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heme.hemolytic-anemia.core.v1PRODUCTION
heme.hemolytic-anemia.core.v1

Haemolytic anaemia (AIHA / G6PD / hereditary spherocytosis — chronic + acute crisis)

hematologychronicacuteadultpediatricpregnancyneonatal
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Care setting:

Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Confirm a haemolytic process and assign working phenotype lane — AIHA (warm/cold) vs hereditary (G6PD/HS/PK) vs MAHA vs drug-induced vs mechanical/infectious (First Intl Consensus AIHA 2020 PMID 31839434)

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Haemolysis confirmed + provisional phenotype lane assigned

Patient inputs (12)

DAT is the pivotal branch — positive → AIHA (IgG vs C3d); negative → hereditary / non-immune (BSH 2017 PMID 28005293)

Spherocytes / schistocytes / bite cells / agglutination differentiate phenotype (Perrotta Lancet 2008 PMID 18940465)

Neonatal jaundice (G6PD/HS), paediatric vs adult dosing, splenectomy timing (Bolton-Maggs BSH 2011 PMID 22055020)

Hb degree + MCV + MCHC (↑MCHC → spherocytosis) + platelets (low → MAHA) (First Intl Consensus AIHA 2020 PMID 31839434)

Reticulocytosis confirms compensated marrow; low retic → aplastic crisis (parvovirus B19) (Perrotta Lancet 2008 PMID 18940465)

↑LDH supports haemolysis; very high LDH → intravascular / MAHA (BSH 2017 PMID 28005293)

Haptoglobin <10 mg/dL is a strong positive likelihood marker for haemolysis (Marchand JAMA 1980)

Oxidant-drug list (G6PD) and drug-induced immune haemolysis offenders (BSH 2017 PMID 28369704)

Known G6PD deficiency mandates oxidant-drug avoidance and changes acute management (Luzzatto NEJM 2018 PMID 29298156)

SLE / CLL / lymphoma / post-allo → secondary AIHA workup and disease-directed therapy (First Intl Consensus AIHA 2020 PMID 31839434)

AIHA management + drug safety in pregnancy (rituximab, azathioprine) (BSH 2017 PMID 28005293)

Unconjugated hyperbilirubinaemia of extravascular haemolysis (BSH 2017 PMID 28005293)

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (7)

7 need judgement
  • informationallife_threateninghyperacute_intravascular_haemolysis
    Hb <6 g/dL OR rapidly falling Hb with marked LDH↑ + haemoglobinuria + symptomatic anaemia (BSH 2017 PMID 28005293)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateninghaemodynamic_instability_in_haemolytic_crisis
    Hypotension / tachycardia / end-organ hypoperfusion during a haemolytic crisis (First Intl Consensus AIHA 2020 PMID 31839434)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningschistocytes_with_thrombocytopenia_route_maha
    Schistocytes on smear + thrombocytopenia + microangiopathic haemolysis (no DAT positivity) (heme.ttp.core.v1)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereg6pd_oxidant_exposure
    G6PD-deficient patient with active oxidant exposure (drug / fava / infection) and acute haemolysis (Luzzatto NEJM 2018 PMID 29298156)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverehs_aplastic_crisis_parvovirus
    Hereditary spherocytosis with acute Hb drop + LOW reticulocyte count (parvovirus B19) (Bolton-Maggs BSH 2011 PMID 22055020)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereaiha_with_thrombosis
    AIHA (or PNH) with new venous/arterial thrombosis during active haemolysis (First Intl Consensus AIHA 2020 PMID 31839434)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatecold_agglutinin_with_cold_exposure
    Cold agglutinin disease patient with cold exposure precipitating acute haemolysis / acrocyanosis (Röth NEJM 2021 PMID 33826820)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

Run this disease's risk and dosing calculators inline.

