875 SUPPORT Human Clinical

"CAD seems to be associated with a slightly increased risk of venous thrombosis."

Independent multinational cohort reaching the same qualitative conclusion, with the authors' own hedge preserved.

Cardiovascular 2

Raynaud Phenomenon OCCASIONAL HP:0030880

Temporal: RECURRENT

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"Nine patients (40.9%) in the sutimlimab group vs 4 patients (20.0%) in the placebo group had acrocyanosis, and 5 patients (22.7%) vs 3 patients (15.0%), respectively, experienced Raynaud phenomenon."

Reports baseline prevalence of Raynaud phenomenon in both arms of a phase 3 CAD cohort, supporting an occasional-frequency assignment.

Livedo Reticularis HP:0033505

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"Cold-induced circulatory symptoms—acrocyanosis of the fingers, toes, ears, and nose, Raynaud-like phenomena, and livedo reticularis—are reported by the great majority of patients (approximately 90%) and can substantially impair daily activities"

Lists livedo reticularis among the cold-induced circulatory manifestations; the 90% figure covers the group as a whole, not livedo individually, so no frequency is asserted for this phenotype.

Digestive 1

Jaundice HP:0000952

Show evidence (1 reference)

PMID:33826820 SUPPORT Human Clinical

"The mean bilirubin levels normalized by week 3."

Bilirubin was abnormal at baseline across the CARDINAL cohort and normalized on treatment, establishing hyperbilirubinemia as a disease-attributable feature.

Genitourinary 1

Hemoglobinuria HP:0003641

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"Patients were required to have symptomatic disease within 3 months of screening, defined as one or more of the following: symptomatic anemia, acrocyanosis, Raynaud phenomenon, hemoglobinuria, disabling circulatory symptoms, and/or major adverse vascular event, including thrombosis."

Hemoglobinuria is enumerated among the recognised symptomatic manifestations of CAD in the CADENZA eligibility definition.

Integument 1

Acrocyanosis FREQUENT HP:0001063

Temporal: RECURRENT

Show evidence (1 reference)

PMID:23757733 SUPPORT Human Clinical

"The most common symptom was acrocyanosis (n = 39 [44%]), and many had symptoms triggered by cold (n = 35 [39%])"

Gives both the frequency (44% of 89 patients) and the rank of acrocyanosis among presenting symptoms in a single-institution cohort.

Constitutional 1

Fatigue VERY_FREQUENT HP:0012378

Show evidence (2 references)

PMID:33826820 SUPPORT Human Clinical

"Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study."

Fatigue was severe enough at baseline in the CARDINAL cohort to permit a clinically meaningful reduction, and it improved within a week of complement blockade.

PMID:35687757 SUPPORT Human Clinical

"Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint."

Confirms in a randomized placebo-controlled setting that fatigue is a measurable, disease-attributable feature rather than a nonspecific complaint.

🧬

Genetic Associations

3

KMT2D (Loss-of-function mutation of this histone H3K4 methyltransferase is the most frequent recurrent somatic lesion in the CAD B-cell clone.)

Gene: KMT2D hgnc:7133 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:42117133 SUPPORT Human Clinical

"Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively"

Gives the mutation frequency of KMT2D (69%) in sequenced CAD patients.

PMID:38133636 SUPPORT Human Clinical

"KMT2D and CARD11 genes are recurrently mutated in CAD B cells. KMT2D has loss-of-function mutations, and CARD11 has gain-of-function mutations"

Specifies that the KMT2D lesions are loss-of-function, which is the functional direction recorded here.

CARD11 (Gain-of-function mutation of this NF-kB scaffold protein constitutively activates B-cell receptor signalling downstream of the receptor itself, a plausible driver of the clonal expansion.)

Gene: CARD11 hgnc:16393 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:42117133 SUPPORT Human Clinical

"Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively"

Gives the mutation frequency of CARD11 (31%) in sequenced CAD patients.

PMID:38133636 SUPPORT Human Clinical

"KMT2D and CARD11 genes are recurrently mutated in CAD B cells. KMT2D has loss-of-function mutations, and CARD11 has gain-of-function mutations"

Specifies that the CARD11 lesions are gain-of-function, which is the functional direction recorded here.

CXCR4 (Somatic CXCR4 mutations occur in the CAD clone and, with CARD11, correlate with hemoglobin level, suggesting they modify disease severity rather than initiate the clone.)

Gene: CXCR4 hgnc:2561 relationship_type: MODIFIER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:38133636 SUPPORT Human Clinical

"Of interest, CARD11 and CXCR4 mutations were correlated with hemoglobin levels, suggesting pathogenic involvement"

Reports the correlation with hemoglobin, which is the modifier claim made here; the source itself frames the pathogenic role as a suggestion.

💊

Medical Actions

10

Cold Avoidance and Thermal Protection

Action: cold avoidance and thermal protection Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Keeping the extremities and the whole body warm reduces the fraction of red cells that become sensitized and directly relieves the agglutination-driven circulatory symptoms. It is the first intervention in every patient and is sufficient in some, but it does not address the year-round complement-mediated hemolysis, which proceeds at core temperature.

Mechanism Target:

INHIBITS Cold-Dependent Erythrocyte Agglutination — Preventing peripheral cooling keeps the blood above the antibody's thermal amplitude, so binding and agglutination do not occur.

Show evidence (2 references)

PMID:35687757 SUPPORT Human Clinical

"Supportive care with cold avoidance alone is often inadequate and does not address complement-mediated symptoms, as chronic hemolytic anemia persists year-round."

Establishes both that cold avoidance is standard supportive care and its specific limitation, which is what this entry's description records.

PMID:21385173 SUPPORT Other

"Non-pharmacological management still seems sufficient in some patients."

Supports the statement that thermal protection alone suffices for a subset of patients.

Rituximab Monotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Platform: Monoclonal antibody

Anti-CD20 depletion of the clonal B-cell population. About half of patients respond, but responses are usually partial, take about six weeks to appear, and last around a year. It is the best-documented single agent and the reference against which combination regimens are measured.

Mechanism Target:

INHIBITS Clonal Bone Marrow B-Cell Lymphoproliferation — Depleting CD20-positive B cells removes the source of the cold agglutinin, which is why the hemoglobin response is delayed by weeks rather than immediate.

Show evidence (1 reference)

PMID:15070665 SUPPORT Human Clinical

"Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months."

The 1.5-month lag to response is the kinetic signature of removing the antibody-producing clone rather than blocking the effector arm.

Show evidence (2 references)

PMID:15070665 SUPPORT Human Clinical

"Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment."

Gives the response rate to first-course and repeat rituximab in the largest prospective monotherapy series.

PMID:15070665 SUPPORT Human Clinical

"We observed 1 complete and 19 partial responses."

Shows that responses to rituximab monotherapy are almost always partial, which is the limitation that motivates combination therapy.

Bendamustine plus Rituximab

Action: chemoimmunotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: bendamustine CHEBI:135515 rituximab NCIT:C1702

Adding the alkylating agent bendamustine to rituximab raises the response rate to roughly three-quarters, produces complete responses in about half, and gives durable remissions — five-year sustained remission of 77% in long-term follow-up. Grade 3-4 neutropenia in a third of patients is the principal cost. It is a recommended first-line regimen for CAD requiring treatment.

Mechanism Target:

INHIBITS Clonal Bone Marrow B-Cell Lymphoproliferation — Cytotoxic clearance of the clone, including the long-lived plasma-cell compartment that rituximab alone spares — which is why responses continue to deepen for many months after treatment ends.

Show evidence (1 reference)

PMID:32374875 SUPPORT Human Clinical

"This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells."

The authors attribute the deepening of responses over time to long-lived plasma cells, which is the mechanistic claim made on this link.

Show evidence (4 references)

PMID:28533306 SUPPORT Human Clinical

"Thirty-two patients (71%) responded; 18 (40%) achieved complete response (CR) and 14 (31%) partial response (PR)."

Primary efficacy result of the prospective Nordic bendamustine-rituximab trial.

PMID:28533306 SUPPORT Human Clinical

"Grade 3-4 neutropenia occurred in 15 patients (33%), but only 5 (11%) experienced infection with or without neutropenia."

Quantifies the principal toxicity and puts it in context, both of which this entry's description records.

PMID:32374875 SUPPORT Human Clinical

"In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%."

Long-term follow-up establishing the durability that distinguishes this regimen from rituximab monotherapy.

+ 1 more reference

Fludarabine plus Rituximab

Action: chemoimmunotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

A highly effective but more toxic B-cell-directed combination: 76% response with 21% complete responses and an estimated median response duration beyond 66 months, at the cost of grade 3-4 hematologic toxicity in 41% and a higher rate of long-term adverse effects than bendamustine-rituximab. Reserved for selected patients.

Mechanism Target:

INHIBITS Clonal Bone Marrow B-Cell Lymphoproliferation — Purine-analogue plus anti-CD20 clearance of the marrow clone.

Show evidence (3 references)

PMID:20634373 SUPPORT Human Clinical

"Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR."

Primary efficacy result of the prospective fludarabine-rituximab trial.

PMID:20634373 SUPPORT Human Clinical

"Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD."

Quantifies the hematologic toxicity that is the reason this regimen is not first choice.

PMID:32374875 SUPPORT Human Clinical

"Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects."

Long-term comparative observation supporting the preference for bendamustine-rituximab.

Sutimlimab

Action: classical-pathway complement inhibition Ontology label: Pharmacotherapy NCIT:C15986

Agent: sutimlimab NCIT:C153093

Platform: Monoclonal antibody

A humanized IgG4 monoclonal antibody that selectively inhibits the classical complement pathway at C1s, leaving the lectin and alternative pathways intact. It blocks the effector arm of the disease without touching the clone, so hemolysis stops within days and the hemoglobin, bilirubin and fatigue all respond within the first weeks — but the cold agglutinin is still produced, and the agglutination-driven circulatory symptoms are not relieved. Approved for CAD on the strength of the CARDINAL and CADENZA trials.

Mechanism Target:

INHIBITS Classical Complement Pathway Activation on the Erythrocyte Surface — C1s is the serine protease of the C1 complex that cleaves C4 and C2; blocking it prevents C3 convertase formation and therefore all downstream opsonization and lysis.

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization."

Ties the clinical benefit to a measured near-complete reduction in classical-pathway activity, which is the pharmacodynamic proof that this is the node being inhibited.

Show evidence (4 references)

PMID:33826820 SUPPORT Human Clinical

"In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue."

Conclusion of the pivotal open-label CARDINAL trial in recently transfused patients.

PMID:35687757 SUPPORT Human Clinical

"Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint."

Randomized placebo-controlled confirmation in CADENZA, which is the stronger evidential basis of the two trials.

PMID:35687757 SUPPORT Human Clinical

"Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups."

Records the adverse events that were more frequent on treatment, including the circulatory symptoms that complement inhibition does not address.

+ 1 more reference

Eculizumab

Action: terminal complement inhibition Ontology label: Pharmacotherapy NCIT:C15986

Agent: complement inhibitor NCIT:C199456

Platform: Monoclonal antibody

Anti-C5 monoclonal antibody, tested prospectively in CAD (the DECADE trial) and informative mainly as a mechanistic control. Blocking the terminal pathway cut LDH substantially but raised hemoglobin only from 9.35 to 10.15 g/dL, because it leaves the C3b-opsonization step — and therefore the dominant hepatic extravascular clearance — completely intact. Cold-induced circulatory symptoms were likewise unaffected, as expected for a branch that is not complement-mediated at all. The trial result is the strongest single piece of evidence that this entry's graph is oriented correctly: inhibiting the minority branch produces a minority benefit.

Mechanism Target:

INHIBITS Terminal Complement Pathway Assembly and Membrane Attack Complex Formation — C5 blockade prevents C5b-9 assembly and so abolishes the intravascular component, while leaving upstream C3b deposition untouched.

Show evidence (1 reference)

PMID:30291112 SUPPORT Human Clinical

"Cold agglutinin disease (CAD) is a complement-dependent disorder, with extravascular and intravascular hemolysis resulting from initial or terminal complement activation, respectively. We tested the efficacy and safety of eculizumab, an inhibitor of the terminal complement pathway."

The trial explicitly separates the initial-activation (extravascular) and terminal (intravascular) arms and targets only the latter, which is the node this link points at.

Show evidence (2 references)

PMID:30291112 SUPPORT Human Clinical

"The median lactate dehydrogenase level decreased from 572 U/L (interquartile range [IQR], 534-685) to 334 U/L (IQR, 243-567; P = .0215), paralleled by an increase in hemoglobin from 9.35 g/dL (IQR, 8.80-10.80) to 10.15 g/dL (IQR, 9.00-11.35; P = .0391; Wilcoxon signed-rank test)."

The large LDH fall with only a 0.8 g/dL hemoglobin gain is the quantitative shape of blocking the minority intravascular branch while the hepatic extravascular branch continues.

PMID:30291112 SUPPORT Human Clinical

"In contrast to hemolysis, cold-induced circulatory symptoms remained unaffected."

Confirms that the acral circulatory branch is untouched by complement inhibition of any kind, which is why this entry models it as a separate limb leaving the agglutination node.

Red Blood Cell Transfusion

Action: red blood cell transfusion Ontology label: Blood Transfusion NCIT:C15192

Supportive transfusion for symptomatic anemia. Around half of patients require it at some point, and transfusion history is what separated the CARDINAL and CADENZA trial populations.

Mechanism Target:

MODULATES Chronic Hemolytic Anemia — Replaces lost red cell mass without altering any upstream step, which is why the effect is transient.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"At least 51% had received red blood cell transfusions."

Establishes how often transfusion is needed across an unselected national cohort.

Corticosteroid Therapy

Action: systemic corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

Platform: Small molecule

Explicitly not recommended in cold agglutinin disease. Response rates are poor and often require unacceptably high maintenance doses. The mechanistic reason is that corticosteroids act largely on Fc-receptor-mediated splenic clearance, which is the warm-AIHA effector arm and not the one operating here. Recorded so that the negative recommendation is machine-readable.

Show evidence (2 references)

PMID:27913484 SUPPORT Other

"CAD should not be treated with corticosteroids."

An unqualified negative recommendation from an ASH education-program review, which is the claim this entry records.

PMID:35687757 SUPPORT Human Clinical

"Despite not being recommended because of poor response rates and often requiring unacceptably high doses, corticosteroids are often used in CAD management."

Gives the reasons behind the negative recommendation and notes the gap between guidance and practice.

Splenectomy

Action: splenectomy Ontology label: Splenectomy NCIT:C15328

Platform: Surgery

Ineffective in cold agglutinin disease and not recommended. The C3b-opsonized red cell is cleared by hepatic Kupffer cells, not by splenic macrophages, so removing the spleen does not remove the effector organ. This is the clearest instance in the entry of mechanism predicting therapeutic failure.

Show evidence (2 references)

PMID:35687757 SUPPORT Human Clinical

"Other approaches such as azathioprine, cyclophosphamide, and splenectomy are not effective in CAD and are also not recommended"

States the ineffectiveness and the recommendation against splenectomy.

PMID:42696222 SUPPORT Other

"it explains why therapies effective in warm AIHA, such as corticosteroids and splenectomy, are largely ineffective in CAD, where hemolysis is complement-driven and predominantly hepatic rather than Fc-mediated and splenic"

Supplies the mechanistic reason recorded in this entry's description: the effector organ is the liver, not the spleen.

Bortezomib

Action: Pharmacotherapy NCIT:C15986

Agent: bortezomib CHEBI:52717

Platform: Small molecule

Proteasome inhibition directed at the antibody-secreting plasma-cell compartment rather than at the CD20-positive B-cell clone or at complement. A prospective phase 2 GIMEMA study in relapsed, anemic patients reported an overall response rate of roughly a third, with responses lasting a little over a year, and peripheral neuropathy as the limiting toxicity. This is a third therapeutic axis alongside B-cell depletion and complement blockade, and it is the only curated treatment acting on production of the cold agglutinin itself.

