Autoimmune haemolytic anaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

AIHA occurs when autoantibody or complement shortens red-cell survival. Warm disease usually involves IgG reacting near core temperature; splenic macrophages remove parts of the membrane, creating spherocytes before clearing the cell. Cold-reactive IgM binds in cooler acral circulation and fixes complement; IgM may dissociate centrally, leaving complement detectable on DAT and promoting hepatic clearance or intravascular injury. Mixed and atypical patterns occur. Symptoms combine anaemia, jaundice, dark urine and splenomegaly with cold-induced acrocyanosis or Raynaud-type discomfort in some complement-mediated disease.

The diagnosis requires evidence of haemolysis and immune coating, not DAT positivity alone. FBC, absolute reticulocytes, bilirubin, LDH, haptoglobin, renal function and film establish severity and mechanism. DAT should report IgG and complement specificity, while eluate, cold-antibody and blood-bank studies are selected by specialists. Reticulocytes may be low early or when marrow reserve, infection, nutrient deficiency or antibody activity against precursors limits compensation. Recent transfusion creates a crucial alternative: a delayed alloimmune reaction can be DAT positive and requires transfusion-laboratory investigation.

Management is determined by physiological severity and subtype. Warm AIHA is treated initially with corticosteroid under BSH-informed haematology care, with rituximab or other therapies considered for severe, refractory or relapsing disease. Cold disease prioritises thermal protection, trigger management and specialist B-cell-directed treatment rather than reflex steroids. Transfusion decisions use symptoms and oxygen delivery; the laboratory may need adsorption and extended matching to uncover alloantibodies, but life-saving transfusion proceeds with the safest blood available after senior discussion.

Key points

Diagnose autoimmune haemolytic anaemia from active destruction plus immune evidence: reticulocytes, bilirubin, LDH, haptoglobin, film and DAT must be interpreted together.
Warm AIHA is usually IgG-mediated and predominantly extravascular, with spherocytes and splenic clearance; cold-antibody disease is commonly complement-mediated and may show agglutination and cold-triggered symptoms.
A positive DAT is not synonymous with AIHA. Recent transfusion, medicines and immunoglobulin treatment can produce coating without sufficient haemolysis, while occasional immune haemolysis is DAT negative by routine methods.
Send pretreatment samples when safe, including group and screen and a detailed transfusion history, but never delay resuscitation or essential transfusion for a complete antibody work-up.
Prednisolone is the supported initial treatment for warm AIHA, commonly 1 mg/kg once daily under haematology supervision, followed by a response-led taper rather than abrupt cessation.
Cold-antibody disease responds poorly to corticosteroids in many patients. Keep the patient and infused fluids warm, treat a reversible trigger and use specialist B-cell-directed therapy when indicated.
Investigate secondary causes through history, examination, FBC and film, immunoglobulins or protein studies, infection tests, autoimmune assessment and imaging or marrow testing selected by the phenotype.
Monitor thrombosis, infection, glucose, blood pressure, bone and gastric risks during treatment as well as haemoglobin and haemolysis; relapse may occur before anaemia becomes severe.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary immune dysregulation

Autoantibodies arise without an identified associated disorder after structured investigation, producing warm, cold or mixed immune haemolysis.

Lymphoid and autoimmune disease

Chronic lymphocytic leukaemia, lymphoma, monoclonal gammopathy, systemic lupus and other immune disorders can drive red-cell autoantibody production.

Infection-associated disease

Mycoplasma, Epstein–Barr virus and other infections can trigger complement-fixing cold antibodies, while broader infections may precipitate haemolysis in susceptible patients.

Medicines and immune exposure

Selected antimicrobials and other medicines, recent transfusion, transplantation and immune therapies can produce drug-dependent antibodies, alloimmune complexity or immune dysregulation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Autoantibody binds red cells
Warm IgG binds optimally near body temperature, whereas cold-reactive IgM fixes complement in cooler peripheral circulation and may detach after warming.
2
Cells become opsonised
Immunoglobulin and complement fragments mark erythrocytes for recognition by splenic and hepatic macrophages or for complement-mediated membrane injury.
3
Clearance exceeds production
Extravascular phagocytosis and variable intravascular destruction shorten survival, while marrow reticulocyte output may initially compensate or fail during severe disease.
4
Secondary injury develops
Free haemoglobin, anaemia, inflammation and immobility contribute to renal stress, cardiovascular compromise and a heightened venous thromboembolic tendency during active haemolysis.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Warm immune phenotype

Anaemia, jaundice, spherocytes, reticulocytosis and a DAT showing IgG with or without complement supports warm-antibody haemolysis after transfusion causes are reviewed.

Cold antibody phenotype

Cold-triggered acrocyanosis, agglutination, complement-positive DAT and haemolysis during infection or cold exposure supports clinically important cold-reactive disease.

Severe intravascular episodeRed flag

Haemoglobinuria, rapid haemoglobin decline, kidney injury, back pain, shock or marked LDH elevation indicates dangerous destruction and urgent organ support.

