12-phase flow (12)

1. 1FRAME
   Assign phenotype tier — TDT (β-major / severe HbE-β / α0/α0 Hb Barts hydrops) vs NTDT (β-intermedia / HbH / mild HbE-β) vs trait/carrier; globin type (α vs β); genotype severity (β0/β0 vs non-β0/β0) (TIF 5th ed 2025 PMID 40045934; NTDT 2023 NBK599489)
   inputs: thalassemia_genotype
   advance: Phenotype tier + globin type assigned
2. 2ENTRY
   Trigger: microcytic anaemia on CBC / known thalassaemia clinic visit / abnormal Hb electrophoresis / positive carrier screen / iron-overload organ failure / family study (TIF 5th ed 2025)
   inputs: cbc_with_indices
   advance: Entry route established
3. 3CONTEXT
   Capture age, transfusion history + pre-transfusion Hb, splenectomy + vaccination/penicillin status, current chelation agent + adherence, ferritin/LIC/cardiac-T2* trend, endocrine/cardiac/hepatic comorbidity, pregnancy/preconception status, alloimmunisation history (TIF 5th ed 2025)
   inputs: age, transfusion_history, splenectomy_status, pregnancy_status
   advance: Disease + comorbidity context complete
4. 4RED_FLAGS
   Bayesian pivots. (1) IRON CARDIOMYOPATHY: cardiac T2* <10 ms / new HF / arrhythmia — RR≈160 for HF (Kirk/Pennell PMID 19801505) → urgent intensive combination chelation (DFP+DFO, Tanner PMID 17372174) + cardiology. (2) APLASTIC CRISIS: acute Hb drop with LOW reticulocytes + parvovirus B19 → transfusion support. (3) POST-SPLENECTOMY FULMINANT SEPSIS: fever in asplenic patient = encapsulated-organism emergency until proven otherwise. (4) NTDT/post-splenectomy THROMBOSIS / pulmonary hypertension (prothrombotic state). (5) PREGNANCY with severe anaemia → intensified transfusion + obstetric haematology. (6) Deferiprone AGRANULOCYTOSIS — ANC <0.5 → STOP deferiprone, broad-spectrum antibiotics (TIF 5th ed 2025)
   inputs: cbc_with_indices, reticulocyte_count
   actions: workup.hemolysis
   advance: Emergent complication excluded or stabilised
5. 5INITIAL_WORKUP
   CBC + indices + RBC count + RDW + Mentzer index (MCV/RBC); reticulocytes; peripheral smear (microcytosis, target cells, basophilic stippling, NRBCs); ferritin + iron studies — the IDA-vs-trait branch (workup.chronic_ida): Mentzer <13 / high-normal RBC / normal RDW / normal-raised ferritin → trait, do NOT iron-load; LDH/haptoglobin/bilirubin for chronic haemolytic component (workup.hemolysis) (TIF 5th ed 2025; cross-cited heme.iron-deficiency-anemia.core.v1)
   inputs: cbc_with_indices, ferritin, reticulocyte_count
   actions: panel.cbc, panel.iron, workup.chronic_ida, cascade.labs_command
   advance: Microcytic pattern characterised; trait-vs-IDA branch resolved
6. 6BRANCHING_WORKUP
   Hb electrophoresis / HPLC (↑HbA2 >3.5% β-trait, ↑HbF; HbH/HbE bands); DNA analysis (β-globin sequencing; α-globin gap-PCR/MLPA for deletions; non-deletional HbH-CS); family studies; prenatal / preimplantation genetic diagnosis + carrier counselling; iron-overload quantitation (ferritin trend, LIC by MRI R2/R2*, cardiac T2*); splenomegaly branch (workup.splenomegaly); endocrine + hepatic complication panels (TIF 5th ed 2025)
   inputs: hb_electrophoresis
   actions: workup.hemolysis, workup.splenomegaly, panel.lft, panel.cmp, panel.hormone, panel.thyroid
   advance: Genotype + iron-burden + complication map established
7. 7DIFFERENTIAL
   Terminal phenotype: β-major / severe HbE-β (TDT) · β-intermedia / HbH / mild HbE-β (NTDT) · α0/α0 Hb Barts hydrops fetalis · α- or β-thalassaemia trait. Discriminate from IDA (Mentzer >13, low ferritin, high RDW → heme.iron-deficiency-anemia.core.v1), anaemia of chronic disease, sideroblastic, lead, and HbS/β compound (sickling phenotype → heme.sickle-cell.core.v1) (TIF 5th ed 2025)