Mechanism Target:

INHIBITS Monoclonal IgM Cold Agglutinin Production — Proteasome inhibition is disproportionately toxic to immunoglobulin-secreting plasma cells, so the point of attack is production of the cold agglutinin rather than the B-cell clone upstream of it or the complement cascade it activates downstream.

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"Bortezomib, through plasma-cell depletion, achieved an overall response rate of approximately 32%, with a median response duration of approximately 16 months in a GIMEMA phase 2 study limited by neuropathy [34,35,36]."

Attributes the effect specifically to plasma-cell depletion, which is what makes this a link to the antibody-production node rather than to the clonal lymphoproliferation node, and gives the response rate and duration observed in the phase 2 study.

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"For patients with relapsed or refractory disease, ibrutinib-, daratumumab-, and bortezomib-based approaches are options, and the next-generation agents riliprubart and iptacopan, although still in the early phase of development, point toward less burdensome and potentially oral complement inhibition."

Places bortezomib among the accepted options in relapsed or refractory disease, which is the setting the GIMEMA study enrolled.

🌍

Environmental Factors

1

Cold exposure of the acral circulation

The climate gradient in the multinational cohort is an association between ambient temperature and diagnosed disease; the authors do not establish whether it reflects true incidence, symptom-driven ascertainment, or both.

Ambient cooling of the peripheral circulation is the proximate trigger for the antibody-binding step of this disease. The monoclonal IgM binds the I antigen only below core temperature, so the fingers, toes, ears and nose — which run several degrees cooler than the trunk — are where agglutination and complement fixation begin. Cold avoidance and thermal protection are the corresponding non-pharmacological management, and are sometimes sufficient. Cold exposure triggers the agglutination and circulatory limb; it does not explain the year-round hemolysis, which continues at core temperature once complement has been fixed.

Show evidence (2 references)

PMID:16585012 SUPPORT Human Clinical

"Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%."

Cold-induced symptoms in 91% of an unselected national cohort establishes cold exposure as a clinically dominant environmental determinant in this disease.

PMID:32374875 SUPPORT Human Clinical

"For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year)."

A fourfold difference in prevalence and incidence between cold and warm climates is population-level evidence that ambient temperature shapes who is diagnosed with this disease.

Mechanism Target:

TRIGGERS Cold-Dependent Erythrocyte Agglutination — Cooling of peripheral blood below the antibody's thermal amplitude is what permits the IgM to bind the I antigen and cross-link red cells.

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"In CAD, immunoglobulin M (IgM) autoantibodies (cold agglutinins) preferentially bind to the “I” antigen on erythrocytes at temperatures ≤37°C and may result in erythrocyte agglutination."

States the temperature condition under which binding and agglutination occur, which is the causal role assigned to cold exposure here.

TRIGGERS Acral Microcirculatory Obstruction — The cold-induced circulatory symptoms are transient and appear on exposure, resolving on rewarming.

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"non-complement-mediated symptoms include transient, cold-induced agglutination-mediated circulatory symptoms, such as acrocyanosis and Raynaud phenomenon"

Attributes the acral circulatory symptoms specifically to cold-induced agglutination.

EXACERBATES Chronic Hemolytic Anemia — Seasonal cooling worsens hemolysis by increasing the fraction of red cells that become sensitized, but does not initiate it; the entry's own pathophysiology chain carries the intermediate steps.

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"Anemia is frequently transfusion-requiring; more than half of the patients receive red blood cell transfusions over the course of their disease, and seasonal worsening during colder months and febrile exacerbations of hemolysis are common"

Documents seasonal worsening of hemolysis in colder months, which is the exacerbating effect recorded on this link.

🔬

Biochemical Markers

8

Cold agglutinin titer (Elevated)

Context: Diagnostic threshold is a titer of at least 64 at 4 degrees Celsius. Thermal amplitude — the highest temperature at which agglutination still occurs — predicts clinical severity better than the titer alone.

Show evidence (2 references)

PMID:35687757 SUPPORT Human Clinical

"A confirmed diagnosis of CAD was defined as the presence of chronic hemolysis, positive polyspecific direct antiglobulin test, monospecific-direct antiglobulin test strongly positive for C3d, IgG-direct antiglobulin test ≤1+, a cold agglutinin titer ≥64 at 4°C, and no evidence of overt malignant disease."

Gives the operational titer threshold used to confirm the diagnosis in a phase 3 trial.

PMID:42696222 SUPPORT Other

"thermal amplitude can predict clinical severity better than titer alone"

Qualifies the titer as an incomplete marker and identifies thermal amplitude as the better predictor, which is what this record's context field states.

Direct antiglobulin test (monospecific) (Positive for C3d, negative or weakly positive for IgG)

Context: The serological signature of CAD, and the finding that separates it from warm autoimmune hemolytic anemia. The IgM elutes on rewarming, so only the covalently bound complement remnant is detected.

Show evidence (2 references)

PMID:42696222 SUPPORT Other

"a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG)"

States the C3d-positive, IgG-negative pattern that defines the test result in CAD.

PMID:41994904 SUPPORT Human Clinical

"Inclusion criteria were presence of chronic hemolysis, a DAT positive for C3d (≥ 2+) and negative or weakly positive for IgG, and presence of cold‐reactive antibodies."

Shows the same pattern used operationally as a cohort inclusion criterion, including the negative-or-weakly-positive IgG qualification recorded in this record's presence field.

Monoclonal IgM kappa paraprotein (Present)

Context: Serum monoclonal immunoglobulin, IgM in about 90% of patients and kappa-restricted in about 94%; the direct product of the marrow clone.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%."

Gives the isotype and light-chain distribution across 86 population-based patients, which is the basis for both percentages in the context field.

Lactate dehydrogenase (Elevated)

Context: Marker of hemolytic rate; falls on effective complement inhibition.

Show evidence (2 references)

PMID:42696222 SUPPORT Other

"The first step is to confirm hemolysis through elevated levels of lactate dehydrogenase (LDH) and indirect bilirubin, reticulocytosis, and reduced levels of haptoglobin, together with a review of the peripheral blood smear, which may show erythrocyte agglutination."

Elevated LDH is named as one of the findings that confirms hemolysis in the diagnostic workup of this disease.

PMID:35687757 SUPPORT Human Clinical

"Eculizumab, a C5 inhibitor, reduces the need for transfusion and reduces lactate dehydrogenase (LDH) levels but elicits only a modest increase in hemoglobin (Hb) levels in patients with CAD because it does not inhibit extravascular hemolysis"

LDH falls when the intravascular (terminal-pathway) component is blocked while hemoglobin barely moves, which is what makes LDH a marker of the intravascular arm specifically rather than of total hemolytic rate.

Haptoglobin (Decreased)

Context: Consumed by free hemoglobin released during hemolysis.

Show evidence (2 references)

PMID:42696222 SUPPORT Other

"The first step is to confirm hemolysis through elevated levels of lactate dehydrogenase (LDH) and indirect bilirubin, reticulocytosis, and reduced levels of haptoglobin, together with a review of the peripheral blood smear, which may show erythrocyte agglutination."

Reduced haptoglobin is named among the findings that confirm hemolysis in the diagnostic workup of this disease.

PMID:35687757 SUPPORT Human Clinical

"In the sutimlimab arm, an increase in the haptoglobin level corresponded to a decrease in the bilirubin level, whereas no change occurred in the placebo arm."

Haptoglobin rose only when hemolysis was blocked, confirming that the low baseline level is consumption by ongoing hemolysis rather than a constitutive feature.

Unconjugated bilirubin (Elevated)

Context: Product of hemoglobin catabolism after extravascular red cell destruction; normalizes within weeks of stopping hemolysis.

Show evidence (1 reference)

PMID:35687757 SUPPORT Human Clinical

"Sutimlimab normalized mean bilirubin by week 1."

Bilirubin was elevated at baseline and tracked hemolytic rate closely enough to normalize within a week of blocking C1s.

Complement C4 (Decreased)

Context: Consumed by continuous classical-pathway activity; recovery of C4 is a pharmacodynamic marker of effective C1s inhibition.

Show evidence (2 references)

PMID:35687757 SUPPORT Human Clinical

"Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization."

C4 normalized only once the classical pathway was blocked, which implies it was being consumed by ongoing classical-pathway activation before treatment.

PMID:10530415 SUPPORT Human Clinical

"Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50."

Direct measurement of low C3, low C4 and reduced CH50 in an untreated CAD series.

Reticulocyte count (Elevated)

Context: Marrow compensatory response to hemolysis; the fourth member of the LDH / haptoglobin / bilirubin panel used to confirm that anemia is hemolytic.

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"The first step is to confirm hemolysis through elevated levels of lactate dehydrogenase (LDH) and indirect bilirubin, reticulocytosis, and reduced levels of haptoglobin, together with a review of the peripheral blood smear, which may show erythrocyte agglutination."

Names reticulocytosis as one of the findings that establishes hemolysis in the diagnostic workup of this disease, alongside the three markers this section already curates.

🔬

Diagnosis

3

Monospecific direct antiglobulin test

Distinguishes immune from non-immune hemolysis and, by typing the coating protein, separates cold agglutinin disease (C3d-positive, IgG-negative or weakly positive) from warm autoimmune hemolytic anemia (IgG-positive).

Results: Strongly positive for C3d; negative or at most weakly positive for IgG.

Show evidence (1 reference)

PMID:31839434 SUPPORT Other

"Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup"

The First International Consensus Meeting makes the monospecific DAT a required step, which is why it heads this entry's diagnostic list.

Cold agglutinin titer at 4 degrees Celsius

A titer of at least 64 at 4 degrees Celsius is the conventional diagnostic threshold, though the cutoff is debated and thermal amplitude carries more prognostic information.

Results: Titer of 64 or greater at 4 degrees Celsius.

Show evidence (1 reference)

PMID:41994904 SUPPORT Human Clinical

"A definite diagnosis requires a cold antibody titer of ≥ 64 at 4°C as well, although this cutoff is debated."

Gives the threshold and records the authors' own reservation about it, which is what this entry's description states.

Bone marrow biopsy with flow cytometry and clonality testing

Establishes the underlying clonal B-cell lymphoproliferative disorder and excludes an overt lymphoma that would reclassify the case as secondary cold agglutinin syndrome. Sensitive ancillary methods matter: in a recent 56-patient series only 11% of confirmed CAD cases met the full WHO-HAEM5 morphological description of CAD-LPD, while 84% showed clonality by ancillary techniques.

Show evidence (2 references)

PMID:41994904 SUPPORT Human Clinical

"Surprisingly, while ancillary methods detected clonality in the majority (84%), only 5 (11%) of 45 CAD cases strictly fulfilled the WHO-HAEM5 morphological description for CAD-LPD. These data imply that sensitive techniques should be used in BM evaluation in CAD."

Directly supports the recommendation for sensitive ancillary clonality testing rather than morphology alone.

PMID:41994904 SUPPORT Human Clinical

"In 10 patients (18%), pathology revision revealed other overt B-cell malignancies leading to a diagnosis of cold agglutinin syndrome."

Shows the discriminating value of expert marrow review: 18% of referred cold-type cases were reclassified as secondary CAS on pathology revision.

📈

Progression

4

Onset

Age: Median age at onset 67 years, range 30-92

A disease of older adults, with a female predominance (male:female ratio 0.55 in the Norwegian cohort).

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"The median age at onset was 67 years (range, 30-92) and the male to female ratio was 0.55."

Source of the age at onset and sex ratio recorded here.

Chronic phase

Hemolysis is chronic and largely stable: most laboratory findings did not change significantly over a median five years of follow-up. Transformation to aggressive lymphoma is uncommon.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"Transformation to aggressive lymphoma occurred in 3.5% during 10 years."

Quantifies the low but nonzero risk of histological transformation of the underlying clone over a decade.

Exacerbation

Two distinct triggers: seasonal cooling, and febrile illness. The febrile trigger is the counterintuitive one, and is attributed to acute-phase repletion of consumed complement rather than to temperature.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"exacerbation of hemolytic anemia during febrile illness in 74%"

Establishes febrile exacerbation as a common rather than exceptional feature of the disease course.

Long-term outcome

Median survival 12.5 years from onset in the Norwegian cohort and 10.6 years in the Mayo series; a Danish registry cohort found excess mortality against matched controls, concentrated in the first five years after diagnosis.

Show evidence (2 references)

PMID:16585012 SUPPORT Human Clinical

"The median survival was 12.5 years from onset."

Source of the Norwegian survival figure.

PMID:31648316 SUPPORT Human Clinical

"Mortality rates 1 and 5 years after diagnosis were 17% and 39% in the CAD group vs 3% and 18% in the comparison cohort, respectively."

Quantifies the excess mortality against matched general-population controls at one and five years.

📊

Prevalence

6

Norway (population-based)

Point Prevalence 1.6 per 100,000 1–9 per 100,000

16 cases per million inhabitants, reported as a national population-based figure.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year."

The Norwegian population-based follow-up study of 86 patients is the source of both the prevalence and the incidence figure recorded here.

Norway (population-based)

Annual Incidence 0.1 per 100,000

1 case per million per year.

Show evidence (1 reference)

PMID:16585012 SUPPORT Human Clinical

"The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year."

Source of the incidence rate recorded here.

Cold-climate regions (Norway and northern Italy)

Point Prevalence 2.0 per 100,000 1–9 per 100,000

20 cases per million in the cold-climate arm of the multinational cohort.

Show evidence (1 reference)

PMID:32374875 SUPPORT Human Clinical

"For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year)."

Source of the cold-climate and warm-climate prevalence and incidence figures recorded in this and the following records.

Warmer-climate regions (multinational cohort)

Point Prevalence 0.5 per 100,000 1–9 per 1,000,000

5 cases per million in the warmer-climate arm of the same cohort.

Show evidence (1 reference)

PMID:32374875 SUPPORT Human Clinical

"For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year)."

Source of the warmer-climate prevalence figure.

Denmark (national patient registry)

Point Prevalence 1.26 per 100,000 1–9 per 100,000

Registry-based figure for 2013; crude incidence in the same year was 0.18 per 100,000 per year.

Show evidence (1 reference)

PMID:31648316 SUPPORT Human Clinical

"For 2013, the most recent year of study, crude incidence of CAD was 0.18 per 100 000 inhabitants per year and prevalence was 1.26 per 100 000 inhabitants."

Danish National Patient Registry figures, derived from administrative coding rather than centrally reviewed diagnoses.

Autoimmune hemolytic anemia cases

Period Prevalence

Not a population rate: the share of all autoimmune hemolytic anemia that is cold agglutinin disease, reported as 15-25%.

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 15%-25% of AIHA cases"

Records CAD's share of the AIHA case mix, which is the denominator relevant to a hematology clinic rather than to a population.

⚖️

Clinical Burden

High

Lifelong transfusion-requiring anemia with seasonal and febrile exacerbations, disabling cold-induced circulatory symptoms in roughly nine of ten patients, elevated thromboembolic risk, and — until sutimlimab — no licensed therapy.

Show evidence (2 references)

PMID:16585012 SUPPORT Human Clinical

"Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%."

In the Norwegian population-based series, circulatory symptoms affected 91% and febrile exacerbation of hemolysis 74%, which is the burden this rating records.

PMID:31648316 SUPPORT Human Clinical

"CAD is a rare illness characterized by increased risk of TEs and mortality."