Inadequate marrow compensationRed flag

Low reticulocytes despite active haemolysis suggests early disease, infection, renal or nutrient limitation, marrow pathology or immune targeting of erythroid precursors.

Secondary disease clues

Lymphadenopathy, splenomegaly, monoclonal protein, lymphocytosis, autoimmune symptoms, infection or recent immune therapy directs investigation beyond a primary AIHA label.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
FBC, reticulocytes and serial haemoglobinFirst step
Why
Measure severity, tempo, marrow compensation and other lineage changes.
Interpretation and limitations
Reticulocytosis usually supports peripheral destruction; a low response increases urgency and prompts nutrient, infection, renal and marrow assessment. Lymphocytosis or additional cytopenias may reveal secondary disease.
02
Bilirubin, LDH, haptoglobin and renal profile
Why
Confirm active haemolysis and detect intravascular organ effects.
Interpretation and limitations
Concordant indirect bilirubin and LDH rise with consumed haptoglobin supports destruction. Liver disease, inflammation and tissue injury modify markers; creatinine and potassium help define emergency severity.
03
Peripheral blood film
Why
Identify spherocytes, agglutination, polychromasia and important alternative morphology.
Interpretation and limitations
Spherocytes support warm immune or hereditary membrane disease; agglutination supports a cold antibody; schistocytes activate microangiopathy assessment rather than being attributed to AIHA.
04
DAT with IgG and complement specificity
Why
Demonstrate immune coating and classify a warm, cold or mixed pattern.
Interpretation and limitations
Relate the result to active haemolysis, recent transfusion and medicines. Strong complement-only reactivity suggests a cold mechanism, but further specialist serology defines clinical significance.
05
Group, screen and transfusion-laboratory studies
Why
Identify alloantibodies and select the safest red cells when transfusion may be required.
Interpretation and limitations
Provide previous antibodies, pregnancies and transfusions. Adsorption, elution, phenotype or genotype matching may be needed; urgency and the laboratory's estimated delay must be communicated continuously.
06
Secondary-cause assessment
Why
Find lymphoid, autoimmune, infectious, medicine-related or immune-treatment drivers.
Interpretation and limitations
Select immunoglobulins and electrophoresis, autoimmune tests, infection studies, imaging, flow cytometry or marrow assessment from age, subtype, examination and FBC rather than ordering every test indiscriminately.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Delayed haemolytic transfusion reaction

Recent transfusion, a newly detectable alloantibody and falling post-transfusion haemoglobin can produce DAT positivity and must be separated through blood-bank investigation.

Hereditary spherocytosis

Family history, lifelong jaundice or gallstones, splenomegaly, raised MCHC and spherocytes with a negative DAT favours an inherited membrane disorder.

Thrombotic microangiopathy

Schistocytes, thrombocytopenia and neurological, renal or cardiac injury indicates fragmentation and demands urgent TTP assessment rather than immune-haemolysis treatment alone.

Oxidative or mechanical haemolysis

Bite cells after an oxidant exposure or fragments with a prosthetic valve supports enzyme-related or mechanical destruction, usually without immune coating.

Ineffective megaloblastic erythropoiesis

B12 or folate deficiency can raise bilirubin and LDH but produces low reticulocytes, macro-ovalocytes and hypersegmented neutrophils rather than peripheral immune destruction.

Additional chapter-specific clues

Transfusion-related alternativeRed flag

Recent transfusion, new antibody, fever or an unexpected post-unit haemoglobin fall requires a haemolytic-reaction pathway even when the DAT is positive.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Severe diseaseSupport oxygen delivery while defining antibodiesFirst stepHaemolysis is rapid or causes chest pain, syncope, heart failure, shock, neurological change or kidney injury.

1Use ABCDE, obtain haemolysis, DAT, group and antibody samples, involve senior haematology and the transfusion laboratory immediately, and treat precipitating infection or another reversible driver.
2PreferredPreferred support is clinically indicated red-cell transfusion using the safest units the laboratory can provide; incompatibility from an autoantibody must not create harmful delay when oxygen delivery is failing.
3EscalationEscalate to critical care for organ compromise and begin subtype-appropriate immunotherapy with specialist oversight while monitoring renal function, thrombosis and the haemoglobin trajectory.

02Warm AIHASuppress warm-antibody destructionActive haemolysis and DAT or specialist serology support a warm IgG-predominant mechanism.

1First lineFirst-line treatment is prednisolone, commonly 1 mg/kg once daily, with gastric, glucose, blood-pressure, infection, bone and thrombosis risk assessed and a response endpoint documented.
2PreferredEscalationBegin a gradual response-led taper with haematology once haemolysis and haemoglobin improve; for steroid failure, dependence or relapse, rituximab is a preferred specialist escalation in many BSH pathways.
3AlternativeUse an alternative later-line immunosuppressive or splenectomy strategy only after secondary-cause, vaccination, infection and thrombosis review in a multidisciplinary plan.

03Cold AIHAReduce complement-triggered haemolysisComplement-predominant serology, cold-triggered symptoms or specialist testing supports clinically important cold-antibody disease.