RISK_STRATIFICATIONoptionalDrives dose adjustment
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Recommended regimen

AIHA immunosuppression (warm AIHA + cold agglutinin disease)
axis: aiha_immunosuppression
Selected axis "AIHA immunosuppression (warm AIHA + cold agglutinin disease)" by default fallback (first axis)
  • prednisolone
    first line
    corticosteroid
    1 mg/kg/day • PO • once daily (max: max ~1 mg/kg/day then taper)
    triggers: warm_aiha
    Warm AIHA first-line; ~70-80% initial response, slow taper over months (First Intl Consensus AIHA 2020 PMID 31839434; BSH 2017 PMID 28005293)
    rxcui 8638
  • prednisone
    first line
    corticosteroid
    1 mg/kg/day • PO • once daily
    triggers: warm_aiha, prednisolone_unavailable
    Interchangeable with prednisolone for warm AIHA induction (First Intl Consensus AIHA 2020 PMID 31839434)
    rxcui 8640
  • methylprednisolone
    rescue
    corticosteroid
    250-1000 mg/day x 1-3 days • IV • once daily pulse
    triggers: severe_symptomatic_warm_aiha, fulminant_haemolysis
    IV pulse for severe/fulminant warm AIHA before oral taper (First Intl Consensus AIHA 2020 PMID 31839434)
    rxcui 6902
  • rituximab
    second line
    anti_cd20_monoclonal
    375 mg/m2 weekly x4 (or 1000 mg x2) • IV • weekly x4
    triggers: warm_aiha_steroid_dependent_or_relapsed, cold_agglutinin_disease, early_first_line_addition
    Birgens RCT — rituximab+prednisolone 75% vs 36% 12-mo response, better relapse-free survival, PMID 23981017; first-line in CAD (First Intl Consensus AIHA 2020 PMID 31839434)
    rxcui 121191
  • sutimlimab
    add on
    complement_c1s_inhibitor
    6.5 g (<75 kg) or 7.5 g (≥75 kg) wk0, wk1, then q2w • IV • q2 weeks
    triggers: cold_agglutinin_disease, transfusion_dependent_cad
    CARDINAL — 54% composite Hb response, 71% transfusion-free wk5-26, PMID 33826820; CADENZA RCT PMID 35687757; meningococcal vaccination required
    rxcui 2591404
  • fostamatinib
    second line
    syk_inhibitor
    100 mg BID, escalate to 150 mg BID • PO • BID
    triggers: warm_aiha_refractory_to_steroid_and_rituximab
    FORWARD phase 3 — durable Hb response benefit in N.America/Australia/W.Europe subgroup, PMID 37929318 (refractory warm AIHA)
    rxcui 2044896
  • azathioprine
    add on
    thiopurine_immunosuppressant
    1-2 mg/kg/day • PO • once daily
    triggers: warm_aiha_steroid_sparing, rituximab_contraindicated
    Steroid-sparing maintenance in warm AIHA (BSH 2017 PMID 28005293); avoid with allopurinol / dose-adjust
    rxcui 1256
  • mycophenolate
    add on
    imdh_inhibitor_immunosuppressant
    500-1000 mg BID • PO • BID
    triggers: warm_aiha_refractory, secondary_aiha_in_sle
    Steroid-sparing / refractory warm AIHA, especially secondary to SLE (First Intl Consensus AIHA 2020 PMID 31839434)
    rxcui 265323
  • cyclophosphamide
    rescue
    alkylating_immunosuppressant
    oral or pulse IV per protocol • PO/IV • per protocol
    triggers: refractory_severe_aiha_multiagent_failure
    Refractory AIHA after steroid + rituximab + splenectomy failure (First Intl Consensus AIHA 2020 PMID 31839434)
    rxcui 3002
  • danazol
    add on
    attenuated_androgen
    200 mg BID-TID • PO • BID-TID
    triggers: warm_aiha_steroid_sparing_adjunct
    Steroid-sparing adjunct in warm AIHA (BSH 2017 PMID 28005293)
    rxcui 3102
  • intravenous_immunoglobulin
    rescue
    immunoglobulin
    triggers: severe_warm_aiha_temporising, paediatric_aiha
    Temporising in severe/paediatric warm AIHA; modest, transient effect (First Intl Consensus AIHA 2020 PMID 31839434)
  • splenectomy
    second line
    surgical_procedure
    triggers: warm_aiha_steroid_rituximab_refractory
    Second/third-line for warm AIHA (NOT effective in cold agglutinin disease); pre-splenectomy vaccination mandatory (First Intl Consensus AIHA 2020 PMID 31839434)
  • plasma_exchange
    rescue
    apheresis
    triggers: cold_agglutinin_disease_pre_warming_for_surgery, fulminant_cold_haemolysis, maha_route_ttp
    Temporising in fulminant CAD / bridge; definitive only when routed to TTP (protocol.ttp)
  • least_incompatible_warmed_transfusion
    rescue
    blood_product
    triggers: life_threatening_anaemia_in_aiha, cold_agglutinin_disease_transfusion
    Do NOT delay transfusion for life-threatening anaemia in AIHA; least-incompatible units, blood-warmer mandatory for CAD (BSH 2017 PMID 28005293)
  • cold_avoidance
    first line
    lifestyle_modification
    triggers: cold_agglutinin_disease
    Cornerstone non-pharmacologic management of cold agglutinin disease (Röth NEJM 2021 PMID 33826820)