The Danish registry cohort found excess thromboembolism and excess mortality relative to matched controls, supporting a high burden rating.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Cold Agglutinin Disease:

Cold agglutinin syndrome (secondary)

Overlapping Features Cold agglutinins arising secondary to an identifiable cause: Mycoplasma pneumoniae or Epstein-Barr virus infection, an overt B-cell lymphoma, or another autoimmune disorder. Post-infectious cold agglutinins are typically polyclonal and transient and resolve with the underlying illness; lymphoma-associated ones are monoclonal but are produced by a clinically or radiologically overt neoplasm rather than by the occult marrow clone of primary CAD. Management is directed at the underlying cause, so the distinction changes treatment.

Distinguishing Features

An identifiable underlying infection, lymphoma or autoimmune disease
Polyclonal and transient cold agglutinins in the post-infectious form
Clinically or radiologically overt lymphoma in the malignancy-associated form

Show evidence (2 references)

PMID:42696222 SUPPORT Other

"in infection-associated CAS, the cold agglutinins are typically polyclonal and transient, resolving with the underlying condition, whereas lymphoma-associated CAS is frequently characterized by monoclonal cold agglutinins produced by an underlying clonal B-cell disorder"

Sets out the two forms of secondary CAS and how each differs from primary CAD, which is the basis for excluding them from this entry.

PMID:35687757 SUPPORT Human Clinical

"CAD is distinguished from cold agglutinin syndrome, which is transient and secondary to infections, overt malignant, or autoimmune conditions."

Independent statement of the same distinction, used as a trial exclusion criterion rather than only as a review assertion.

Warm autoimmune hemolytic anemia

Overlapping Features IgG autoantibodies active at 37 degrees Celsius, cleared by Fc receptor-bearing splenic macrophages. The direct antiglobulin test is IgG-positive, corticosteroids and splenectomy work, and there is no cold-induced circulatory syndrome. The mechanistic contrast — spleen and Fc receptor versus liver and complement receptor — is what makes the two diseases respond to different drugs.

Distinguishing Features

IgG-positive direct antiglobulin test rather than C3d-positive
Response to corticosteroids and splenectomy
No cold-induced acrocyanosis or Raynaud-like symptoms

Show evidence (1 reference)

PMID:42696222 SUPPORT Other

"Unlike warm AIHA, which is driven by immunoglobulin G (IgG)-mediated, Fc receptor-dependent splenic clearance, CAD is defined by the convergence of two processes"

States the mechanistic contrast that underlies every one of the distinguishing features listed here.

Paroxysmal cold hemoglobinuria

Overlapping Features A separate cold-reactive, complement-dependent hemolytic anemia mediated by a biphasic IgG Donath-Landsteiner antibody with anti-P specificity, causing predominantly intravascular hemolysis. Classically post-viral and self-limiting in children.

Distinguishing Features

Biphasic IgG Donath-Landsteiner antibody rather than a monoclonal IgM agglutinin
Predominantly intravascular rather than hepatic extravascular hemolysis

Show evidence (1 reference)

PMID:25705656 SUPPORT Other

"Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders. The details of complement..."

Places PCH alongside CAD as a complement-dependent cold-reactive anemia while stating that the complement mechanisms differ, which is why it is a differential rather than a subtype.

📊

Related Datasets

1

OncoScan CNV Assay (Thermo Fisher Scientific/Affymetrix) data for 13 cold agglutinin disease samples geo:GSE140415

Copy-number profiling of 13 primary cold agglutinin disease samples by SNP array. Trisomy 3 or partial 3q was present in 12 of 13 cases, and trisomy 12 or trisomy 18 (never both) in 9 of 13 — the cytogenetic counterpart of the recurrent somatic mutation profile recorded in this entry's `genetic:` section.

human MICROARRAY n=13 OncoScan CNV Assay (Thermo Fisher...

The only DIRECT candidate returned by `just discover-datasets Cold_Agglutinin_Disease`; the eleven GENE_ONLY candidates were rejected on relevance triage, since they matched on KMT2D, CARD11 or CXCR4 in unrelated diseases (B-cell lymphoma, colorectal cancer, HIV host factors, neurodevelopmental disorders) rather than on cold agglutinin disease.

Show evidence (1 reference)

GEO:GSE140415 SUPPORT Human Clinical

"In 12/13 cases complete or partial trisomy 3/3q was detected."

The repository's own summary reports near-universal trisomy 3/3q in primary CAD samples, which is the finding this dataset record is curated for.

🔬

Clinical Trials

6

NCT03347396 PHASE_III COMPLETED

CARDINAL, a phase 3 open-label single-arm study of intravenous sutimlimab in patients with primary cold agglutinin disease and a recent history of transfusion. Thirteen of 24 patients (54%) met the composite primary endpoint; classical-pathway activity was rapidly inhibited and hemolysis halted.

Target Phenotypes: Chronic complement-mediated hemolytic anemia HP:0001878 Fatigue HP:0012378

Show evidence (2 references)

clinicaltrials:NCT03347396 SUPPORT Other

"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 registry record establishing the trial's population and primary objective.

PMID:33826820 SUPPORT Human Clinical

"A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point."

Primary endpoint result as published.

NCT03347422 PHASE_III COMPLETED

CADENZA, a phase 3 randomized double-blind placebo-controlled study of sutimlimab in patients with primary cold agglutinin disease without a recent transfusion history. Sixteen of 22 patients (73%) on sutimlimab met the composite primary endpoint versus 3 of 20 (15%) on placebo. This is the controlled evidence that the classical complement pathway is the causal effector arm of the disease.

Target Phenotypes: Chronic complement-mediated hemolytic anemia HP:0001878 Fatigue HP:0012378

Show evidence (2 references)

clinicaltrials:NCT03347422 SUPPORT Other

"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 registry record establishing the trial's population and primary objective.

PMID:35687757 SUPPORT Human Clinical

"CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history."

Design of the trial as published.

NCT02689986 PHASE_II COMPLETED

The CAD5 study, a prospective non-randomized international multicenter trial of bendamustine plus rituximab in chronic cold agglutinin disease. Thirty-two of 45 patients (71%) responded, 40% completely; long-term follow-up showed 77% five-year sustained remission.

Target Phenotypes: Chronic complement-mediated hemolytic anemia HP:0001878

Show evidence (2 references)

clinicaltrials:NCT02689986 SUPPORT Other

"Prospective, non-randomized multicenter study on the safety and efficacy of combination therapy with bendamustine and rituximab for chronic cold agglutinin disease."

The registry record establishing the trial's identity, design and intervention.

PMID:28533306 SUPPORT Human Clinical

"In a prospective, nonrandomized multicenter trial, 45 eligible patients received rituximab 375 mg/m2 day 1 and bendamustine 90 mg/m2 days 1 and 2 for 4 cycles at a 28-day interval."

Enrolment and regimen as published.

NCT01303952 PHASE_II COMPLETED

DECADE, an open-label prospective bicentric non-randomized phase 2 trial of the anti-C5 antibody eculizumab in chronic cold agglutinin disease. LDH fell substantially and transfusion independence was gained by 8 of 13 patients, but the hemoglobin gain was modest and cold-induced circulatory symptoms did not change — the trial that established the limits of terminal-complement inhibition in this disease.

Target Phenotypes: Chronic complement-mediated hemolytic anemia HP:0001878

Show evidence (2 references)

clinicaltrials:NCT01303952 SUPPORT Other

"Evaluation of the efficacy and safety of eculizumab in symptomatic or transfusion-dependent patients with untreated or refractory hemolytic cold agglutinin disease"

The registry record establishing the trial's identity, intervention and population.

PMID:30291112 SUPPORT Human Clinical

"Three patients maintained and 8 patients acquired transfusion independence, and 1 patient each showed a reduced or increased transfusion requirement, respectively (P = .0215; exact McNemar's test)."

Transfusion outcome as published.

NCT05096403 PHASE_III COMPLETED

A phase 3 randomized, double-blind, placebo-controlled study of pegcetacoplan, a C3-level complement inhibitor, in primary cold agglutinin disease, completed with 24 participants. This is the most direct available test of the entry's central claim: if C3b opsonization is the dominant effector step, inhibition at C3 should outperform terminal-pathway blockade, which eculizumab showed to be largely ineffective here.

Target Phenotypes: Chronic complement-mediated hemolytic anemia HP:0001878

Show evidence (1 reference)

clinicaltrials:NCT05096403 SUPPORT Other

"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)."

The registry record establishing the population, the comparator and the primary objective.

NCT05086744 PHASE_II TERMINATED

An open-label phase 2 basket study of iptacopan in autoimmune benign haematological disorders, including primary cold agglutinin disease, terminated after enrolling 19 participants. The registry records the reason as a business decision rather than a safety or efficacy signal, which is worth recording because a terminated trial is otherwise easily read as a negative result.

Target Phenotypes: Chronic complement-mediated hemolytic anemia HP:0001878

Show evidence (1 reference)

clinicaltrials:NCT05086744 SUPPORT Other

"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."

The registry record establishing that this basket study covered primary cold agglutinin disease.

{ }

Source YAML

click to show

name: Cold Agglutinin Disease
creation_date: '2026-09-05T18:20:00Z'
category: Autoimmune
categories:
- Acquired
- Clonal B-cell lymphoproliferative disorder
- Complement-mediated disease
parents:
- Autoimmune Hemolytic Anemia
- Hematologic Disease
- B-Cell Lymphoproliferative Disorder
disease_term:
  preferred_term: Primary cold agglutinin disease
  term:
    id: MONDO:0018922
    label: cold agglutinin disease
synonyms:
- CAD
- primary cold agglutinin disease
- chronic cold agglutinin disease
- cold antibody hemolytic anemia
- CAD-associated lymphoproliferative disorder
description: >-
  A chronic, complement-mediated autoimmune hemolytic anemia that arises from a
  low-grade clonal B-cell lymphoproliferative disorder of the bone marrow. The
  clone secretes a monoclonal IgM cold agglutinin — almost always kappa-restricted
  and IGHV4-34-encoded, with anti-I specificity — that binds erythrocytes in the
  cooler acral circulation, agglutinates them, and fixes C1. Because IgM is a
  potent activator of the classical pathway, C3b is deposited on the red cell
  surface; when the cell returns to core temperature the IgM elutes but the C3b
  remains, so the dominant destruction is extravascular, C3b-mediated and hepatic
  (Kupffer cell) rather than splenic and Fc-mediated. Terminal-pathway completion
  to C5b-9 adds a smaller intravascular component, mainly during acute
  exacerbations. Agglutination itself, independent of hemolysis, produces
  cold-induced acrocyanosis and Raynaud-like circulatory symptoms. This dual
  clonal-plus-complement architecture is why corticosteroids and splenectomy fail
  in this disease, why B-cell-directed therapy (rituximab, bendamustine) works,
  and why classical-pathway inhibition at C1s (sutimlimab) works. Primary CAD is a
  distinct entity from secondary cold agglutinin syndrome (CAS), which follows
  Mycoplasma pneumoniae or Epstein-Barr virus infection or accompanies an overt
  lymphoma.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016450
      label: autoimmune hemolytic anemia, cold type
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    notes: >-
      The MONDO parent of MONDO:0018922. Recorded as a cross-reference only:
      the cold-type AIHA class also covers secondary cold agglutinin syndrome
      and paroxysmal cold hemoglobinuria, which this entry deliberately
      excludes.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:42696222
      reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 15%-25% of AIHA cases and is characterized by two interdependent features: a clonal bone marrow B-cell lymphoproliferative disorder producing monoclonal immunoglobulin M (IgM)-κ autoantibodies, and complement-mediated hemolysis driven by the classical pathway."
      explanation: >-
        CAD is simultaneously a hemolytic anemia and a clonal bone-marrow
        lymphoproliferative disorder, both of which Harrison's covers in the
        Oncology and Hematology Part.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Secondary placement: the effector arm is an autoantibody-initiated,
      classical-complement-pathway disease.
    evidence:
    - reference: PMID:25705656
      reference_title: "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autoimmune hemolytic anemia (AIHA) is a collective term for several diseases characterized by autoantibody-initiated destruction of red blood cells (RBCs)."
      explanation: >-
        Frames the disease family, CAD included, as autoantibody-initiated
        immune destruction, which is the immunologic axis this second Part
        assignment records.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Lifelong transfusion-requiring anemia with seasonal and febrile
    exacerbations, disabling cold-induced circulatory symptoms in roughly nine
    of ten patients, elevated thromboembolic risk, and — until sutimlimab — no
    licensed therapy.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%."
    explanation: >-
      In the Norwegian population-based series, circulatory symptoms affected
      91% and febrile exacerbation of hemolysis 74%, which is the burden this
      rating records.
  - reference: PMID:31648316
    reference_title: "Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAD is a rare illness characterized by increased risk of TEs and mortality."
    explanation: >-
      The Danish registry cohort found excess thromboembolism and excess
      mortality relative to matched controls, supporting a high burden rating.

pathophysiology:
- name: Somatic KMT2D and CARD11 Mutation in the CAD B-Cell Clone
  description: >-
    The bone-marrow clone that underlies CAD carries recurrent somatic lesions,
    most consistently loss-of-function mutation of the histone
    methyltransferase gene KMT2D and gain-of-function mutation of the NF-kB
    scaffold gene CARD11, together with trisomies of chromosomes 3, 12 and 18.
    These are somatic events in the neoplastic B cells, not germline
    predisposition alleles, and their combination is one of the features that
    separates the CAD clone from lymphoplasmacytic lymphoma, in which MYD88
    L265P is near-universal and absent here.
  biological_scale: MOLECULAR
  genetic_context:
    genes:
    - preferred_term: KMT2D
      term:
        id: hgnc:7133
        label: KMT2D
    - preferred_term: CARD11
      term:
        id: hgnc:16393
        label: CARD11
    variant_origin: SOMATIC
    functional_impact: >-
      KMT2D carries loss-of-function mutations and CARD11 gain-of-function
      mutations; the two impacts differ, so no single
      functional_impact_category value describes the pair.
    description: >-
      Recurrent somatic mutations in the clonal B cells of primary cold
      agglutinin disease.
  downstream:
  - target: Clonal Bone Marrow B-Cell Lymphoproliferation
    causal_link_type: DIRECT
    description: >-
      CARD11 gain of function activates NF-kB signalling and KMT2D loss removes
      an epigenetic brake, driving the clonal expansion.
    evidence:
    - reference: PMID:38133636
      reference_title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KMT2D and CARD11 genes are recurrently mutated in CAD B cells. KMT2D has loss-of-function mutations, and CARD11 has gain-of-function mutations"
      explanation: >-
        States the direction of each lesion in the clonal B cells, which is what
        makes this an oncogenic driver edge rather than a bystander association.
  evidence:
  - reference: PMID:42117133
    reference_title: "A diagnostic pitfall in cold agglutinin disease: KMT2D-mutated CAD-associated lymphoproliferative disorder with a CLL-like immunophenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively"
    explanation: >-
      Quantifies how often each somatic lesion is found in CAD patients,
      establishing them as recurrent rather than anecdotal.
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of recurrent somatic mutations in the KMT2D and CARD11 genes and trisomies of chromosomes 3, 12, and 18 in a proportion of CAD patients further strengthens the notion of it being a distinct entity"
    explanation: >-
      Places the somatic mutation profile alongside the recurrent trisomies and
      ties it to the recognition of CAD-LPD as its own entity.