1Keep the patient, environment, intravenous fluids and transfused blood warm, avoid cold exposure and investigate infection or an underlying lymphoid clone; use a blood warmer under the transfusion protocol.
2PreferredEscalationCorticosteroids are often ineffective, so the preferred disease-directed escalation is specialist rituximab-based therapy when anaemia or circulatory symptoms justify treatment.
3EscalationEscalate brisk intravascular haemolysis, renal injury, thrombosis or severe acrocyanosis urgently, and coordinate any complement-directed or later-line therapy through a specialist centre.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Reduces macrophage-mediated clearance and autoantibody effects in warm-antibody haemolysis and is the usual initial disease-directed treatment.

Prednisolone

A common BSH initial regimen for warm AIHA is 1 mg/kg by mouth once daily, followed by a gradual haematology-directed taper after response.

Screen and monitor infection, glucose, blood pressure, mood, gastric, bone and thrombotic risks. Do not stop abruptly after prolonged treatment, and avoid repeated unplanned courses without a steroid-sparing strategy.

Depletes CD20-positive B cells in steroid-refractory or relapsing warm AIHA and in clinically significant cold-antibody disease.

Rituximab

A commonly used off-label specialist regimen is 375 mg/m² intravenously once weekly for four doses; follow the haematology protocol and current product guidance.

Specialist screening includes hepatitis B and infection risk, vaccination planning and immunoglobulin context. Infusion reactions, prolonged immune suppression and viral reactivation require protocol monitoring.

Supports sustained marrow reticulocyte production when accelerated erythropoiesis increases folate use during haemolysis.

Folic acid

Give 5 mg by mouth once daily when active or chronic haemolysis creates a documented increased folate requirement, with duration reviewed as haemolysis resolves.

Assess vitamin B12 before prolonged treatment, do not let supplementation substitute for haemolysis control, and review the need once reticulocyte demand normalises.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Critical oxygen-delivery failure

Rapid haemoglobin loss can cause syncope, myocardial ischaemia, heart failure, shock or tissue hypoxia before compatibility investigations are complete.

Venous thromboembolism

Active intravascular and immune haemolysis creates a prothrombotic state, compounded by inflammation, steroids, cancer and reduced mobility.

Kidney injury

Severe intravascular haemolysis releases filtered haemoglobin that promotes tubular injury, while hypotension and thrombosis further threaten renal function.

Relapse and treatment toxicity

Recurrent disease creates cumulative corticosteroid, immunosuppression, infection, metabolic and bone harm and may require successive specialist therapies.

Transfusion complexity

Broad autoantibody reactivity can mask clinically important alloantibodies, delay compatible selection and increase future reaction risk without close blood-bank coordination.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend haemoglobin, absolute reticulocytes, bilirubin, LDH and haptoglobin frequently during active disease, interpreting marker discordance with liver, renal and marrow context.
Monitor renal function, potassium, urine colour, symptoms and observations during intravascular episodes and escalate any deteriorating organ function.
Assess venous thromboembolism risk throughout active haemolysis and hospitalisation, using the local prophylaxis pathway and investigating compatible symptoms promptly.
During corticosteroids, monitor glucose, blood pressure, infection, mood, gastric symptoms, weight and bone protection, and record a taper with relapse criteria.
Before and after rituximab, follow hepatitis B and infection screening, vaccination timing, immunoglobulins where indicated, infusion reactions and delayed infection risk.
Maintain an accurate transfusion and antibody record and ensure future blood-bank teams can see alloantibodies, phenotype or genotype work and reaction history.
Investigate secondary disease at baseline and revisit it when the subtype changes, relapse is early or lymphadenopathy, monoclonal protein or cytopenias evolve.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

A positive DAT needs haemolysis

Immune coating can occur without shortened survival. The diagnosis requires a compatible falling haemoglobin and destruction pattern in clinical context.

Spherocytes are not uniquely immune

Warm AIHA and hereditary spherocytosis both lose membrane in the spleen. DAT, age, family history and specialist membrane testing distinguish them.

Compatibility is not a binary label

Autoantibodies can react broadly while transfusion scientists identify underlying alloantibodies and select the safest available units for the clinical urgency.

Reticulocytopenia can be dangerous

Failure of marrow compensation during brisk destruction predicts rapid oxygen-carriage loss and should prompt urgent nutrient, infection and marrow assessment.

Cold disease is mechanistically different

Complement-mediated clearance and temperature-dependent binding explain why warming and B-cell-directed therapy matter and why corticosteroid response is often poor.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing AIHA from DAT positivity without confirming haemolysis.
02
Delaying essential transfusion while waiting for perfect serological compatibility.
03
Missing a delayed alloimmune transfusion reaction in a recently transfused patient.
04
Using corticosteroids reflexively for complement-predominant cold-antibody disease.
05
Tapering prednisolone rapidly without haemolysis markers and a relapse plan.
06
Starting rituximab without hepatitis B and infection-risk assessment.
07
Calling disease primary without proportionate investigation for lymphoid, autoimmune and infectious drivers.