outpatient playbook — drug actions (5)

  1. 1. folic acid
    rxcui 4511
    1-5 mg • PO • once daily
    trigger: Any chronic haemolysis
    Lifelong folate replacement (Perrotta Lancet 2008 PMID 18940465)
  2. 2. prednisolone
    rxcui 8638
    1 mg/kg/day then slow taper • PO • once daily
    trigger: Warm AIHA induction
    Warm AIHA first-line (First Intl Consensus AIHA 2020 PMID 31839434)
  3. 3. rituximab
    rxcui 121191
    375 mg/m2 weekly x4 (or 1000 mg x2) • IV • weekly x4
    trigger: Steroid-dependent/relapsed warm AIHA OR cold agglutinin disease
    Birgens RCT PMID 23981017; CAD first-line (First Intl Consensus AIHA 2020 PMID 31839434)
  4. 4. sutimlimab
    rxcui 2591404
    6.5/7.5 g wk0, wk1, then q2w • IV • q2 weeks
    trigger: Cold agglutinin disease, transfusion-dependent
    CARDINAL PMID 33826820; CADENZA PMID 35687757
  5. 5. azathioprine or mycophenolate
    rxcui 1256
    AZA 1-2 mg/kg/day or MMF 500-1000 mg BID • PO • daily/BID
    trigger: Steroid-sparing maintenance warm AIHA
    Steroid-sparing (BSH 2017 PMID 28005293)

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Anaemia + reticulocytosis (haemolytic pattern) (First Intl Consensus AIHA 2020 PMID 31839434); ↑LDH + ↓haptoglobin + ↑indirect bilirubin → haemolysis screen (BSH 2017 PMID 28005293); Jaundice / dark urine (haemoglobinuria — intravascular) (Luzzatto NEJM 2018 PMID 29298156).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Haemolytic anaemia (AIHA / G6PD / hereditary spherocytosis — chronic + acute crisis)** (heme.hemolytic-anemia.core.v1).
Phenotype framing: Terminal phenotype: warm AIHA (primary vs secondary SLE/CLL/lymphoma/drug/post-allo); cold agglutinin disease (primary vs secondary to lymphoma/Mycoplasma/EBV); paroxysmal cold haemoglobinuria; G6PD episodic / neonatal; hereditary spherocytosis (± aplastic crisis); PK deficiency; drug-induced immune; MAHA (route); mechanical; PNH; infection-driven (First Intl Consensus AIHA 2020 PMID 31839434)
Scope: Confirm a haemolytic process and assign working phenotype lane — AIHA (warm/cold) vs hereditary (G6PD/HS/PK) vs MAHA vs drug-induced vs mechanical/infectious (First Intl Consensus AIHA 2020 PMID 31839434)

No severity triggers fired against current inputs.