- name: Downregulation of Complement Receptor 1 on Clonal B Cells
  description: >-
    RNA sequencing and flow cytometry of sorted clonal CAD B cells show
    complement receptor 1 (CR1/CD35) to be the most strongly downregulated gene
    relative to IgM+ memory B cells from healthy donors. CR1 is a negative
    regulator of B-cell activation and differentiation, so its loss is proposed
    to lower the activation threshold of the CAD clone and increase its
    antibody output. The functional consequence is inferred from CR1 biology
    rather than demonstrated in CAD, so this node is provisional.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: clonal CAD B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Clonal Bone Marrow B-Cell Lymphoproliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed, not demonstrated: loss of an inhibitory receptor is expected to
      favour proliferation and immunoglobulin secretion by the clone.
    evidence:
    - reference: PMID:38133636
      reference_title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells."
      explanation: >-
        The authors state the causal step as a hypothesis ("may increase"), which
        is why this edge is typed as indirect and the node marked hypothetical.
  evidence:
  - reference: PMID:38133636
    reference_title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells"
    explanation: >-
      Quantifies the expression difference measured by RNA sequencing of sorted
      clonal B cells against IgM+ memory B cells from healthy controls.

- name: Clonal Bone Marrow B-Cell Lymphoproliferation
  description: >-
    A small, low-grade clonal B-cell population sits in the bone marrow as
    circumscribed intraparenchymatous nodules of monotonous CD20+, surface
    IgM+, IgD+, CD27+, CD23-negative B cells, with a limited number of
    monotypic IgM+ plasma cells scattered diffusely outside the nodules. It
    lacks plasmacytoid cytology, the plasma-cell transcription factors MUM1,
    XBP1 and BLIMP1, and the MYD88 L265P mutation, which is what distinguishes
    CAD-associated lymphoproliferative disorder from lymphoplasmacytic lymphoma
    and Waldenstrom macroglobulinemia. The WHO fifth edition recognises it as a
    distinct entity. This clone is the source of the pathogenic cold agglutinin
    and the target of B-cell-directed therapy.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: clonal CD20+ IgM+ CD27+ marrow B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: monotypic IgM+ kappa plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: clonal B cell proliferation in the bone marrow
    term:
      id: GO:0042100
      label: B cell proliferation
    modifier: INCREASED
  downstream:
  - target: Monoclonal IgM Cold Agglutinin Production
    causal_link_type: DIRECT
    description: >-
      The clone and its associated monotypic plasma cells secrete the
      monoclonal IgM that is the pathogenic autoantibody.
    evidence:
    - reference: PMID:42696222
      reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "a low-grade clonal B-cell lymphoproliferative disorder (B-LPD) of the bone marrow that secretes a monoclonal immunoglobulin M (IgM) cold agglutinin"
      explanation: >-
        States the secretory relationship between the marrow clone and the cold
        agglutinin, which is the edge being asserted here.
  evidence:
  - reference: PMID:24143001
    reference_title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype."
    explanation: >-
      The defining histology and immunophenotype of the CAD marrow clone in the
      54-patient Nordic pathology series.
  - reference: PMID:24143001
    reference_title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases)."
    explanation: >-
      Absence of MYD88 L265P in every tested case is the negative finding that
      separates this clone from lymphoplasmacytic lymphoma.
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The 2022 World Health Organization classification formally recognized CAD-associated lymphoproliferative disease as a distinct entity from lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinemia (WM)"
    explanation: >-
      Records the nosological status of the clone as a WHO-recognised entity,
      not merely an autoantibody-producing cell population.
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary CAD represents a spectrum of clonal lymphoproliferative bone marrow disorders, in most cases with morphological signs of lymphoma."
    explanation: >-
      The population-based Norwegian series reached the same conclusion from 86
      unselected patients.

- name: Monoclonal IgM Cold Agglutinin Production
  description: >-
    The secreted paraprotein is a monoclonal IgM, kappa-restricted in about 94%
    of patients and encoded by IGHV4-34 with somatic hypermutation, whose
    variable region recognises the carbohydrate blood-group antigen I on the
    erythrocyte surface. Binding is temperature-dependent: affinity is maximal
    well below 37 degrees Celsius, and the thermal amplitude — the highest
    temperature at which the antibody still agglutinates — rather than the titre
    alone determines whether an individual cold agglutinin is pathogenic in
    vivo.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: cold-dependent binding of IgM to the erythrocyte I antigen
    term:
      id: GO:0003823
      label: antigen binding
  biological_processes:
  - preferred_term: monoclonal IgM production by the CAD clone
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  downstream:
  - target: Cold-Dependent Erythrocyte Agglutination
    causal_link_type: DIRECT
    description: >-
      Pentameric IgM has ten binding sites and can bridge adjacent red cells
      once bound at low temperature.
    evidence:
    - reference: PMID:41994904
      reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition, the pentameric IgM bridges the distance between RBCs, causing hemagglutination and circulatory symptoms in the acral areas"
      explanation: >-
        Names the physical mechanism — pentameric bridging — by which bound IgM
        becomes agglutination.
  evidence:
  - reference: PMID:24143001
    reference_title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I."
    explanation: >-
      Establishes both the IGHV4-34 gene usage and the anti-I specificity of the
      pathogenic antibody.
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%."
    explanation: >-
      Quantifies the isotype and light-chain restriction across an unselected
      national cohort, supporting "almost always IgM-kappa".
  - reference: PMID:10530415
    reference_title: "Clinical immunology of chronic cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had V(H)4-34 encoded IgM kappa cold agglutinins (CA) in high titre."
    explanation: >-
      An independent clinical-immunology series in which every patient's cold
      agglutinin was VH4-34-encoded IgM kappa.
  - reference: PMID:10530415
    reference_title: "Clinical immunology of chronic cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data also indicate that both CA titre and thermal amplitude are important characteristics when predicting complement activation and clinical course in CAD."
    explanation: >-
      Supports the statement that thermal amplitude, not titre alone, governs
      whether the antibody is pathogenic.

- name: Cold-Dependent Erythrocyte Agglutination
  description: >-
    In the cooler acral circulation — fingers, toes, ears, nose — the monoclonal
    IgM binds the I antigen and cross-links red cells into agglutinates. This
    step is purely antibody-mediated and requires no complement: it is the
    origin of the cold-induced circulatory symptoms, and it is reversible, since
    the agglutinates disperse as the blood is rewarmed centrally.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: IgM-mediated erythrocyte-erythrocyte adhesion
    term:
      id: GO:0007155
      label: cell adhesion
    modifier: INCREASED
  downstream:
  - target: Classical Complement Pathway Activation on the Erythrocyte Surface
    causal_link_type: DIRECT
    description: >-
      The bound antigen-IgM complex is the trigger that recruits C1 to the red
      cell surface.
    evidence:
    - reference: PMID:35687757
      reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The antigen-IgM antibody complex, a potent trigger of the classical complement pathway, binds to the C1 complement complex, resulting in activation of C1s (a C1 complex serine protease), which activates C2 and C4, and in turn generates C3 convertase, resulting in cleavage of C3 into C3a and C3b."
      explanation: >-
        Traces the step from bound IgM to C1 engagement, which is exactly the
        edge asserted here.
  - target: Acral Microcirculatory Obstruction
    causal_link_type: DIRECT
    description: >-
      The same agglutinates physically impede flow through acral capillaries,
      independently of any complement activation.
    evidence:
    - reference: PMID:35687757
      reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "non-complement-mediated symptoms include transient, cold-induced agglutination-mediated circulatory symptoms, such as acrocyanosis and Raynaud phenomenon"
      explanation: >-
        Attributes the circulatory symptoms to agglutination specifically and
        marks them as not complement-mediated, which is why this branch of the
        graph leaves the complement chain here.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In CAD, immunoglobulin M (IgM) autoantibodies (cold agglutinins) preferentially bind to the “I” antigen on erythrocytes at temperatures ≤37°C and may result in erythrocyte agglutination."
    explanation: >-
      States the temperature dependence of binding and that agglutination is its
      direct consequence.
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cold agglutinins are immunoglobulin heavy chain (IGH) gene V4‐34 encoded immunoglobulin M kappa (IgMκ), with optimal binding below body temperatures."
    explanation: >-
      Confirms that optimal binding occurs below core body temperature, which is
      what confines agglutination to the acral circulation.

- name: Classical Complement Pathway Activation on the Erythrocyte Surface
  description: >-
    IgM is the most efficient physiological activator of the classical pathway.
    The surface-bound antigen-IgM complex recruits C1, C1s cleaves C4 and C2,
    and the assembled C4b2a C3 convertase cleaves C3. Because complement
    activation proceeds at core temperature once the antibody has bound in the
    periphery, hemolysis in CAD continues year-round even though the antibody
    binding step is cold-dependent. Chronic low-grade consumption of C3 and C4
    is measurable in the serum of many patients.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: classical complement pathway activation on the red cell surface
    term:
      id: GO:0006958
      label: complement activation, classical pathway
    modifier: INCREASED
  downstream:
  - target: C3b Opsonization of Erythrocytes
    causal_link_type: DIRECT
    description: >-
      C3 convertase activity deposits C3b covalently on the erythrocyte
      membrane.
    evidence:
    - reference: PMID:41994904
      reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sensitization by IgM and deposition of complement component C3b on RBCs activates the classical complement cascade, resulting in extravascular hemolysis"
      explanation: >-
        Links IgM sensitization to C3b deposition on the red cell, the step this
        edge encodes.
  evidence:
  - reference: PMID:27913484
    reference_title: "Cold agglutinin disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b."
    explanation: >-
      States that hemolysis in CAD is wholly complement-dependent and runs
      through the classical pathway, which is the claim of this node.
  - reference: PMID:10530415
    reference_title: "Clinical immunology of chronic cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50. Such data indicate that patients with CAD experience a continuous low-grade complement consumption."
    explanation: >-
      Measured C3/C4 depletion is the in-vivo footprint of continuous classical
      pathway consumption asserted by this node.

- name: Acute-Phase Complement Repletion During Febrile Illness
  description: >-
    Complement components are acute-phase reactants. During infection or other
    febrile illness their production rises, restoring the substrate that chronic
    low-grade consumption had depleted and transiently increasing the hemolytic
    capacity of an unchanged cold agglutinin. This is the mechanistic
    explanation for the characteristic paradox that CAD hemolysis worsens during
    fever rather than improving with the higher body temperature.
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Classical Complement Pathway Activation on the Erythrocyte Surface
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Increased availability of complement components raises the achievable rate
      of classical-pathway activation on already-sensitized red cells.
    evidence:
    - reference: PMID:10530415
      reference_title: "Clinical immunology of chronic cold agglutinin disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results indicate that some patients with CAD have a relative deficit of complement in their serum and that an increase of complement production occurs during an acute phase reaction which enhances haemolysis."
      explanation: >-
        States the proposed sequence — acute-phase rise in complement, then
        enhanced hemolysis — that this edge encodes.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%."
    explanation: >-
      Establishes that febrile exacerbation is common (74%) and therefore a real
      feature of the disease, not an anecdote.

- name: C3b Opsonization of Erythrocytes
  description: >-
    C3b is deposited covalently on the erythrocyte surface. When the cell
    circulates back to core temperature the IgM dissociates, but the covalently
    bound C3b does not — which is why the direct antiglobulin test in CAD is
    strongly positive for C3d (the degradation remnant of C3b) and negative or
    only weakly positive for IgG. The opsonized cell is now marked for
    phagocytic clearance and, if the cascade continues, for terminal-pathway
    lysis.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: C3b opsonization of the erythrocyte membrane
    term:
      id: GO:0008228
      label: opsonization
    modifier: INCREASED
  downstream:
  - target: Hepatic Extravascular Hemolysis
    causal_link_type: DIRECT
    description: >-
      C3b-opsonized red cells are recognised and phagocytosed by hepatic
      macrophages, the dominant route of destruction.
    evidence:
    - reference: PMID:42696222
      reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The C3b opsonization of erythrocytes leads to their clearance by Kupffer cells in the liver, which predominantly produces extravascular hemolysis."
      explanation: >-
        Names both the effector cell and the site, which is the substance of
        this edge.
  - target: Terminal Complement Pathway Assembly and Membrane Attack Complex Formation
    causal_link_type: DIRECT
    description: >-
      Dense C3b deposition builds C5 convertase and drives the cascade on to
      C5b-9; this is the minority route and occurs mainly during exacerbations.
    evidence:
    - reference: PMID:35687757
      reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although hemolysis is primarily driven by classical complement and extravascular hemolysis in CAD, severe disease may see further, terminal complement activation, with increased C3b deposition contributing to C5 convertase formation, membrane attack complex production, and intravascular hemolysis."
      explanation: >-
        States the conditional progression from C3b deposition to C5 convertase
        and MAC, and marks it as the lesser pathway.
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis rests on evidence of hemolysis, a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG), a cold agglutinin titer ≥ 1:64, and bone marrow evaluation; thermal amplitude can predict clinical severity better than titer alone."
    explanation: >-
      The C3d-positive, IgG-negative serological signature is the direct
      clinical readout of C3b deposition without persistent IgG coating.

- name: Hepatic Extravascular Hemolysis
  description: >-
    Kupffer cells, the resident macrophages of the liver sinusoids, express
    complement receptors that bind C3b-opsonized erythrocytes and phagocytose
    them. This hepatic, complement-receptor-driven clearance is the dominant
    mechanism of red cell destruction in CAD, and it is the reason splenectomy
    fails: unlike warm autoimmune hemolytic anemia, where IgG-coated cells are
    removed by Fc-receptor-bearing splenic red-pulp macrophages, the effector
    organ here is the liver.
  biological_scale: TISSUE
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  cell_types:
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  - preferred_term: C3b-opsonized erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: erythrophagocytosis by hepatic macrophages
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: INCREASED
  - preferred_term: hepatic clearance of opsonized erythrocytes
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  downstream:
  - target: Chronic Hemolytic Anemia
    causal_link_type: DIRECT
  - target: Prothrombotic State of Chronic Complement-Mediated Hemolysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic complement activation and hemolysis are associated with excess
      venous and arterial thrombosis; the intermediate steps are not
      established.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C3b deposition on erythrocytes results in extravascular hemolysis in the liver, the predominant mechanism of erythrocyte destruction in CAD."
    explanation: >-
      Identifies hepatic extravascular hemolysis as the predominant destruction
      mechanism, which is the claim of this node.
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it explains why therapies effective in warm AIHA, such as corticosteroids and splenectomy, are largely ineffective in CAD, where hemolysis is complement-driven and predominantly hepatic rather than Fc-mediated and splenic"
    explanation: >-
      Makes the liver-versus-spleen contrast explicit and connects it to the
      therapeutic consequence recorded in this entry's treatments.

- name: Terminal Complement Pathway Assembly and Membrane Attack Complex Formation
  description: >-
    When C3b density is high enough, C5 convertase forms and the terminal
    pathway proceeds to the C5b-9 membrane attack complex on the erythrocyte
    surface. Progression this far is limited in CAD because CD55 and CD59
    remain intact on the red cell, unlike in paroxysmal nocturnal
    hemoglobinuria, so the terminal pathway contributes a minority of hemolysis
    and does so mainly during acute exacerbations. This is also why C5
    inhibition alone gives only a modest hemoglobin response in CAD.
  biological_scale: MOLECULAR
  conforms_to: "complement_dysregulation#C5 Convertase Activation and Terminal Pathway Assembly"
  biological_processes:
  - preferred_term: membrane attack complex assembly on the erythrocyte
    term:
      id: GO:0001905
      label: activation of membrane attack complex
    modifier: INCREASED
  downstream:
  - target: Intravascular Hemolysis
    causal_link_type: DIRECT
    description: >-
      Completed C5b-9 pores lyse the red cell within the circulation, releasing
      free hemoglobin.
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complete progression to the membrane attack complex (C5b-9) causes intravascular hemolysis, which occurs mainly during acute exacerbations."
    explanation: >-
      States both the effect of terminal-pathway completion and its restriction
      to exacerbations, which is what makes this the minority branch.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "because of intact CD55- and CD59-mediated regulation in CAD"
    explanation: >-
      Gives the reason terminal-pathway lysis stays limited in CAD, which is why
      this node is modelled as a minority branch rather than the main route.
  notes: >-
    Conformance is declared against the terminal node of
    `complement_dysregulation`, not its trigger node. That module scopes itself
    to alternative-pathway regulator failure and states explicitly that
    classical-pathway-initiated disease enters downstream, at the node its
    curated content actually models.

