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1. Definition - Hematopoietic disorders defined at the stem cell and lineage level
2. Classification - 5 major categories with all subtypes (anemias, marrow failure, myeloid neoplasms, lymphoid neoplasms, platelet disorders)
3. Causes - Etiology for each major disorder, including genetic mutations (JAK2 V617F, BCR-ABL, FLT3, NPM1, SF3B1, CALR, TP53)
4. Pathology - Molecular and cellular mechanisms for each disorder (hepcidin regulation in IDA; T-cell immune destruction in aplastic anemia; JAK-STAT in MPN; BCR-ABL constitutive kinase in CML; Reed-Sternberg cells in HL)
5. Diagnostic Approach - CBC interpretation, bone marrow biopsy findings, flow cytometry panels, cytogenetics, molecular testing, and disease-specific criteria (WHO 2022, IPSS-R, CRAB, Ann Arbor staging)
6. Management & Pharmacology - Complete drug regimens with doses (7+3 for AML, ABVD/R-CHOP for lymphomas, TKI table for CML, VRd/DaraVRd for myeloma, hATG + CsA + eltrombopag for aplastic anemia, HMAs for MDS, JAK inhibitors for MPN)
7. Complications - Disease and treatment-related complications including tumor lysis syndrome, APL differentiation syndrome, blast crisis, secondary malignancies, ONJ, and organ toxicities
8. Drug Mechanism Table - 25+ drugs organized by class, target, and indication

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Bleeding and Coagulation Disorders: A Comprehensive Reference

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1. DEFINITION

1. Primary hemostasis - Vascular injury → vasoconstriction → platelet adhesion (via vWF binding to collagen using GPIb receptor) → platelet activation → platelet aggregation (via fibrinogen bridging GPIIb/IIIa receptors) → platelet plug (temporary "white thrombus")
2. Secondary hemostasis - Coagulation cascade activation → thrombin generation → fibrinogen → fibrin mesh reinforces the platelet plug → "red thrombus"
3. Fibrinolysis - Plasmin cleaves fibrin → controlled clot dissolution

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2. CLASSIFICATION / TYPES

A. Disorders of Primary Hemostasis (Platelet/Vascular)

B. Disorders of Secondary Hemostasis (Coagulation Factor Deficiencies)

C. Combined / Mixed Disorders

• DIC - consumes both platelets AND coagulation factors
• von Willebrand disease - impairs platelet adhesion (primary) and factor VIII level (secondary)
• Liver failure - deficient factor synthesis + thrombocytopenia + hyperfibrinolysis

D. Thrombophilia / Hypercoagulable States

• Inherited: Factor V Leiden (activated protein C resistance), Prothrombin G20210A mutation, Protein C deficiency, Protein S deficiency, Antithrombin III deficiency
• Acquired: Antiphospholipid syndrome (APS/lupus anticoagulant), malignancy, pregnancy, immobility, obesity, nephrotic syndrome

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3. CAUSES / ETIOLOGY

Immune Thrombocytopenia (ITP)

• Autoantibodies (predominantly IgG anti-GPIIb/IIIa) coat platelets → splenic macrophage destruction
• Primary (idiopathic) or secondary: SLE, HIV, hepatitis C, H. pylori, CLL, drugs (quinine, heparin - see HIT)
• Bimodal: children (acute, post-viral, self-limited) and adults (chronic, female predominance)

Heparin-Induced Thrombocytopenia (HIT)

• Type I: Non-immune, mild, transient; occurs within 1-2 days; direct platelet activation by heparin
• Type II (clinically significant): IgG antibodies against platelet factor 4 (PF4)-heparin complex → activates platelets → platelet consumption AND paradoxical thrombosis (HIT + thrombosis = HITT)
• Occurs 5-10 days after starting heparin; unfractionated heparin more immunogenic than LMWH

Thrombotic Thrombocytopenic Purpura (TTP)