Plan

Regimen axis: **AIHA immunosuppression (warm AIHA + cold agglutinin disease)**.
1. prednisolone 1 mg/kg/day PO once daily (corticosteroid, first line) — Warm AIHA first-line; ~70-80% initial response, slow taper over months (First Intl Consensus AIHA 2020 PMID 31839434; BSH 2017 PMID 28005293)
2. prednisone 1 mg/kg/day PO once daily (corticosteroid, first line) — Interchangeable with prednisolone for warm AIHA induction (First Intl Consensus AIHA 2020 PMID 31839434)
3. methylprednisolone 250-1000 mg/day x 1-3 days IV once daily pulse (corticosteroid, rescue) — IV pulse for severe/fulminant warm AIHA before oral taper (First Intl Consensus AIHA 2020 PMID 31839434)
4. rituximab 375 mg/m2 weekly x4 (or 1000 mg x2) IV weekly x4 (anti_cd20_monoclonal, second line) — Birgens RCT — rituximab+prednisolone 75% vs 36% 12-mo response, better relapse-free survival, PMID 23981017; first-line in CAD (First Intl Consensus AIHA 2020 PMID 31839434)
5. sutimlimab 6.5 g (<75 kg) or 7.5 g (≥75 kg) wk0, wk1, then q2w IV q2 weeks (complement_c1s_inhibitor, add on) — CARDINAL — 54% composite Hb response, 71% transfusion-free wk5-26, PMID 33826820; CADENZA RCT PMID 35687757; meningococcal vaccination required
6. fostamatinib 100 mg BID, escalate to 150 mg BID PO BID (syk_inhibitor, second line) — FORWARD phase 3 — durable Hb response benefit in N.America/Australia/W.Europe subgroup, PMID 37929318 (refractory warm AIHA)
7. azathioprine 1-2 mg/kg/day PO once daily (thiopurine_immunosuppressant, add on) — Steroid-sparing maintenance in warm AIHA (BSH 2017 PMID 28005293); avoid with allopurinol / dose-adjust
8. mycophenolate 500-1000 mg BID PO BID (imdh_inhibitor_immunosuppressant, add on) — Steroid-sparing / refractory warm AIHA, especially secondary to SLE (First Intl Consensus AIHA 2020 PMID 31839434)
9. cyclophosphamide oral or pulse IV per protocol PO/IV per protocol (alkylating_immunosuppressant, rescue) — Refractory AIHA after steroid + rituximab + splenectomy failure (First Intl Consensus AIHA 2020 PMID 31839434)
10. danazol 200 mg BID-TID PO BID-TID (attenuated_androgen, add on) — Steroid-sparing adjunct in warm AIHA (BSH 2017 PMID 28005293)
11. intravenous_immunoglobulin (immunoglobulin, rescue) — Temporising in severe/paediatric warm AIHA; modest, transient effect (First Intl Consensus AIHA 2020 PMID 31839434)
12. splenectomy (surgical_procedure, second line) — Second/third-line for warm AIHA (NOT effective in cold agglutinin disease); pre-splenectomy vaccination mandatory (First Intl Consensus AIHA 2020 PMID 31839434)
13. plasma_exchange (apheresis, rescue) — Temporising in fulminant CAD / bridge; definitive only when routed to TTP (protocol.ttp)
14. least_incompatible_warmed_transfusion (blood_product, rescue) — Do NOT delay transfusion for life-threatening anaemia in AIHA; least-incompatible units, blood-warmer mandatory for CAD (BSH 2017 PMID 28005293)
15. cold_avoidance (lifestyle_modification, first line) — Cornerstone non-pharmacologic management of cold agglutinin disease (Röth NEJM 2021 PMID 33826820)