- name: Intravascular Hemolysis
  description: >-
    Lysis of erythrocytes within the vasculature releases free hemoglobin, which
    saturates haptoglobin and appears in the urine as hemoglobinuria. In CAD
    this accounts for a minority of red cell loss and is most evident during
    cold- or infection-triggered exacerbations.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: complement-mediated lysis of erythrocytes
    term:
      id: GO:0097278
      label: complement-dependent cytotoxicity
    modifier: INCREASED
  downstream:
  - target: Chronic Hemolytic Anemia
    causal_link_type: DIRECT
  - target: Hemoglobinuria
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients were required to have symptomatic disease within 3 months of screening, defined as one or more of the following: symptomatic anemia, acrocyanosis, Raynaud phenomenon, hemoglobinuria, disabling circulatory symptoms, and/or major adverse vascular event, including thrombosis."
    explanation: >-
      Hemoglobinuria is one of the recognised disease manifestations used to
      define symptomatic CAD in a phase 3 trial, which is the clinical signature
      of the intravascular component.

- name: Chronic Hemolytic Anemia
  description: >-
    Destruction of erythrocytes outstrips compensatory erythropoiesis, so
    hemoglobin falls. Mean hemoglobin at presentation is around 9 g/dL, but a
    quarter of patients are below 8 g/dL and about half require red-cell
    transfusion at some point. The anemia is chronic and year-round rather than
    purely seasonal, because the complement-mediated effector arm operates at
    core temperature.
  biological_scale: ORGANISM
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Hemolytic Anemia"
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
    modifier: ABNORMAL
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
  - target: Fatigue
    causal_link_type: DIRECT
  - target: Jaundice
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL."
    explanation: >-
      Quantifies the severity distribution of the anemia across 232 patients in
      five countries.
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least 51% had received red blood cell transfusions. The mean initial hemoglobin level was 9.2 g/dL (range, 4.5-15.6)"
    explanation: >-
      Independent population-based confirmation of the hemoglobin level and of
      how often the anemia becomes transfusion-dependent.

- name: Acral Microcirculatory Obstruction
  description: >-
    Agglutinated red cells impede flow through the small vessels of fingers,
    toes, ears and nose on cold exposure, producing acrocyanosis, Raynaud-like
    phenomena and livedo reticularis. This branch of the mechanism is purely
    agglutination-driven: it does not require complement, and complement
    inhibitors therefore do not relieve it — a distinction with direct
    therapeutic consequences, since a patient whose dominant complaint is
    circulatory rather than hemolytic will not benefit from sutimlimab.
  biological_scale: TISSUE
  downstream:
  - target: Acrocyanosis
    causal_link_type: DIRECT
  - target: Raynaud Phenomenon
    causal_link_type: DIRECT
  - target: Livedo Reticularis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Importantly, these symptoms are not complement-mediated and are therefore not addressed by complement inhibitors, a distinction with direct therapeutic relevance."
    explanation: >-
      Establishes that this branch is independent of the complement chain, which
      is why it is modelled as a separate limb of the graph.
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cold-induced circulatory symptoms in 91%"
    explanation: >-
      Gives the frequency of this branch in an unselected national cohort.

- name: Prothrombotic State of Chronic Complement-Mediated Hemolysis
  description: >-
    Patients with CAD have a higher incidence of venous thromboembolism, and of
    arterial events, than matched controls. Complement-driven endothelial
    activation is the proposed mediator, but the intermediate steps have not
    been established in CAD, so this node records an epidemiological association
    with a hypothesised mechanism rather than a demonstrated causal chain.
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  downstream:
  - target: Venous Thromboembolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31648316
    reference_title: "Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk of TEs was higher in the CAD patient cohort than in the comparison cohort at 1 year (7.2% of CAD patients had TEs vs 1.9% of comparisons)"
    explanation: >-
      Quantifies the excess thromboembolic risk against a matched general
      population cohort.
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complement-driven endothelial activation is thought to contribute to this prothrombotic state."
    explanation: >-
      The proposed mechanism, stated by the source as a belief rather than an
      established finding, which is why this node is marked hypothetical.

phenotypes:
- name: Anemia
  category: Hematological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  description: >-
    Chronic anemia of hemolytic type, mean hemoglobin around 9 g/dL, with a
    substantial minority below 8 g/dL and about half of patients needing
    transfusion at some point in their course.
  evidence:
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL."
    explanation: >-
      Anemia was present in every patient of this 232-patient multinational
      cohort, with the quoted distribution of severity.

- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  description: >-
    Profound fatigue out of proportion to the hemoglobin level, and one of the
    fastest-responding endpoints to complement inhibition.
  evidence:
  - reference: PMID:33826820
    reference_title: "Sutimlimab in Cold Agglutinin Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study."
    explanation: >-
      Fatigue was severe enough at baseline in the CARDINAL cohort to permit a
      clinically meaningful reduction, and it improved within a week of
      complement blockade.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint."
    explanation: >-
      Confirms in a randomized placebo-controlled setting that fatigue is a
      measurable, disease-attributable feature rather than a nonspecific
      complaint.

- name: Acrocyanosis
  category: Vascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cold-induced acrocyanosis of fingers, toes, ears and nose
    term:
      id: HP:0001063
      label: Acrocyanosis
    temporality: RECURRENT
  description: >-
    Bluish discoloration of the extremities on cold exposure, caused by
    agglutinate-induced stasis in the acral microcirculation rather than by
    hemolysis. It was the single most common presenting symptom in the Mayo
    Clinic series.
  evidence:
  - reference: PMID:23757733
    reference_title: "Cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptom was acrocyanosis (n = 39 [44%]), and many had symptoms triggered by cold (n = 35 [39%])"
    explanation: >-
      Gives both the frequency (44% of 89 patients) and the rank of acrocyanosis
      among presenting symptoms in a single-institution cohort.

- name: Raynaud Phenomenon
  category: Vascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Raynaud-like cold-induced digital ischemia
    term:
      id: HP:0030880
      label: Raynaud phenomenon
    temporality: RECURRENT
  description: >-
    Cold-triggered episodic digital pallor, cyanosis and pain. In CADENZA it was
    present at baseline in 22.7% of the sutimlimab arm and 15.0% of the placebo
    arm.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine patients (40.9%) in the sutimlimab group vs 4 patients (20.0%) in the placebo group had acrocyanosis, and 5 patients (22.7%) vs 3 patients (15.0%), respectively, experienced Raynaud phenomenon."
    explanation: >-
      Reports baseline prevalence of Raynaud phenomenon in both arms of a phase
      3 CAD cohort, supporting an occasional-frequency assignment.

- name: Livedo Reticularis
  category: Dermatologic
  phenotype_term:
    preferred_term: Livedo reticularis
    term:
      id: HP:0033505
      label: Livedo reticularis
  description: >-
    Net-like violaceous mottling of the skin, one of the cold-induced
    circulatory manifestations of erythrocyte agglutination.
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cold-induced circulatory symptoms—acrocyanosis of the fingers, toes, ears, and nose, Raynaud-like phenomena, and livedo reticularis—are reported by the great majority of patients (approximately 90%) and can substantially impair daily activities"
    explanation: >-
      Lists livedo reticularis among the cold-induced circulatory
      manifestations; the 90% figure covers the group as a whole, not livedo
      individually, so no frequency is asserted for this phenotype.

- name: Jaundice
  category: Hepatic
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  description: >-
    Unconjugated hyperbilirubinemia from accelerated hemoglobin catabolism.
    Bilirubin is sensitive enough to hemolytic rate that it normalized within
    one to three weeks of starting sutimlimab in both pivotal trials.
  evidence:
  - reference: PMID:33826820
    reference_title: "Sutimlimab in Cold Agglutinin Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean bilirubin levels normalized by week 3."
    explanation: >-
      Bilirubin was abnormal at baseline across the CARDINAL cohort and
      normalized on treatment, establishing hyperbilirubinemia as a
      disease-attributable feature.

- name: Hemoglobinuria
  category: Renal
  phenotype_term:
    preferred_term: Hemoglobinuria
    term:
      id: HP:0003641
      label: Hemoglobinuria
  description: >-
    Free hemoglobin in the urine, the clinical marker of the intravascular
    (C5b-9-mediated) component of hemolysis. Typically episodic, during
    exacerbations.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients were required to have symptomatic disease within 3 months of screening, defined as one or more of the following: symptomatic anemia, acrocyanosis, Raynaud phenomenon, hemoglobinuria, disabling circulatory symptoms, and/or major adverse vascular event, including thrombosis."
    explanation: >-
      Hemoglobinuria is enumerated among the recognised symptomatic
      manifestations of CAD in the CADENZA eligibility definition.

- name: Venous Thromboembolism
  category: Vascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Venous thromboembolism
    term:
      id: HP:0004936
      label: Venous thrombosis
  description: >-
    Excess venous thrombotic events relative to matched controls, reported at
    7.2% within one year of diagnosis in a Danish registry cohort.
  evidence:
  - reference: PMID:31648316
    reference_title: "Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk of TEs was higher in the CAD patient cohort than in the comparison cohort at 1 year (7.2% of CAD patients had TEs vs 1.9% of comparisons)"
    explanation: >-
      Supplies both the presence of the phenotype and the quantitative excess
      over a matched comparison cohort, which is what the OCCASIONAL band
      records.
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAD seems to be associated with a slightly increased risk of venous thrombosis."
    explanation: >-
      Independent multinational cohort reaching the same qualitative conclusion,
      with the authors' own hedge preserved.

histopathology:
- name: Nodular Clonal B-Cell Infiltrate of the Bone Marrow
  description: >-
    The marrow lesion of CAD-associated lymphoproliferative disorder is a small,
    circumscribed, intraparenchymatous nodular infiltrate of monotonous
    monoclonal B cells, typically occupying only about a tenth of marrow
    cellularity. It resembles marginal zone lymphoma architecturally while
    lacking extramedullary disease.
  frequency: Present in about three quarters of CAD marrows examined in dedicated series.
  finding_term:
    preferred_term: nodular clonal B-cell infiltrate of bone marrow
    term:
      id: NCIT:C199388
      label: Bone Marrow Clonal B-Cell Lymphocytic Infiltrate
  evidence:
  - reference: PMID:24143001
    reference_title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype."
    explanation: >-
      Gives the architecture, the proportion of patients showing it, the degree
      of marrow involvement, and the immunophenotype, in the largest dedicated
      marrow series.
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority (74%) displayed a small homogeneous lymphoid infiltration, characterized by nodular B‐cell aggregates strongly resembling MZL, but without extramedullary disease."
    explanation: >-
      Independently reports the same nodular pattern and its frequency, and
      names the marginal zone lymphoma resemblance that makes CAD marrows liable
      to misclassification.

- name: Monotypic Plasma Cells Outside the Lymphoid Nodules
  description: >-
    Monoclonal IgM-positive plasma cells are present but sit outside the B-cell
    nodules, scattered through the marrow, and the infiltrating B cells
    themselves show no plasmacytoid differentiation. This spatial separation is
    the morphological argument that the lesion is not lymphoplasmacytic
    lymphoma.
  diagnostic: true
  evidence:
  - reference: PMID:24143001
    reference_title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow."
    explanation: >-
      Establishes that the plasma cells are extranodular, which is the
      observation that separates this lesion from the lymphoplasmacytic pattern.
  - reference: PMID:24143001
    reference_title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma."
    explanation: >-
      The authors' own summary of the four features that make this a distinct
      entity, which is the claim the entry makes elsewhere about CAD-LPD.
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of monotypic plasma cells was consistent with LPL, but key morphological findings diagnostic of LPL were lacking, including paratrabecular growth and lymphoplasmacytoid cells."
    explanation: >-
      Names the two LPL features that are absent, which is what the
      extranodular plasma-cell pattern has to be read against.

- name: Strict WHO-HAEM5 CAD-LPD Morphology Is Met by a Minority
  description: >-
    The WHO-HAEM5 morphological description of CAD-LPD is a desirable rather
    than an essential criterion, and in practice most CAD marrows do not meet it
    in full even when clonality is demonstrable by other means. Treating the
    strict morphological picture as a diagnostic requirement would therefore
    misclassify the majority of genuine cases, which is why sensitive ancillary
    techniques are recommended alongside morphology.
  diagnostic: false
  evidence:
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, while ancillary methods detected clonality in the majority (84%), only 5 (11%) of 45 CAD cases strictly fulfilled the WHO-HAEM5 morphological description for CAD-LPD."
    explanation: >-
      Quantifies the gap between demonstrable clonality and strict WHO-HAEM5
      morphology, which is the reason this section records the morphology as
      characteristic rather than as a diagnostic requirement.

biochemical:
- name: Cold agglutinin titer
  presence: Elevated
  context: >-
    Diagnostic threshold is a titer of at least 64 at 4 degrees Celsius.
    Thermal amplitude — the highest temperature at which agglutination still
    occurs — predicts clinical severity better than the titer alone.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A confirmed diagnosis of CAD was defined as the presence of chronic hemolysis, positive polyspecific direct antiglobulin test, monospecific-direct antiglobulin test strongly positive for C3d, IgG-direct antiglobulin test ≤1+, a cold agglutinin titer ≥64 at 4°C, and no evidence of overt malignant disease."
    explanation: >-
      Gives the operational titer threshold used to confirm the diagnosis in a
      phase 3 trial.
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "thermal amplitude can predict clinical severity better than titer alone"
    explanation: >-
      Qualifies the titer as an incomplete marker and identifies thermal
      amplitude as the better predictor, which is what this record's context
      field states.

- name: Direct antiglobulin test (monospecific)
  presence: Positive for C3d, negative or weakly positive for IgG
  context: >-
    The serological signature of CAD, and the finding that separates it from
    warm autoimmune hemolytic anemia. The IgM elutes on rewarming, so only the
    covalently bound complement remnant is detected.
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG)"
    explanation: >-
      States the C3d-positive, IgG-negative pattern that defines the test result
      in CAD.
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inclusion criteria were presence of chronic hemolysis, a DAT positive for C3d (≥ 2+) and negative or weakly positive for IgG, and presence of cold‐reactive antibodies."
    explanation: >-
      Shows the same pattern used operationally as a cohort inclusion criterion,
      including the negative-or-weakly-positive IgG qualification recorded in
      this record's presence field.

- name: Monoclonal IgM kappa paraprotein
  presence: Present
  context: >-
    Serum monoclonal immunoglobulin, IgM in about 90% of patients and
    kappa-restricted in about 94%; the direct product of the marrow clone.
  biomarker_term:
    preferred_term: monoclonal IgM kappa cold agglutinin
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%."
    explanation: >-
      Gives the isotype and light-chain distribution across 86 population-based
      patients, which is the basis for both percentages in the context field.

- name: Lactate dehydrogenase
  presence: Elevated
  context: Marker of hemolytic rate; falls on effective complement inhibition.
  biomarker_term:
    preferred_term: Serum lactate dehydrogenase
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The first step is to confirm hemolysis through elevated levels of lactate dehydrogenase (LDH) and indirect bilirubin, reticulocytosis, and reduced levels of haptoglobin, together with a review of the peripheral blood smear, which may show erythrocyte agglutination."
    explanation: >-
      Elevated LDH is named as one of the findings that confirms hemolysis in
      the diagnostic workup of this disease.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eculizumab, a C5 inhibitor, reduces the need for transfusion and reduces lactate dehydrogenase (LDH) levels but elicits only a modest increase in hemoglobin (Hb) levels in patients with CAD because it does not inhibit extravascular hemolysis"
    explanation: >-
      LDH falls when the intravascular (terminal-pathway) component is blocked
      while hemoglobin barely moves, which is what makes LDH a marker of the
      intravascular arm specifically rather than of total hemolytic rate.