• Acquired TTP: Autoantibodies against ADAMTS13 (vWF-cleaving metalloprotease) → ultra-large vWF multimers accumulate → spontaneous platelet aggregation in microvasculature → microthrombi → thrombocytopenia + microangiopathic hemolytic anemia (MAHA)
• Congenital TTP (Upshaw-Schulman): Hereditary ADAMTS13 deficiency
• Triggers: drugs (quinine, ticlopidine), pregnancy, HIV, malignancy

Hemophilia A and B

• Hemophilia A: X-linked recessive, mutation in F8 gene on Xq28 → Factor VIII deficiency; 1:5,000 male births; ~1/3 are de novo mutations
• Hemophilia B (Christmas disease): X-linked recessive, mutation in F9 gene on Xq27 → Factor IX deficiency; 1:30,000 males; clinically identical to Hemophilia A
• Severity: Severe <1% factor activity, Moderate 1-5%, Mild 5-40%

von Willebrand Disease (VWD) - Most Common Inherited Bleeding Disorder

• Type 1 (75-80%): Partial quantitative deficiency of vWF; autosomal dominant; vWF activity 30-50% of normal
• Type 2 (qualitative defects):
  • 2A: Absence of high-molecular-weight (HMW) multimers → decreased platelet adhesion
  • 2B: "Gain of function" mutation → HMW multimers bind spontaneously to platelets → consumed → thrombocytopenia
  • 2M: Decreased vWF-platelet interaction (but HMW multimers present)
  • 2N ("Normandy"): Decreased vWF binding to Factor VIII → low factor VIII (mimics Hemophilia A)
• Type 3 (severe, rare): Near-complete absence of vWF; autosomal recessive; behaves like hemophilia

Disseminated Intravascular Coagulation (DIC)

• Infections: Gram-negative sepsis (endotoxin activates monocytes → TF expression), Rocky Mountain spotted fever, malaria, meningococcemia
• Obstetric: Amniotic fluid embolism (TF-rich), abruptio placentae, retained dead fetus, preeclampsia/HELLP, septic abortion
• Malignancy: APL (granules rich in TF), adenocarcinoma of pancreas, colon; mucin activates Factor X
• Trauma/Tissue injury: Head injury (brain TF), crush injury, burns, fat embolism
• Immunologic: Transfusion reaction (ABO incompatibility), CAR-T therapy, organ rejection
• Vascular: Giant hemangioma (Kasabach-Merritt syndrome), aortic aneurysm
• Liver failure, acute pancreatitis, envenomation

Vitamin K Deficiency

• Newborns (low stores, sterile gut - leads to hemorrhagic disease of newborn)
• Malabsorption: cholestasis, celiac disease, Crohn's disease, short bowel syndrome
• Dietary deficiency (rare in adults; seen with prolonged antibiotic use destroying gut flora)
• Drugs: warfarin (competitive antagonist of vitamin K epoxide reductase)

Antiphospholipid Syndrome (APS)

• Autoantibodies against phospholipid-binding proteins (primarily β2-glycoprotein I) → interference with protein C activation, antithrombin III activity, and annexin V → pro-thrombotic state
• Primary (isolated) or secondary to SLE (20-40% of SLE patients), other autoimmune diseases, lymphoproliferative malignancies, drugs

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4. PATHOLOGY / PATHOPHYSIOLOGY

Coagulation Cascade (The Framework)

• Antithrombin III (ATIII): Neutralizes thrombin, Xa, IXa, XIa (heparin accelerates this 1,000-fold)
• Protein C + Protein S: Thrombomodulin + thrombin → Protein C activation → degrades Factors Va and VIIIa
• TFPI (Tissue factor pathway inhibitor): Inactivates TF-VIIa complex
• Plasmin/fibrinolytic system: tPA + plasminogen → plasmin → cleaves fibrin (generates FDPs/D-dimers)

Hemophilia Pathophysiology

von Willebrand Disease Pathophysiology

1. Bridges damaged subendothelial collagen to platelet GPIb receptor → primary platelet adhesion
2. Carries and protects Factor VIII from proteolysis in plasma → secondary hemostasis