Setting playbook (outpatient) — Chronic phenotype-directed management — confirm phenotype, immunosuppression/relapse surveillance for AIHA/CAD, supportive care + trigger avoidance for G6PD/HS, lifelong folate + post-splenectomy prophylaxis (First Intl Consensus AIHA 2020 PMID 31839434)
16. folic acid 1-5 mg PO once daily — Any chronic haemolysis (Lifelong folate replacement (Perrotta Lancet 2008 PMID 18940465))
17. prednisolone 1 mg/kg/day then slow taper PO once daily — Warm AIHA induction (Warm AIHA first-line (First Intl Consensus AIHA 2020 PMID 31839434))
18. rituximab 375 mg/m2 weekly x4 (or 1000 mg x2) IV weekly x4 — Steroid-dependent/relapsed warm AIHA OR cold agglutinin disease (Birgens RCT PMID 23981017; CAD first-line (First Intl Consensus AIHA 2020 PMID 31839434))
19. sutimlimab 6.5/7.5 g wk0, wk1, then q2w IV q2 weeks — Cold agglutinin disease, transfusion-dependent (CARDINAL PMID 33826820; CADENZA PMID 35687757)
20. azathioprine or mycophenolate AZA 1-2 mg/kg/day or MMF 500-1000 mg BID PO daily/BID — Steroid-sparing maintenance warm AIHA (Steroid-sparing (BSH 2017 PMID 28005293))

Non-pharmacologic actions:
- Cold avoidance counselling for cold agglutinin disease (Röth NEJM 2021 PMID 33826820)
- G6PD oxidant-drug avoidance card + fava-bean avoidance (Luzzatto NEJM 2018 PMID 29298156)
- Post-splenectomy lifelong penicillin prophylaxis + vaccination + asplenia alert (Bolton-Maggs BSH 2011 PMID 22055020)
- Pregnancy planning + drug-safety review (BSH 2017 PMID 28005293)

AVOID / contraindication checks:
- Anti_pattern:corticosteroids and splenectomy are generally INEFFECTIVE in cold agglutinin disease — do not use as primary CAD therapy (First Intl Consensus AIHA 2020 PMID 31839434)
- Rituximab — screen HBsAg + anti HBc before therapy (HBV reactivation risk) (BSH 2017 PMID 28005293)
- Sutimlimab and eculizumab — complete meningococcal (and pneumococcal/Hib) vaccination before complement inhibition (Röth NEJM 2021 PMID 33826820)
- Pre splenectomy pneumococcal + meningococcal + Hib vaccination ≥2 weeks pre op; lifelong post splenectomy penicillin prophylaxis (Bolton Maggs BSH 2011 PMID 22055020)
- Azathioprine — reduce dose / avoid with allopurinol (xanthine oxidase inhibition); check TPMT (BSH 2017 PMID 28005293)
- Cyclophosphamide / mycophenolate / azathioprine teratogenic — pregnancy contraindication; rituximab/azathioprine preferred if immunosuppression needed in pregnancy (BSH 2017 PMID 28005293)

Monitoring

Regimen monitoring:
- Hb + reticulocyte + LDH + haptoglobin q1-2w during steroid taper then per stability (First Intl Consensus AIHA 2020 PMID 31839434)
- DAT and cold agglutinin titre / thermal amplitude on therapy response (BSH 2017 PMID 28005293)
- HBV serology + IgG levels + B-cell count with rituximab (BSH 2017 PMID 28005293)
- CBC + LFTs on azathioprine/MMF/cyclophosphamide (BSH 2017 PMID 28005293)
- Complement-pathway activity / haemolysis markers on sutimlimab; surveillance for encapsulated-organism infection (Röth NEJM 2021 PMID 33826820)

Setting (outpatient) monitoring:
- CBC + retic + LDH + haptoglobin q1-3m per phenotype/stability (First Intl Consensus AIHA 2020 PMID 31839434)
- HBV serology + B-cell count on rituximab (BSH 2017 PMID 28005293)
- Ferritin if transfusion-dependent (Perrotta Lancet 2008 PMID 18940465)

Follow-up plan: Chronic haemolysis maintenance: lifelong folic acid; gallstone surveillance + iron-overload surveillance; post-splenectomy lifelong pneumococcal/meningococcal/Hib vaccination + penicillin prophylaxis + asplenia education; G6PD drug-avoidance card; relapse precautions for AIHA/CAD; periodic re-evaluation for secondary cause emergence (CLL/lymphoma); pregnancy planning + drug-safety review (BSH 2017 PMID 28005293)
- Close-out criterion: Maintenance + return-precaution plan documented

