12-phase flow (12)

1. 1FRAME
   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)
   inputs: age, g6pd_status
   advance: Haemolysis confirmed + provisional phenotype lane assigned
2. 2ENTRY
   Triage acuity — haemodynamic stability, Hb nadir, intravascular vs extravascular markers, exposure history (oxidant drug / fava / cold / transfusion) (Luzzatto NEJM 2018 PMID 29298156)
   inputs: cbc_with_diff
   actions: cascade.labs_command
   advance: Acuity triaged
3. 3CONTEXT
   Capture age, family history, medication list (oxidant + DIIHA offenders), autoimmune / lymphoproliferative comorbidity, pregnancy, splenectomy/vaccination status, transfusion history (BSH 2017 PMID 28369704)
   inputs: age, current_medications, autoimmune_or_lymphoproliferative, pregnancy_status, g6pd_status
   advance: Context complete
4. 4RED_FLAGS
   Bayesian pivots — HYPERACUTE intravascular haemolysis / Hb <6 with haemodynamic instability → resuscitate + transfuse (do NOT delay AIHA transfusion if life-threatening — least-incompatible warmed units). SCHISTOCYTES + thrombocytopenia → presume MAHA: route TTP (protocol.ttp / heme.ttp.core.v1) vs DIC (heme.dic.v1) — TTP is rapidly fatal untreated. ACUTE Hb drop + LOW retic + parvovirus exposure in HS → aplastic crisis. G6PD with active oxidant exposure → stop trigger + supportive. Cold-agglutinin patient exposed to cold → rewarm + complement-directed plan (Röth NEJM 2021 PMID 33826820)
   inputs: peripheral_smear, reticulocyte_count
   actions: workup.hemolysis, workup.transfusion_reaction, protocol.ttp
   advance: Life-threatening process excluded or stabilised
5. 5INITIAL_WORKUP
   Confirm haemolysis: CBC + retic + smear; LDH + haptoglobin + indirect bilirubin; urine haemosiderin / free Hb (intravascular vs extravascular); type & screen (BSH 2017 PMID 28005293)
   inputs: cbc_with_diff, reticulocyte_count, ldh, haptoglobin, indirect_bilirubin
   actions: panel.cbc, panel.lft, workup.hemolysis
   advance: Haemolysis biochemically confirmed
6. 6BRANCHING_WORKUP
   DAT is the pivot. DAT+ → monospecific DAT (IgG vs C3d): IgG±C3 → warm AIHA; C3-only → cold agglutinin titre + thermal amplitude (CAD if titre ≥64 at 4°C with monoclonal IgM). DAT− → smear-driven branch: spherocytes (no DAT) → EMA-binding / osmotic fragility (HS); bite/blister cells + Heinz bodies → G6PD quantitative assay (retest off-episode — false-normal during acute haemolysis/high retic); schistocytes → MAHA (TTP/HUS/DIC — route); flow cytometry CD55/CD59 → PNH; mechanical (prosthetic valve), infection (malaria film, Mycoplasma, EBV), Wilson, Zieve. Secondary-AIHA screen (ANA, immunoglobulins/SPEP, flow for CLL, CT) if warm AIHA (First Intl Consensus AIHA 2020 PMID 31839434)
   inputs: direct_antiglobulin_test, peripheral_smear
   actions: workup.hemolysis, workup.splenomegaly, workup.pancytopenia
   advance: Phenotype confirmed by DAT + smear + confirmatory assay
7. 7DIFFERENTIAL
   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)
   inputs: direct_antiglobulin_test
   advance: Terminal phenotype assigned
8. 8RISK_STRATIFICATION
   Severity tier (Hb nadir, intravascular vs extravascular, transfusion dependence, thrombosis risk in AIHA/PNH); secondary-cause burden; renal function for drug dosing (calc.ckd_epi_2021); depression screen for chronic transfusion-dependent disease (calc.phq9) (First Intl Consensus AIHA 2020 PMID 31839434)
   actions: calc.ckd_epi_2021, calc.phq9
   advance: Risk profile + treatment intensity decided
9. 9TREATMENT
   Phenotype-directed. Warm AIHA: corticosteroids first-line (prednisolone 1 mg/kg/day; ~70-80% initial response, frequent relapse on taper), rituximab early/2nd-line (Birgens RCT — 75% vs 36% 12-mo response added to steroids, PMID 23981017), splenectomy, fostamatinib (FORWARD PMID 37929318), azathioprine/MMF/cyclophosphamide/danazol; treat secondary cause. Cold agglutinin disease: cold AVOIDANCE; rituximab ± bendamustine; sutimlimab (C1s inhibitor — CARDINAL 54% composite Hb response, 71% transfusion-free wk5-26, PMID 33826820; CADENZA RCT PMID 35687757); steroids/splenectomy generally INEFFECTIVE (anti-pattern). G6PD: remove trigger, supportive, transfuse if severe; NEVER methylene blue. HS: folate, transfusion support, splenectomy (with pre-splenectomy vaccination + post-splenectomy penicillin prophylaxis), cholecystectomy for gallstones. ALL chronic haemolysis: folic acid supplementation; thrombosis vigilance in AIHA/PNH (First Intl Consensus AIHA 2020 PMID 31839434)
   inputs: direct_antiglobulin_test, g6pd_status
   actions: workup.hemolysis
   advance: Phenotype-directed treatment plan executed
10. 10DISPOSITION
    ICU for hyperacute intravascular haemolysis / haemodynamic instability / MAHA needing PLEX; inpatient for severe symptomatic anaemia, transfusion, immunosuppression initiation, aplastic crisis; outpatient haematology for chronic phenotype management (First Intl Consensus AIHA 2020 PMID 31839434)
    advance: Disposition set
11. 11MONITORING
    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)
    inputs: cbc_with_diff, reticulocyte_count, ldh
    actions: panel.cbc, panel.iron
    advance: Monitoring cadence documented
12. 12FOLLOWUP
    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)
    advance: Maintenance + return-precaution plan documented