DIC Pathophysiology

1. Procoagulant entry (tissue factor) → systemic thrombin generation → widespread fibrin-platelet microthrombi in microvasculature
2. Microvascular occlusion → ischemia and microinfarcts in kidneys (cortical necrosis), adrenals (Waterhouse-Friderichsen), brain, and heart
3. Consumptive coagulopathy: Depletion of platelets, fibrinogen, Factors V and VIII → paradoxical bleeding
4. Secondary fibrinolysis: Plasminogen activators released → plasmin cleaves fibrin + Factors V/VIII → fibrin degradation products (FDPs) → inhibit platelet aggregation, have anti-thrombin activity, impair fibrin polymerization → worsens bleeding
5. Red cells passing through fibrin-narrowed vessels → MAHA (microangiopathic hemolytic anemia) with schistocytes

HIT Pathophysiology

TTP Pathophysiology

Antiphospholipid Syndrome

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5. DIAGNOSTIC APPROACH

Initial Bleeding History and Physical Exam

• Onset: congenital (family history, lifelong bleeding) vs. acquired
• Type of bleeding: mucocutaneous (petechiae, purpura, menorrhagia, epistaxis - primary hemostasis) vs. deep (hemarthroses, muscle hematomas, delayed post-surgical bleeding - secondary hemostasis)
• Drug history: aspirin, NSAIDs, anticoagulants, heparin, chemotherapy
• Past: easy bruising, post-dental/surgical bleeding, umbilical stump bleeding

Specific Disorder Workup

Hemophilia A and B (Goldman-Cecil Medicine, Ch. 160)

• aPTT prolonged; PT normal (intrinsic pathway defect only)
• Confirm with specific factor assays: Factor VIII activity (Hemophilia A) or Factor IX activity (Hemophilia B)
• Severity: Severe <1%, Moderate 1-5%, Mild 5-40% of normal
• VWD distinguished by normal ristocetin cofactor and normal vWF antigen in hemophilia
• Inhibitor screen: incubation study (Bethesda assay quantifies inhibitor titer in Bethesda units)
• Genetic testing: F8 gene inversion mutation (40-45% of severe Hemophilia A); F9 mutations
• Note: Mild hemophilia may have normal aPTT - not a sufficiently sensitive screen

von Willebrand Disease

• Ristocetin cofactor activity (functional vWF test): measures ability of vWF to agglutinate platelets in presence of ristocetin → decreased in all VWD types
• vWF antigen (vWF:Ag): Immunologic quantity of vWF protein
• Factor VIII activity: Decreased in Type 2N and Type 3 (vWF protects FVIII)
• vWF multimer analysis: Required to classify Type 2 subtypes (2A - absent HMW multimers; 2B - absent HMW multimers + ristocetin-induced platelet agglutination at low dose)
• RIPA (ristocetin-induced platelet aggregation): Increased at low ristocetin dose in Type 2B
• Bleeding time/PFA-100: Prolonged (primary hemostasis defect)
• PT normal; aPTT variable (prolonged if FVIII low)

DIC

• Thrombocytopenia (falling platelet count is often the first sign)
• PT and aPTT both prolonged (both pathways affected by consumed factors)
• Low fibrinogen (<150 mg/dL or rapidly falling)
• Elevated D-dimer (very sensitive for DIC; reflects secondary fibrinolysis)
• Elevated FDPs (fibrin/fibrinogen degradation products)
• Peripheral smear: schistocytes (microangiopathic hemolytic anemia)
• ISTH DIC Score: Platelet count + prolonged PT ratio + fibrinogen level + D-dimer → score ≥5 = overt DIC

• Liver failure: PT prolonged but ADAMTS13 normal; D-dimer elevated; fibrinogen often elevated (acute phase); schistocytes uncommon
• TTP: PT/aPTT/fibrinogen/D-dimer NORMAL; only thrombocytopenia + MAHA; ADAMTS13 severely reduced (<10%)
• DIC: ALL parameters abnormal simultaneously