- name: Haptoglobin
  presence: Decreased
  context: Consumed by free hemoglobin released during hemolysis.
  biomarker_term:
    preferred_term: Serum haptoglobin
    term:
      id: HP:0020181
      label: Reduced haptoglobin level
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The first step is to confirm hemolysis through elevated levels of lactate dehydrogenase (LDH) and indirect bilirubin, reticulocytosis, and reduced levels of haptoglobin, together with a review of the peripheral blood smear, which may show erythrocyte agglutination."
    explanation: >-
      Reduced haptoglobin is named among the findings that confirm hemolysis in
      the diagnostic workup of this disease.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the sutimlimab arm, an increase in the haptoglobin level corresponded to a decrease in the bilirubin level, whereas no change occurred in the placebo arm."
    explanation: >-
      Haptoglobin rose only when hemolysis was blocked, confirming that the low
      baseline level is consumption by ongoing hemolysis rather than a
      constitutive feature.

- name: Unconjugated bilirubin
  presence: Elevated
  context: >-
    Product of hemoglobin catabolism after extravascular red cell destruction;
    normalizes within weeks of stopping hemolysis.
  biomarker_term:
    preferred_term: Serum total bilirubin
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sutimlimab normalized mean bilirubin by week 1."
    explanation: >-
      Bilirubin was elevated at baseline and tracked hemolytic rate closely
      enough to normalize within a week of blocking C1s.

- name: Complement C4
  presence: Decreased
  context: >-
    Consumed by continuous classical-pathway activity; recovery of C4 is a
    pharmacodynamic marker of effective C1s inhibition.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization."
    explanation: >-
      C4 normalized only once the classical pathway was blocked, which implies
      it was being consumed by ongoing classical-pathway activation before
      treatment.
  - reference: PMID:10530415
    reference_title: "Clinical immunology of chronic cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50."
    explanation: >-
      Direct measurement of low C3, low C4 and reduced CH50 in an untreated CAD
      series.

- name: Reticulocyte count
  presence: Elevated
  context: >-
    Marrow compensatory response to hemolysis; the fourth member of the
    LDH / haptoglobin / bilirubin panel used to confirm that anemia is hemolytic.
  biomarker_term:
    preferred_term: Reticulocytosis
    term:
      id: HP:0001923
      label: Reticulocytosis
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The first step is to confirm hemolysis through elevated levels of lactate dehydrogenase (LDH) and indirect bilirubin, reticulocytosis, and reduced levels of haptoglobin, together with a review of the peripheral blood smear, which may show erythrocyte agglutination."
    explanation: >-
      Names reticulocytosis as one of the findings that establishes hemolysis in
      the diagnostic workup of this disease, alongside the three markers this
      section already curates.

genetic:
- name: KMT2D
  gene_term:
    preferred_term: KMT2D
    term:
      id: hgnc:7133
      label: KMT2D
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  presence: Somatically mutated in roughly two-thirds of primary CAD clones.
  association: >-
    Loss-of-function mutation of this histone H3K4 methyltransferase is the most
    frequent recurrent somatic lesion in the CAD B-cell clone.
  notes: >-
    A somatic event in the neoplastic clone, not an inherited susceptibility
    allele. Germline KMT2D variants cause Kabuki syndrome, an unrelated
    developmental disorder; nothing in this entry should be read as connecting
    the two.
  evidence:
  - reference: PMID:42117133
    reference_title: "A diagnostic pitfall in cold agglutinin disease: KMT2D-mutated CAD-associated lymphoproliferative disorder with a CLL-like immunophenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively"
    explanation: >-
      Gives the mutation frequency of KMT2D (69%) in sequenced CAD patients.
  - reference: PMID:38133636
    reference_title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KMT2D and CARD11 genes are recurrently mutated in CAD B cells. KMT2D has loss-of-function mutations, and CARD11 has gain-of-function mutations"
    explanation: >-
      Specifies that the KMT2D lesions are loss-of-function, which is the
      functional direction recorded here.

- name: CARD11
  gene_term:
    preferred_term: CARD11
    term:
      id: hgnc:16393
      label: CARD11
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  presence: Somatically mutated in roughly one-third of primary CAD clones.
  association: >-
    Gain-of-function mutation of this NF-kB scaffold protein constitutively
    activates B-cell receptor signalling downstream of the receptor itself, a
    plausible driver of the clonal expansion.
  evidence:
  - reference: PMID:42117133
    reference_title: "A diagnostic pitfall in cold agglutinin disease: KMT2D-mutated CAD-associated lymphoproliferative disorder with a CLL-like immunophenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively"
    explanation: >-
      Gives the mutation frequency of CARD11 (31%) in sequenced CAD patients.
  - reference: PMID:38133636
    reference_title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KMT2D and CARD11 genes are recurrently mutated in CAD B cells. KMT2D has loss-of-function mutations, and CARD11 has gain-of-function mutations"
    explanation: >-
      Specifies that the CARD11 lesions are gain-of-function, which is the
      functional direction recorded here.

- name: CXCR4
  gene_term:
    preferred_term: CXCR4
    term:
      id: hgnc:2561
      label: CXCR4
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  association: >-
    Somatic CXCR4 mutations occur in the CAD clone and, with CARD11, correlate
    with hemoglobin level, suggesting they modify disease severity rather than
    initiate the clone.
  evidence:
  - reference: PMID:38133636
    reference_title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of interest, CARD11 and CXCR4 mutations were correlated with hemoglobin levels, suggesting pathogenic involvement"
    explanation: >-
      Reports the correlation with hemoglobin, which is the modifier claim made
      here; the source itself frames the pathogenic role as a suggestion.

environmental:
- name: Cold exposure of the acral circulation
  description: >-
    Ambient cooling of the peripheral circulation is the proximate trigger for
    the antibody-binding step of this disease. The monoclonal IgM binds the I
    antigen only below core temperature, so the fingers, toes, ears and nose —
    which run several degrees cooler than the trunk — are where agglutination
    and complement fixation begin. Cold avoidance and thermal protection are
    the corresponding non-pharmacological management, and are sometimes
    sufficient. Cold exposure triggers the agglutination and circulatory limb;
    it does not explain the year-round hemolysis, which continues at core
    temperature once complement has been fixed.
  exposure_term:
    preferred_term: exposure to decreased ambient temperature
    term:
      id: ECTO:0001057
      label: exposure to decreased temperature
  effect: Triggers erythrocyte agglutination and cold-induced circulatory symptoms.
  influences_mechanisms:
  - target: Cold-Dependent Erythrocyte Agglutination
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Cooling of peripheral blood below the antibody's thermal amplitude is what
      permits the IgM to bind the I antigen and cross-link red cells.
    evidence:
    - reference: PMID:35687757
      reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In CAD, immunoglobulin M (IgM) autoantibodies (cold agglutinins) preferentially bind to the “I” antigen on erythrocytes at temperatures ≤37°C and may result in erythrocyte agglutination."
      explanation: >-
        States the temperature condition under which binding and agglutination
        occur, which is the causal role assigned to cold exposure here.
  - target: Acral Microcirculatory Obstruction
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The cold-induced circulatory symptoms are transient and appear on
      exposure, resolving on rewarming.
    evidence:
    - reference: PMID:35687757
      reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "non-complement-mediated symptoms include transient, cold-induced agglutination-mediated circulatory symptoms, such as acrocyanosis and Raynaud phenomenon"
      explanation: >-
        Attributes the acral circulatory symptoms specifically to cold-induced
        agglutination.
  - target: Chronic Hemolytic Anemia
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Seasonal cooling worsens hemolysis by increasing the fraction of red cells
      that become sensitized, but does not initiate it; the entry's own
      pathophysiology chain carries the intermediate steps.
    evidence:
    - reference: PMID:42696222
      reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Anemia is frequently transfusion-requiring; more than half of the patients receive red blood cell transfusions over the course of their disease, and seasonal worsening during colder months and febrile exacerbations of hemolysis are common"
      explanation: >-
        Documents seasonal worsening of hemolysis in colder months, which is the
        exacerbating effect recorded on this link.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%."
    explanation: >-
      Cold-induced symptoms in 91% of an unselected national cohort establishes
      cold exposure as a clinically dominant environmental determinant in this
      disease.
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year)."
    explanation: >-
      A fourfold difference in prevalence and incidence between cold and warm
      climates is population-level evidence that ambient temperature shapes who
      is diagnosed with this disease.
  notes: >-
    The climate gradient in the multinational cohort is an association between
    ambient temperature and diagnosed disease; the authors do not establish
    whether it reflects true incidence, symptom-driven ascertainment, or both.

prevalence:
- population: Norway (population-based)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.6
  notes: 16 cases per million inhabitants, reported as a national population-based figure.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year."
    explanation: >-
      The Norwegian population-based follow-up study of 86 patients is the
      source of both the prevalence and the incidence figure recorded here.
- population: Norway (population-based)
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 0.1
  notes: 1 case per million per year.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year."
    explanation: Source of the incidence rate recorded here.
- population: Cold-climate regions (Norway and northern Italy)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.0
  notes: 20 cases per million in the cold-climate arm of the multinational cohort.
  evidence:
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year)."
    explanation: >-
      Source of the cold-climate and warm-climate prevalence and incidence
      figures recorded in this and the following records.
- population: Warmer-climate regions (multinational cohort)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.5
  notes: 5 cases per million in the warmer-climate arm of the same cohort.
  evidence:
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year)."
    explanation: Source of the warmer-climate prevalence figure.
- population: Denmark (national patient registry)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.26
  notes: >-
    Registry-based figure for 2013; crude incidence in the same year was 0.18
    per 100,000 per year.
  evidence:
  - reference: PMID:31648316
    reference_title: "Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For 2013, the most recent year of study, crude incidence of CAD was 0.18 per 100 000 inhabitants per year and prevalence was 1.26 per 100 000 inhabitants."
    explanation: >-
      Danish National Patient Registry figures, derived from administrative
      coding rather than centrally reviewed diagnoses.
- population: Autoimmune hemolytic anemia cases
  measure_type: PERIOD_PREVALENCE
  notes: >-
    Not a population rate: the share of all autoimmune hemolytic anemia that is
    cold agglutinin disease, reported as 15-25%.
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 15%-25% of AIHA cases"
    explanation: >-
      Records CAD's share of the AIHA case mix, which is the denominator
      relevant to a hematology clinic rather than to a population.

progression:
- phase: Onset
  age_range: Median age at onset 67 years, range 30-92
  notes: >-
    A disease of older adults, with a female predominance (male:female ratio
    0.55 in the Norwegian cohort).
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at onset was 67 years (range, 30-92) and the male to female ratio was 0.55."
    explanation: Source of the age at onset and sex ratio recorded here.
- phase: Chronic phase
  notes: >-
    Hemolysis is chronic and largely stable: most laboratory findings did not
    change significantly over a median five years of follow-up. Transformation
    to aggressive lymphoma is uncommon.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transformation to aggressive lymphoma occurred in 3.5% during 10 years."
    explanation: >-
      Quantifies the low but nonzero risk of histological transformation of the
      underlying clone over a decade.
- phase: Exacerbation
  notes: >-
    Two distinct triggers: seasonal cooling, and febrile illness. The febrile
    trigger is the counterintuitive one, and is attributed to acute-phase
    repletion of consumed complement rather than to temperature.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exacerbation of hemolytic anemia during febrile illness in 74%"
    explanation: >-
      Establishes febrile exacerbation as a common rather than exceptional
      feature of the disease course.
- phase: Long-term outcome
  notes: >-
    Median survival 12.5 years from onset in the Norwegian cohort and 10.6 years
    in the Mayo series; a Danish registry cohort found excess mortality against
    matched controls, concentrated in the first five years after diagnosis.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median survival was 12.5 years from onset."
    explanation: Source of the Norwegian survival figure.
  - reference: PMID:31648316
    reference_title: "Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mortality rates 1 and 5 years after diagnosis were 17% and 39% in the CAD group vs 3% and 18% in the comparison cohort, respectively."
    explanation: >-
      Quantifies the excess mortality against matched general-population
      controls at one and five years.

diagnosis:
- name: Monospecific direct antiglobulin test
  description: >-
    Distinguishes immune from non-immune hemolysis and, by typing the coating
    protein, separates cold agglutinin disease (C3d-positive, IgG-negative or
    weakly positive) from warm autoimmune hemolytic anemia (IgG-positive).
  results: Strongly positive for C3d; negative or at most weakly positive for IgG.
  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: OTHER
    snippet: "Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup"
    explanation: >-
      The First International Consensus Meeting makes the monospecific DAT a
      required step, which is why it heads this entry's diagnostic list.

- name: Cold agglutinin titer at 4 degrees Celsius
  description: >-
    A titer of at least 64 at 4 degrees Celsius is the conventional diagnostic
    threshold, though the cutoff is debated and thermal amplitude carries more
    prognostic information.
  results: Titer of 64 or greater at 4 degrees Celsius.
  evidence:
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A definite diagnosis requires a cold antibody titer of ≥ 64 at 4°C as well, although this cutoff is debated."
    explanation: >-
      Gives the threshold and records the authors' own reservation about it,
      which is what this entry's description states.

- name: Bone marrow biopsy with flow cytometry and clonality testing
  description: >-
    Establishes the underlying clonal B-cell lymphoproliferative disorder and
    excludes an overt lymphoma that would reclassify the case as secondary cold
    agglutinin syndrome. Sensitive ancillary methods matter: in a recent
    56-patient series only 11% of confirmed CAD cases met the full WHO-HAEM5
    morphological description of CAD-LPD, while 84% showed clonality by
    ancillary techniques.
  evidence:
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, while ancillary methods detected clonality in the majority (84%), only 5 (11%) of 45 CAD cases strictly fulfilled the WHO-HAEM5 morphological description for CAD-LPD. These data imply that sensitive techniques should be used in BM evaluation in CAD."
    explanation: >-
      Directly supports the recommendation for sensitive ancillary clonality
      testing rather than morphology alone.
  - reference: PMID:41994904
    reference_title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 10 patients (18%), pathology revision revealed other overt B-cell malignancies leading to a diagnosis of cold agglutinin syndrome."
    explanation: >-
      Shows the discriminating value of expert marrow review: 18% of referred
      cold-type cases were reclassified as secondary CAS on pathology revision.

differential_diagnoses:
- name: Cold agglutinin syndrome (secondary)
  description: >-
    Cold agglutinins arising secondary to an identifiable cause: Mycoplasma
    pneumoniae or Epstein-Barr virus infection, an overt B-cell lymphoma, or
    another autoimmune disorder. Post-infectious cold agglutinins are typically
    polyclonal and transient and resolve with the underlying illness;
    lymphoma-associated ones are monoclonal but are produced by a clinically or
    radiologically overt neoplasm rather than by the occult marrow clone of
    primary CAD. Management is directed at the underlying cause, so the
    distinction changes treatment.
  distinguishing_features:
  - An identifiable underlying infection, lymphoma or autoimmune disease
  - Polyclonal and transient cold agglutinins in the post-infectious form
  - Clinically or radiologically overt lymphoma in the malignancy-associated form
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "in infection-associated CAS, the cold agglutinins are typically polyclonal and transient, resolving with the underlying condition, whereas lymphoma-associated CAS is frequently characterized by monoclonal cold agglutinins produced by an underlying clonal B-cell disorder"
    explanation: >-
      Sets out the two forms of secondary CAS and how each differs from primary
      CAD, which is the basis for excluding them from this entry.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAD is distinguished from cold agglutinin syndrome, which is transient and secondary to infections, overt malignant, or autoimmune conditions."
    explanation: >-
      Independent statement of the same distinction, used as a trial exclusion
      criterion rather than only as a review assertion.