   inputs: hb_electrophoresis, ferritin
   advance: Phenotype + trait-vs-mimic resolved
8. 8RISK_STRATIFICATION
   Pesaro risk class for HSCT (hepatomegaly, portal fibrosis, chelation-history); iron-overload risk by ferritin / LIC / cardiac-T2* (T2* >20 normal; 10–20 intensify; <10 high HF risk RR≈160, Kirk/Pennell PMID 19801505); transfusion-dependency tier; disease-modifying / curative candidacy (luspatercept, beti-cel, exa-cel); eGFR (CKD-EPI 2021) for deferasirox renal monitoring; PHQ-9 for chronic-disease QoL/fatigue overlap (TIF 5th ed 2025)
   inputs: cardiac_t2_star, liver_iron_concentration
   actions: calc.ckd_epi_2021, calc.phq9
   advance: Risk class + iron-burden tier + DMT/curative plan set
9. 9TREATMENT
   TDT: regular RBC transfusion to pre-transfusion Hb ~9.5–10.5 g/dL; iron chelation — deferasirox first-line PO, deferoxamine SC/IV (pregnancy-safe / intensive 24-h for siderotic cardiomyopathy), deferiprone PO (superior cardiac iron clearance); COMBINATION DFP+DFO for cardiac T2* <10 ms (Tanner Circulation 2007 PMID 17372174); luspatercept SC q3wk reduces transfusion burden (BELIEVE NEJM 2020 PMID 32212518); curative — matched-sib HSCT by Pesaro class, beti-cel/Zynteglo (HGB-207 PMID 34891223; HGB-212 PMID 39527960, ~87–91% transfusion-independent), exa-cel/Casgevy (CLIMB THAL-111 PMID 38657265, 32/35 transfusion-free ≥12 mo). NTDT: selective transfusion (growth/EMH/PHTN/pregnancy), chelate by LIC/ferritin (GI-absorption iron loading even untreated), luspatercept (BEYOND PMID 36007538, 94.8% Hb ↑≥1 g/dL) / hydroxyurea (HbF induction), manage thrombosis/PHTN/EMH, restrictive splenectomy. TRAIT: reassurance, NO iron unless co-existent proven deficiency (hard anti-pattern), genetic counselling + partner testing (TIF 5th ed 2025; NTDT 2023 NBK599489)
   inputs: transfusion_history, ferritin, cardiac_t2_star
   advance: Tier-specific treatment plan executed
10. 10DISPOSITION
    Comprehensive thalassaemia clinic (outpatient) for the large majority; inpatient/transition for severe transfusion reaction, iron cardiomyopathy / decompensated HF, therapeutic splenectomy, HSCT / gene-therapy conditioning; refer cardiology (T2* <10 ms), endocrinology, hepatology (cirrhosis/HCC), obstetric haematology, transplant/gene-therapy centre, clinical genetics (TIF 5th ed 2025)
    advance: Disposition + multidisciplinary referrals set
11. 11MONITORING
    Pre-transfusion Hb each visit (target ~9.5–10.5 in TDT); ferritin q3 months; LIC + cardiac T2* annually (more often if T2* <20 ms); ANC WEEKLY on deferiprone (agranulocytosis); renal (eGFR CKD-EPI 2021) + hepatic + GI on deferasirox; alloantibody screen each transfusion episode; growth/pubertal staging in children; LFT trend for hepatic siderosis (TIF 5th ed 2025; Tanner PMID 17372174)
    inputs: ferritin, cardiac_t2_star, cbc_with_indices
    actions: panel.cbc, panel.iron, panel.lft, panel.renal, calc.ckd_epi_2021
    advance: Iron-burden + chelation-safety monitoring documented
12. 12FOLLOWUP
    Annual endocrinopathy screen — hypogonadism, growth failure, diabetes, hypothyroidism, hypoparathyroidism, osteoporosis (bone densitometry; calcium + vitamin D); cardiac + hepatic surveillance (HCC screening if cirrhotic — route gi.cirrhosis.core.v1); fertility / pregnancy planning + pre-conception chelation washout; vaccination + lifelong penicillin if splenectomised; transition pediatric→adult care; partner + family genetic counselling, prenatal/PGT options (TIF 5th ed 2025; NTDT 2023 NBK599489)
    inputs: age
    actions: panel.hormone, panel.thyroid, panel.cmp
    advance: Complication-surveillance + counselling plan documented