Immune Thrombocytopenia (ITP)

• Isolated thrombocytopenia (<100×10⁹/L) with no other explanation
• Diagnosis of exclusion - no direct test for ITP antibodies is clinically validated for routine use
• Normal PT, aPTT, fibrinogen, D-dimer (coagulation intact)
• Bone marrow biopsy (optional in typical cases; indicated if unusual features or age >60): normal or increased megakaryocytes
• Distinguish from HIT (recent heparin exposure), TTP (schistocytes, renal/neuro), SLE (ANA), HIV/HCV (serology)

HIT

• Clinical scoring: 4T Score (Thrombocytopenia, Timing, Thrombosis, other causes of Thrombocytopenia): Low (0-3), Intermediate (4-5), High (6-8)
• Anti-PF4/heparin ELISA: Highly sensitive (>95%) but low specificity; negative result rules out HIT
• Functional assay - Serotonin Release Assay (SRA) or Heparin-Induced Platelet Activation (HIPA): Gold standard confirmatory test (high specificity)
• Platelet count typically 30-80% decrease from baseline; usually not <20×10⁹/L
• Timing: Day 5-14 after heparin initiation (or within 24 hours if recent prior heparin exposure)

TTP

• ADAMTS13 activity <10% = diagnostic for immune TTP (send before plasma exchange)
• ADAMTS13 inhibitor antibody (present in immune TTP)
• Peripheral smear: schistocytes (helmet cells, fragmented RBCs), thrombocytopenia
• LDH elevated (hemolysis), bilirubin elevated, haptoglobin low or absent
• Direct Coombs test: NEGATIVE (non-immune hemolysis - key distinction from AIHA)
• PT, aPTT, fibrinogen, D-dimer: NORMAL (distinguish from DIC)

Antiphospholipid Syndrome (Sapporo/Sydney Criteria)

• Arterial, venous, or small-vessel thrombosis
• Pregnancy morbidity (≥3 early miscarriages, ≥1 late miscarriage, ≥1 premature birth due to eclampsia/placental insufficiency)

• Lupus anticoagulant (LA): Prolonged aPTT that does NOT correct on 1:1 mixing; corrects with excess phospholipid (hexagonal phase assay, dRVVT)
• Anticardiolipin antibody (aCL): IgG or IgM, moderate to high titer (>40 GPL or MPL units), by ELISA
• Anti-β2-glycoprotein-I antibody: IgG or IgM, >99th percentile, by ELISA

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6. MANAGEMENT AND PHARMACOLOGY

6A. Hemophilia A

• Recombinant FVIII concentrates (first-line; safest): Standard half-life (octocog alfa, turoctocog alfa), Extended half-life (EHL): Efmoroctocog alfa (rFVIIIFc) - Fc-fusion doubles half-life; Rurioctocog alfa pegol - PEGylated
• Plasma-derived FVIII/vWF concentrates: Contain vWF; useful in Type 3 VWD
• Target factor levels:
  • Minor bleeds (hemarthrosis, muscle): Peak 30-50%; duration 1-3 days
  • Major bleeds (CNS, retroperitoneal, surgical): Peak 80-100%; duration 7-14 days
  • Life-threatening bleed: 100% activity → continuous infusion to maintain ≥50%

• Primary prophylaxis: Begin before 2nd joint bleed; prevents development of target joints and arthropathy
• Typical regimen: 25-40 IU/kg IV 3 times weekly (standard FVIII) or twice weekly (EHL products)

• Emicizumab (Hemlibra): Bispecific antibody mimicking Factor VIII cofactor function - bridges FIXa and FX; SC injection every 1, 2, or 4 weeks; effective for Hemophilia A WITH or WITHOUT inhibitors; does not require IV access → major quality-of-life advance