- name: Warm autoimmune hemolytic anemia
  description: >-
    IgG autoantibodies active at 37 degrees Celsius, cleared by Fc
    receptor-bearing splenic macrophages. The direct antiglobulin test is
    IgG-positive, corticosteroids and splenectomy work, and there is no
    cold-induced circulatory syndrome. The mechanistic contrast — spleen and Fc
    receptor versus liver and complement receptor — is what makes the two
    diseases respond to different drugs.
  distinguishing_features:
  - IgG-positive direct antiglobulin test rather than C3d-positive
  - Response to corticosteroids and splenectomy
  - No cold-induced acrocyanosis or Raynaud-like symptoms
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unlike warm AIHA, which is driven by immunoglobulin G (IgG)-mediated, Fc receptor-dependent splenic clearance, CAD is defined by the convergence of two processes"
    explanation: >-
      States the mechanistic contrast that underlies every one of the
      distinguishing features listed here.

- name: Paroxysmal cold hemoglobinuria
  description: >-
    A separate cold-reactive, complement-dependent hemolytic anemia mediated by
    a biphasic IgG Donath-Landsteiner antibody with anti-P specificity, causing
    predominantly intravascular hemolysis. Classically post-viral and
    self-limiting in children.
  distinguishing_features:
  - Biphasic IgG Donath-Landsteiner antibody rather than a monoclonal IgM agglutinin
  - Predominantly intravascular rather than hepatic extravascular hemolysis
  evidence:
  - reference: PMID:25705656
    reference_title: "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders. The details of complement involvement differ among these subtypes."
    explanation: >-
      Places PCH alongside CAD as a complement-dependent cold-reactive anemia
      while stating that the complement mechanisms differ, which is why it is a
      differential rather than a subtype.

treatments:
- name: Cold Avoidance and Thermal Protection
  description: >-
    Keeping the extremities and the whole body warm reduces the fraction of red
    cells that become sensitized and directly relieves the agglutination-driven
    circulatory symptoms. It is the first intervention in every patient and is
    sufficient in some, but it does not address the year-round
    complement-mediated hemolysis, which proceeds at core temperature.
  treatment_term:
    preferred_term: cold avoidance and thermal protection
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Cold-Dependent Erythrocyte Agglutination
    treatment_effect: INHIBITS
    description: >-
      Preventing peripheral cooling keeps the blood above the antibody's thermal
      amplitude, so binding and agglutination do not occur.
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive care with cold avoidance alone is often inadequate and does not address complement-mediated symptoms, as chronic hemolytic anemia persists year-round."
    explanation: >-
      Establishes both that cold avoidance is standard supportive care and its
      specific limitation, which is what this entry's description records.
  - reference: PMID:21385173
    reference_title: "How I manage cold agglutinin disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-pharmacological management still seems sufficient in some patients."
    explanation: >-
      Supports the statement that thermal protection alone suffices for a
      subset of patients.

- name: Rituximab Monotherapy
  description: >-
    Anti-CD20 depletion of the clonal B-cell population. About half of patients
    respond, but responses are usually partial, take about six weeks to appear,
    and last around a year. It is the best-documented single agent and the
    reference against which combination regimens are measured.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: Clonal Bone Marrow B-Cell Lymphoproliferation
    treatment_effect: INHIBITS
    description: >-
      Depleting CD20-positive B cells removes the source of the cold agglutinin,
      which is why the hemoglobin response is delayed by weeks rather than
      immediate.
    evidence:
    - reference: PMID:15070665
      reference_title: "Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months."
      explanation: >-
        The 1.5-month lag to response is the kinetic signature of removing the
        antibody-producing clone rather than blocking the effector arm.
  evidence:
  - reference: PMID:15070665
    reference_title: "Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment."
    explanation: >-
      Gives the response rate to first-course and repeat rituximab in the
      largest prospective monotherapy series.
  - reference: PMID:15070665
    reference_title: "Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed 1 complete and 19 partial responses."
    explanation: >-
      Shows that responses to rituximab monotherapy are almost always partial,
      which is the limitation that motivates combination therapy.

- name: Bendamustine plus Rituximab
  description: >-
    Adding the alkylating agent bendamustine to rituximab raises the response
    rate to roughly three-quarters, produces complete responses in about half,
    and gives durable remissions — five-year sustained remission of 77% in
    long-term follow-up. Grade 3-4 neutropenia in a third of patients is the
    principal cost. It is a recommended first-line regimen for CAD requiring
    treatment.
  treatment_term:
    preferred_term: chemoimmunotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bendamustine
      term:
        id: CHEBI:135515
        label: bendamustine
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Clonal Bone Marrow B-Cell Lymphoproliferation
    treatment_effect: INHIBITS
    description: >-
      Cytotoxic clearance of the clone, including the long-lived plasma-cell
      compartment that rituximab alone spares — which is why responses continue
      to deepen for many months after treatment ends.
    evidence:
    - reference: PMID:32374875
      reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells."
      explanation: >-
        The authors attribute the deepening of responses over time to long-lived
        plasma cells, which is the mechanistic claim made on this link.
  evidence:
  - reference: PMID:28533306
    reference_title: "Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-two patients (71%) responded; 18 (40%) achieved complete response (CR) and 14 (31%) partial response (PR)."
    explanation: >-
      Primary efficacy result of the prospective Nordic bendamustine-rituximab
      trial.
  - reference: PMID:28533306
    reference_title: "Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Grade 3-4 neutropenia occurred in 15 patients (33%), but only 5 (11%) experienced infection with or without neutropenia."
    explanation: >-
      Quantifies the principal toxicity and puts it in context, both of which
      this entry's description records.
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%."
    explanation: >-
      Long-term follow-up establishing the durability that distinguishes this
      regimen from rituximab monotherapy.
  - 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: OTHER
    snippet: "Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy."
    explanation: >-
      The First International Consensus recommendation placing this regimen in
      the first line.
  notes: >-
    `therapeutic_modality` is deliberately absent: the regimen combines a small
    molecule with a monoclonal antibody, and the slot is single-valued.

- name: Fludarabine plus Rituximab
  description: >-
    A highly effective but more toxic B-cell-directed combination: 76% response
    with 21% complete responses and an estimated median response duration beyond
    66 months, at the cost of grade 3-4 hematologic toxicity in 41% and a higher
    rate of long-term adverse effects than bendamustine-rituximab. Reserved for
    selected patients.
  treatment_term:
    preferred_term: chemoimmunotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Clonal Bone Marrow B-Cell Lymphoproliferation
    treatment_effect: INHIBITS
    description: Purine-analogue plus anti-CD20 clearance of the marrow clone.
  evidence:
  - reference: PMID:20634373
    reference_title: "High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR."
    explanation: Primary efficacy result of the prospective fludarabine-rituximab trial.
  - reference: PMID:20634373
    reference_title: "High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD."
    explanation: >-
      Quantifies the hematologic toxicity that is the reason this regimen is not
      first choice.
  - reference: PMID:32374875
    reference_title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects."
    explanation: >-
      Long-term comparative observation supporting the preference for
      bendamustine-rituximab.
  notes: >-
    Only rituximab is bound in `therapeutic_agent`; fludarabine was left unbound
    at curation time rather than guessed at, and is named in the entry name and
    description instead.

- name: Sutimlimab
  description: >-
    A humanized IgG4 monoclonal antibody that selectively inhibits the classical
    complement pathway at C1s, leaving the lectin and alternative pathways
    intact. It blocks the effector arm of the disease without touching the
    clone, so hemolysis stops within days and the hemoglobin, bilirubin and
    fatigue all respond within the first weeks — but the cold agglutinin is
    still produced, and the agglutination-driven circulatory symptoms are not
    relieved. Approved for CAD on the strength of the CARDINAL and CADENZA
    trials.
  treatment_term:
    preferred_term: classical-pathway complement inhibition
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sutimlimab
      term:
        id: NCIT:C153093
        label: Sutimlimab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: Classical Complement Pathway Activation on the Erythrocyte Surface
    treatment_effect: INHIBITS
    description: >-
      C1s is the serine protease of the C1 complex that cleaves C4 and C2;
      blocking it prevents C3 convertase formation and therefore all downstream
      opsonization and lysis.
    evidence:
    - reference: PMID:35687757
      reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization."
      explanation: >-
        Ties the clinical benefit to a measured near-complete reduction in
        classical-pathway activity, which is the pharmacodynamic proof that this
        is the node being inhibited.
  evidence:
  - reference: PMID:33826820
    reference_title: "Sutimlimab in Cold Agglutinin Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue."
    explanation: >-
      Conclusion of the pivotal open-label CARDINAL trial in recently transfused
      patients.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint."
    explanation: >-
      Randomized placebo-controlled confirmation in CADENZA, which is the
      stronger evidential basis of the two trials.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups."
    explanation: >-
      Records the adverse events that were more frequent on treatment, including
      the circulatory symptoms that complement inhibition does not address.
  - 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: >-
      Hemolysis returns when the drug is withdrawn, which is the direct clinical
      demonstration that sutimlimab suppresses the effector arm without touching
      the marrow clone that produces the antibody.

- name: Eculizumab
  description: >-
    Anti-C5 monoclonal antibody, tested prospectively in CAD (the DECADE trial)
    and informative mainly as a mechanistic control. Blocking the terminal
    pathway cut LDH substantially but raised hemoglobin only from 9.35 to 10.15
    g/dL, because it leaves the C3b-opsonization step — and therefore the
    dominant hepatic extravascular clearance — completely intact. Cold-induced
    circulatory symptoms were likewise unaffected, as expected for a branch
    that is not complement-mediated at all. The trial result is the strongest
    single piece of evidence that this entry's graph is oriented correctly:
    inhibiting the minority branch produces a minority benefit.
  treatment_term:
    preferred_term: terminal complement inhibition
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: complement inhibitor
      term:
        id: NCIT:C199456
        label: Complement Inhibitor
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: Terminal Complement Pathway Assembly and Membrane Attack Complex Formation
    treatment_effect: INHIBITS
    description: >-
      C5 blockade prevents C5b-9 assembly and so abolishes the intravascular
      component, while leaving upstream C3b deposition untouched.
    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: "Cold agglutinin disease (CAD) is a complement-dependent disorder, with extravascular and intravascular hemolysis resulting from initial or terminal complement activation, respectively. We tested the efficacy and safety of eculizumab, an inhibitor of the terminal complement pathway."
      explanation: >-
        The trial explicitly separates the initial-activation (extravascular)
        and terminal (intravascular) arms and targets only the latter, which is
        the node this link points at.
  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: "The median lactate dehydrogenase level decreased from 572 U/L (interquartile range [IQR], 534-685) to 334 U/L (IQR, 243-567; P = .0215), paralleled by an increase in hemoglobin from 9.35 g/dL (IQR, 8.80-10.80) to 10.15 g/dL (IQR, 9.00-11.35; P = .0391; Wilcoxon signed-rank test)."
    explanation: >-
      The large LDH fall with only a 0.8 g/dL hemoglobin gain is the quantitative
      shape of blocking the minority intravascular branch while the hepatic
      extravascular branch continues.
  - 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: >-
      Confirms that the acral circulatory branch is untouched by complement
      inhibition of any kind, which is why this entry models it as a separate
      limb leaving the agglutination node.

- name: Red Blood Cell Transfusion
  description: >-
    Supportive transfusion for symptomatic anemia. Around half of patients
    require it at some point, and transfusion history is what separated the
    CARDINAL and CADENZA trial populations.
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Chronic Hemolytic Anemia
    treatment_effect: MODULATES
    description: >-
      Replaces lost red cell mass without altering any upstream step, which is
      why the effect is transient.
  evidence:
  - reference: PMID:16585012
    reference_title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least 51% had received red blood cell transfusions."
    explanation: >-
      Establishes how often transfusion is needed across an unselected national
      cohort.

- name: Corticosteroid Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Explicitly not recommended in cold agglutinin disease. Response rates are
    poor and often require unacceptably high maintenance doses. The mechanistic
    reason is that corticosteroids act largely on Fc-receptor-mediated splenic
    clearance, which is the warm-AIHA effector arm and not the one operating
    here. Recorded so that the negative recommendation is machine-readable.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
  evidence:
  - reference: PMID:27913484
    reference_title: "Cold agglutinin disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CAD should not be treated with corticosteroids."
    explanation: >-
      An unqualified negative recommendation from an ASH education-program
      review, which is the claim this entry records.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite not being recommended because of poor response rates and often requiring unacceptably high doses, corticosteroids are often used in CAD management."
    explanation: >-
      Gives the reasons behind the negative recommendation and notes the gap
      between guidance and practice.

- name: Splenectomy
  description: >-
    Ineffective in cold agglutinin disease and not recommended. The
    C3b-opsonized red cell is cleared by hepatic Kupffer cells, not by splenic
    macrophages, so removing the spleen does not remove the effector organ.
    This is the clearest instance in the entry of mechanism predicting
    therapeutic failure.
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other approaches such as azathioprine, cyclophosphamide, and splenectomy are not effective in CAD and are also not recommended"
    explanation: >-
      States the ineffectiveness and the recommendation against splenectomy.
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it explains why therapies effective in warm AIHA, such as corticosteroids and splenectomy, are largely ineffective in CAD, where hemolysis is complement-driven and predominantly hepatic rather than Fc-mediated and splenic"
    explanation: >-
      Supplies the mechanistic reason recorded in this entry's description: the
      effector organ is the liver, not the spleen.

- name: Bortezomib
  description: >-
    Proteasome inhibition directed at the antibody-secreting plasma-cell
    compartment rather than at the CD20-positive B-cell clone or at complement.
    A prospective phase 2 GIMEMA study in relapsed, anemic patients reported an
    overall response rate of roughly a third, with responses lasting a little
    over a year, and peripheral neuropathy as the limiting toxicity. This is a
    third therapeutic axis alongside B-cell depletion and complement blockade,
    and it is the only curated treatment acting on production of the cold
    agglutinin itself.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bortezomib
      term:
        id: CHEBI:52717
        label: bortezomib
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Monoclonal IgM Cold Agglutinin Production
    treatment_effect: INHIBITS
    description: >-
      Proteasome inhibition is disproportionately toxic to immunoglobulin-secreting
      plasma cells, so the point of attack is production of the cold agglutinin
      rather than the B-cell clone upstream of it or the complement cascade it
      activates downstream.
    evidence:
    - reference: PMID:42696222
      reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Bortezomib, through plasma-cell depletion, achieved an overall response rate of approximately 32%, with a median response duration of approximately 16 months in a GIMEMA phase 2 study limited by neuropathy [34,35,36]."
      explanation: >-
        Attributes the effect specifically to plasma-cell depletion, which is
        what makes this a link to the antibody-production node rather than to
        the clonal lymphoproliferation node, and gives the response rate and
        duration observed in the phase 2 study.
  evidence:
  - reference: PMID:42696222
    reference_title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For patients with relapsed or refractory disease, ibrutinib-, daratumumab-, and bortezomib-based approaches are options, and the next-generation agents riliprubart and iptacopan, although still in the early phase of development, point toward less burdensome and potentially oral complement inhibition."
    explanation: >-
      Places bortezomib among the accepted options in relapsed or refractory
      disease, which is the setting the GIMEMA study enrolled.
  notes: >-
    The trial report itself (PMID:29898955, Rossi et al., Blood 2018) is a
    Letter that PubMed exposes without an abstract and whose full text is
    paywalled, so no snippet can be verified against it; it is listed in the
    top-level `references:` block for provenance and the result is quoted from
    the 2026 review, which reports it. Note that the review gives 16 months as
    the median response duration; a "16% complete response" figure circulating
    in secondary summaries could not be verified against any cached source and
    is deliberately not recorded here.

clinical_trials:
- name: NCT03347396
  description: >-
    CARDINAL, a phase 3 open-label single-arm study of intravenous sutimlimab in
    patients with primary cold agglutinin disease and a recent history of
    transfusion. Thirteen of 24 patients (54%) met the composite primary
    endpoint; classical-pathway activity was rapidly inhibited and hemolysis
    halted.
  phase: PHASE_III
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  - preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  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: OTHER
    snippet: "obviated the need for blood transfusion during treatment in participants with primary cold agglutinin disease (CAD) who had a recent history of blood transfusion"
    explanation: >-
      The registry record establishing the trial's population and primary
      objective.
  - reference: PMID:33826820
    reference_title: "Sutimlimab in Cold Agglutinin Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point."
    explanation: Primary endpoint result as published.