Monitoring phase: Hb + reticulocyte + LDH + haptoglobin + indirect bilirubin trend; DAT/cold agglutinin titre on therapy; CBC during steroid taper; HBV screen + B-cell monitoring on rituximab; CBC + LFTs on azathioprine/MMF; iron/ferritin if transfusion-dependent (iron overload); folate adequacy (First Intl Consensus AIHA 2020 PMID 31839434)

Disposition

Current setting: outpatient — Chronic phenotype-directed management — confirm phenotype, immunosuppression/relapse surveillance for AIHA/CAD, supportive care + trigger avoidance for G6PD/HS, lifelong folate + post-splenectomy prophylaxis (First Intl Consensus AIHA 2020 PMID 31839434)

Disposition criteria:
- Continue current regimen if haemolysis controlled (First Intl Consensus AIHA 2020 PMID 31839434)
- Escalate immunosuppression line if steroid-dependent/relapsed warm AIHA (Birgens PMID 23981017)
- Refer surgery for HS splenectomy if moderate-severe / transfusion-dependent (Bolton-Maggs BSH 2011 PMID 22055020)

Escalation triggers (move to higher acuity):
- Rapid Hb fall / haemodynamic symptoms → ED (First Intl Consensus AIHA 2020 PMID 31839434)
- Schistocytes + thrombocytopenia → MAHA route (TTP/HUS/DIC) (heme.ttp.core.v1)
- Acute Hb drop + low retic in HS → aplastic crisis evaluation (Bolton-Maggs BSH 2011 PMID 22055020)
- New lymphadenopathy / lymphocytosis → secondary CLL/lymphoma workup (First Intl Consensus AIHA 2020 PMID 31839434)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Hb <6 g/dL OR rapidly falling Hb with marked LDH↑ + haemoglobinuria + symptomatic anaemia (BSH 2017 PMID 28005293)
- [LIFE_THREATENING] Hypotension / tachycardia / end-organ hypoperfusion during a haemolytic crisis (First Intl Consensus AIHA 2020 PMID 31839434)
- [LIFE_THREATENING] Schistocytes on smear + thrombocytopenia + microangiopathic haemolysis (no DAT positivity) (heme.ttp.core.v1)

Citations

- First International Consensus Meeting — Diagnosis & Treatment of AIHA in Adults (Jäger/Barcellini, Blood Reviews 2020) + BSH 2017 primary AIHA + BSH 2017 drug-induced/secondary AIHA + WHO 2022 G6PD classification + BSH 2011 hereditary spherocytosis [PMID:31839434](https://pubmed.ncbi.nlm.nih.gov/31839434/)
- Cited evidence (PMID 28005293) [PMID:28005293](https://pubmed.ncbi.nlm.nih.gov/28005293/)
- Cited evidence (PMID 28369704) [PMID:28369704](https://pubmed.ncbi.nlm.nih.gov/28369704/)
- Cited evidence (PMID 23981017) [PMID:23981017](https://pubmed.ncbi.nlm.nih.gov/23981017/)
- Cited evidence (PMID 37929318) [PMID:37929318](https://pubmed.ncbi.nlm.nih.gov/37929318/)

Last reconciled with current guidelines: 2026-05-16.
References
  • First International Consensus Meeting — Diagnosis & Treatment of AIHA in Adults (Jäger/Barcellini, Blood Reviews 2020) + BSH 2017 primary AIHA + BSH 2017 drug-induced/secondary AIHA + WHO 2022 G6PD classification + BSH 2011 hereditary spherocytosis — PMID:31839434
  • Cited evidence (PMID 28005293) — PMID:28005293
  • Cited evidence (PMID 28369704) — PMID:28369704
  • Cited evidence (PMID 23981017) — PMID:23981017
  • Cited evidence (PMID 37929318) — PMID:37929318