- name: NCT03347422
  description: >-
    CADENZA, a phase 3 randomized double-blind placebo-controlled study of
    sutimlimab in patients with primary cold agglutinin disease without a recent
    transfusion history. Sixteen of 22 patients (73%) on sutimlimab met the
    composite primary endpoint versus 3 of 20 (15%) on placebo. This is the
    controlled evidence that the classical complement pathway is the causal
    effector arm of the disease.
  phase: PHASE_III
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  - preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  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: OTHER
    snippet: "increase in hemoglobin (Hgb) level and avoidance of transfusion in participants with primary cold agglutinin disease (CAD) without a recent history of blood transfusion"
    explanation: >-
      The registry record establishing the trial's population and primary
      objective.
  - reference: PMID:35687757
    reference_title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history."
    explanation: Design of the trial as published.

- name: NCT02689986
  description: >-
    The CAD5 study, a prospective non-randomized international multicenter trial
    of bendamustine plus rituximab in chronic cold agglutinin disease.
    Thirty-two of 45 patients (71%) responded, 40% completely; long-term
    follow-up showed 77% five-year sustained remission.
  phase: PHASE_II
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: clinicaltrials:NCT02689986
    reference_title: "The CAD5 Study::Therapy for Chronic Cold Agglutinin Disease: A Prospective, Non-randomized International Multicenter Trial on the Safety and Efficacy of Bendamustine and Rituximab Combination Therapy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prospective, non-randomized multicenter study on the safety and efficacy of combination therapy with bendamustine and rituximab for chronic cold agglutinin disease."
    explanation: >-
      The registry record establishing the trial's identity, design and
      intervention.
  - reference: PMID:28533306
    reference_title: "Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a prospective, nonrandomized multicenter trial, 45 eligible patients received rituximab 375 mg/m2 day 1 and bendamustine 90 mg/m2 days 1 and 2 for 4 cycles at a 28-day interval."
    explanation: Enrolment and regimen as published.

- name: NCT01303952
  description: >-
    DECADE, an open-label prospective bicentric non-randomized phase 2 trial of
    the anti-C5 antibody eculizumab in chronic cold agglutinin disease. LDH fell
    substantially and transfusion independence was gained by 8 of 13 patients,
    but the hemoglobin gain was modest and cold-induced circulatory symptoms did
    not change — the trial that established the limits of terminal-complement
    inhibition in this disease.
  phase: PHASE_II
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  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: OTHER
    snippet: "Evaluation of the efficacy and safety of eculizumab in symptomatic or transfusion-dependent patients with untreated or refractory hemolytic cold agglutinin disease"
    explanation: >-
      The registry record establishing the trial's identity, intervention and
      population.
  - 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: "Three patients maintained and 8 patients acquired transfusion independence, and 1 patient each showed a reduced or increased transfusion requirement, respectively (P = .0215; exact McNemar's test)."
    explanation: Transfusion outcome as published.

- name: NCT05096403
  description: >-
    A phase 3 randomized, double-blind, placebo-controlled study of
    pegcetacoplan, a C3-level complement inhibitor, in primary cold agglutinin
    disease, completed with 24 participants. This is the most direct available
    test of the entry's central claim: if C3b opsonization is the dominant
    effector step, inhibition at C3 should outperform terminal-pathway blockade,
    which eculizumab showed to be largely ineffective here.
  phase: PHASE_III
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  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: OTHER
    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: >-
      The registry record establishing the population, the comparator and the
      primary objective.
  notes: >-
    Results are not curated: no peer-reviewed report of this trial was found in
    a cached record at time of writing, so only the registered design is
    recorded.

- name: NCT05086744
  description: >-
    An open-label phase 2 basket study of iptacopan in autoimmune benign
    haematological disorders, including primary cold agglutinin disease,
    terminated after enrolling 19 participants. The registry records the reason
    as a business decision rather than a safety or efficacy signal, which is
    worth recording because a terminated trial is otherwise easily read as a
    negative result.
  phase: PHASE_II
  status: TERMINATED
  target_phenotypes:
  - preferred_term: Chronic complement-mediated hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  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: OTHER
    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: >-
      The registry record establishing that this basket study covered primary
      cold agglutinin disease.

datasets:
- accession: geo:GSE140415
  title: OncoScan CNV Assay (Thermo Fisher Scientific/Affymetrix) data for 13 cold agglutinin disease samples
  description: >-
    Copy-number profiling of 13 primary cold agglutinin disease samples by SNP
    array. Trisomy 3 or partial 3q was present in 12 of 13 cases, and trisomy 12
    or trisomy 18 (never both) in 9 of 13 — the cytogenetic counterpart of the
    recurrent somatic mutation profile recorded in this entry's `genetic:`
    section.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 13
  platform: OncoScan CNV Assay (Thermo Fisher Scientific/Affymetrix)
  evidence:
  - reference: GEO:GSE140415
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 12/13 cases complete or partial trisomy 3/3q was detected."
    explanation: >-
      The repository's own summary reports near-universal trisomy 3/3q in
      primary CAD samples, which is the finding this dataset record is curated
      for.
  notes: >-
    The only DIRECT candidate returned by `just discover-datasets
    Cold_Agglutinin_Disease`; the eleven GENE_ONLY candidates were rejected on
    relevance triage, since they matched on KMT2D, CARD11 or CXCR4 in unrelated
    diseases (B-cell lymphoma, colorectal cancer, HIV host factors,
    neurodevelopmental disorders) rather than on cold agglutinin disease.

references:
- reference: PMID:42696222
  title: "Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape."
- reference: PMID:24143001
  title: "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma."
- reference: PMID:41994904
  title: "Bone Marrow Pathology in Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia: A Study of 56 Cases."
- reference: PMID:38133636
  title: "Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease."
- reference: PMID:42117133
  title: "A diagnostic pitfall in cold agglutinin disease: KMT2D-mutated CAD-associated lymphoproliferative disorder with a CLL-like immunophenotype."
- reference: PMID:16585012
  title: "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients."
- reference: PMID:32374875
  title: "Cold agglutinin disease revisited: a multinational, observational study of 232 patients."
- reference: PMID:31648316
  title: "Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease."
- reference: PMID:23757733
  title: "Cold agglutinin disease."
- reference: PMID:10530415
  title: "Clinical immunology of chronic cold agglutinin disease."
- reference: PMID:33826820
  title: "Sutimlimab in Cold Agglutinin Disease."
- reference: PMID:35687757
  title: "Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial."
- reference: PMID:28533306
  title: "Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial."
- reference: PMID:20634373
  title: "High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease."
- reference: PMID:15070665
  title: "Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients."
- reference: PMID:27913484
  title: "Cold agglutinin disease."
- reference: PMID:21385173
  title: "How I manage cold agglutinin disease."
- reference: PMID:25705656
  title: "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy."
- reference: PMID:31839434
  title: "Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting."
- reference: PMID:38938203
  title: "The impact of individual clinical features in cold agglutinin disease: hemolytic versus non-hemolytic symptoms."
- reference: PMID:30291112
  title: "Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial."
- reference: PMID:39091672
  title: "Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B."
- reference: PMID:33891703
  title: "The mutational landscape of cold agglutinin disease: CARD11 and CXCR4 mutations are correlated with lower hemoglobin levels."
- reference: PMID:29265349
  title: "Frequent somatic mutations of KMT2D (MLL2) and CARD11 genes in primary cold agglutinin disease."
- reference: PMID:29898955
  title: "Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: a phase 2 prospective GIMEMA study."

discussions:
- discussion_id: cr1_downregulation_causal_role
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is reduced complement receptor 1 on the clonal B cells a driver of the
    hemolytic phenotype in cold agglutinin disease, or a bystander marker of the
    clone?
  attaches_to:
  - pathophysiology#Downregulation of Complement Receptor 1 on Clonal B Cells
  rationale: >-
    CR1 is a regulator of C3b handling, so reduced expression is mechanistically
    suggestive: less CR1 would mean less cofactor activity restraining C3b
    deposition, which is the step this entry treats as dominant. But the
    observation curated here is differential expression in clonal B cells, not a
    demonstration that it changes C3b handling on erythrocytes, and the two are
    different cell populations. The node is marked
    `mechanism_confidence: HYPOTHETICAL` for that reason; this records the open
    question structurally rather than leaving it as a confidence flag.
- discussion_id: prothrombotic_mechanism_in_cad
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What mechanism links chronic complement-mediated hemolysis in cold
    agglutinin disease to its excess thromboembolic risk?
  attaches_to:
  - pathophysiology#Prothrombotic State of Chronic Complement-Mediated Hemolysis
  rationale: >-
    The epidemiological association between cold agglutinin disease and venous
    thromboembolism is curated from cohort data, but the mechanism is not
    established in this disease. Candidate routes borrowed from other hemolytic
    states (cell-free heme and nitric oxide scavenging, complement activation on
    platelets and endothelium, erythrocyte-derived microvesicles) have not been
    shown to operate here, and CAD hemolysis is predominantly extravascular,
    which weakens the cell-free-hemoglobin argument that applies to
    intravascular hemolytic diseases. Resolving this matters clinically because
    it determines whether complement inhibition should be expected to reduce
    thrombotic risk.

notes: >-
  Scope, and its relation to `Autoimmune_Hemolytic_Anemia`. The AIHA entry is
  the parent concept (MONDO:0020108) and already carries a pathophysiology node
  named "Cold Agglutinin-Mediated Hemolysis", which correctly states that IgM
  binds red cells in the cold, activates complement, and destroys C3b-coated
  cells extravascularly in the liver. This entry does not contradict that node;
  it is the standalone disease behind it (MONDO:0018922), and it adds the three
  things the parent entry does not carry: the clonal bone-marrow
  lymphoproliferative disorder that produces the antibody, the somatic
  KMT2D/CARD11 lesions in that clone, and the CAD-specific therapeutic biology
  (why steroids and splenectomy fail, why rituximab-bendamustine and sutimlimab
  work). The parent entry has no cold agglutinin disease subtype; adding one
  there, or reconciling the two entries' shared citations, was deliberately not
  attempted here and is left for whoever next edits that file.

  Primary CAD versus secondary cold agglutinin syndrome. They are separate
  entities and this entry covers only the first. Secondary CAS -
  post-Mycoplasma pneumoniae, post-Epstein-Barr virus, or lymphoma-associated -
  is recorded under `differential_diagnoses`, not as a subtype, because its
  antibody is polyclonal and transient (post-infectious) or produced by an
  overt neoplasm (lymphoma-associated), and because its management is directed
  at the underlying cause rather than at the marrow clone. The two are commonly
  conflated in the older literature and in MONDO's own parent class
  (MONDO:0016450, "autoimmune hemolytic anemia, cold type"), which is why that
  mapping is recorded as `skos:broadMatch` rather than a narrow or exact match.

  Why the graph branches where it does. Two branches leave "Cold-Dependent
  Erythrocyte Agglutination": one into the complement chain, one into acral
  microcirculatory obstruction. That split is the clinically load-bearing
  feature of this disease - the circulatory limb is not complement-mediated, so
  a patient whose dominant complaint is acrocyanosis rather than anemia will
  not benefit from sutimlimab. Berentsen and colleagues make the same division
  the basis of a three-phenotype clinical classification (PMID:38938203).

  What is not modelled, and what is. Bortezomib is curated as a treatment: it
  has a prospective phase 2 GIMEMA trial, which clears the same bar that admits
  eculizumab, and it is the only agent here acting on cold agglutinin
  production rather than on the B-cell clone or on complement. Riliprubart and
  BTK inhibitors remain uncurated as treatments, because their CAD evidence is
  early-phase or case-report level and no cached record supported a snippet.
  Iptacopan is likewise not curated as a treatment, but its terminated phase 2
  basket study is now recorded under `clinical_trials:` alongside the completed
  pegcetacoplan phase 3, since both bear directly on where in the complement
  cascade intervention has to act. Sutimlimab's CADENZA Part B extension is
  curated on the sutimlimab treatment, where the post-withdrawal rebound in
  hemolytic markers is the evidence that the drug suppresses the effector arm
  without touching the marrow clone; the CARDINAL extension is not curated, and
  the entry cites the CARDINAL Part A result only.

review_notes: >-
  Deep research. Two providers ran. `just research-disorder asta` returned in 6
  seconds with 37 resolved references and a 0.0 confabulation rate, but only 3
  of its 20 retrieved papers were about cold agglutinin disease - the rest were
  unrelated (rare skeletal dysplasia, obesity-associated asthma
  transcriptomics, goat pregnancy toxemia), and its own reference-validation
  section reported 17/37 on topic. `just research-disorder falcon` returned
  after 14 minutes with 17 references, all 17 resolved, 8 judged on topic, one
  quote checked and valid, and one artifact; its `needs_review: true` flag is
  driven solely by a label mismatch on MONDO:0018922 where the "reported label"
  is the template's own placeholder string "if available", not a real
  mislabelling. Falcon's causal chain and quantitative table agree with the
  entry as built, and it contributed the eculizumab (DECADE) and CADENZA Part B
  material added after the first pass. Neither report's suggested CURIEs were
  lifted directly: asta's term-validation section found zero, and falcon's were
  re-derived against `cache/` and OLS. The bulk of the reference base is a
  systematic PubMed sweep via E-utilities, since falcon cites by author-year key
  and DOI rather than PMID.

  Two primary sources could not be quoted and so are not cited in any evidence
  item. PMID:29265349 (Malecka et al. 2018, the original KMT2D/CARD11 report)
  and PMID:33891703 (Malecka et al. 2021, the full mutational landscape) are
  both PubMed records without abstracts; their cache entries are
  `content_type: unavailable`, so no snippet can be verified against either.
  Both are listed in the top-level `references:` block for provenance, and the
  same findings are quoted instead from PMID:42117133 and PMID:38133636, which
  report them in verifiable text. Falcon's own reference validator hit the same
  wall on the 2021 paper, recording its quote as "resolved but exposes no
  abstract or full text to search".

  Term-cache drift. HP:0020181 is bound here with the label `Reduced
  haptoglobin level`, which is what `cache/hp/terms.csv` holds and what the two
  other KB entries using this term carry. Live OLS returns `Decreased
  circulating haptoglobin concentration` for the same CURIE, so the committed
  cache is behind HPO. Following the cache was a deliberate choice not to
  hand-touch a shared derived artifact; the drift affects
  `Atypical_Hemolytic_Uremic_Syndrome` and `HELLP_Syndrome` equally and should
  be fixed by re-deriving the cache row, not by editing entries one at a time.

  Dataset triage. `just discover-datasets` returned 12 candidates, of which one
  was DIRECT (geo:GSE140415, CNV profiling of 13 CAD samples) and eleven were
  GENE_ONLY hits on KMT2D, CARD11 or CXCR4 in unrelated diseases. Only the
  DIRECT one was curated; the rejection reason is recorded on the dataset
  record itself.

📚

References & Deep Research