• Recombinant Factor VIIa (rFVIIa, NovoSeven): Bypasses FVIII/IX by directly activating Factor X via tissue-factor-independent mechanism; 90-120 mcg/kg IV q2h until hemostasis achieved; short half-life (~2.5 hours)
• Activated prothrombin complex concentrate (aPCC/FEIBA): Contains activated Factors II, VII, IX, X; 50-100 IU/kg q8-12h; max 200 IU/kg/day
• Immune tolerance induction (ITI): High-dose FVIII infusions daily for months to eradicate inhibitor

• DDAVP (Desmopressin): Releases endogenous vWF and FVIII from endothelial storage (Weibel-Palade bodies) → raises FVIII 2-3-fold; IV 0.3 mcg/kg or IN 150 mcg (each nostril); effective only for mild Hemophilia A; tachyphylaxis after 3-4 doses
• Tranexamic acid / epsilon-aminocaproic acid (EACA): Antifibrinolytic agents; inhibit plasminogen-streptokinase complex; useful for mucosal bleeding (oral/dental, epistaxis, menorrhagia); tranexamic acid 25 mg/kg TID PO or 10 mg/kg IV TID

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6B. Hemophilia B (Factor IX Deficiency)

• Recombinant Factor IX concentrates: Each 1 IU/kg raises FIX by ~1% (less efficient than FVIII due to distribution volume)
• Extended half-life FIX: Eftrenonacog alfa (FIX-Fc fusion, t½ ~84 hours, weekly dosing); nonacog beta pegol (PEGylated, t½ ~93 hours, weekly dosing)
• Gene therapy breakthrough: Fidanacogene elaparvovec (Beqvez) - AAV5-mediated FIX gene delivery; single IV infusion; achieves sustained >40% FIX activity in most patients; FDA approved 2024
• Prophylaxis: 25-40 IU/kg twice weekly (standard) or once weekly (EHL)
• DDAVP NOT effective for Hemophilia B (does not release FIX)
• Cryoprecipitate contains NO FIX - no value in Hemophilia B treatment

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6C. von Willebrand Disease

• Releases vWF and Factor VIII from Weibel-Palade bodies (endothelium) and platelet alpha-granules
• IV: 0.3 mcg/kg in 50 mL NS over 30 minutes; intranasal: 150 mcg per nostril (300 mcg total)
• Raises vWF and FVIII 2-5-fold within 30-60 minutes, lasting 6-8 hours
• Tachyphylaxis after 3-4 doses (stores depleted); water restriction required (antidiuretic effect → hyponatremia risk)
• Contraindicated in Type 2B: DDAVP releases HMW multimers that spontaneously bind platelets → worsens thrombocytopenia
• Not effective in Type 3 (no vWF stores to release)

• Plasma-derived vWF/FVIII concentrates (Wilate, Alphanate, Humate-P): Maintain vWF activity ≥50 IU/dL; repeat daily for 3+ days post-surgery (major surgery: ≥50 IU/dL for 5-10 days)
• Recombinant vWF (rVWF, Vonvendi): Enriched in HMW multimers, lacks FVIII; co-infuse recombinant FVIII with first dose

• Tranexamic acid 1 g TID PO or 10 mg/kg IV TID; start pre-operatively, continue 7-10 days post-op
• EACA (epsilon-aminocaproic acid) 50 mg/kg q4-6h PO/IV

• Combined OCP or progesterone: Increases vWF levels (estrogen stimulates vWF synthesis); useful for menorrhagia in Type 1 VWD

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6D. DIC

• Sepsis → appropriate antibiotics + source control
• Obstetric cause → delivery/evacuation of uterus
• APL → ATRA + arsenic trioxide (rapidly reduces procoagulant load)
• Malignancy → treat underlying malignancy

• Fresh Frozen Plasma (FFP): Contains all coagulation factors + inhibitors; 10-15 mL/kg IV; target PT/aPTT <1.5× control
• Cryoprecipitate: Rich in fibrinogen, Factor VIII, vWF, Factor XIII; 1 pool (10 units) IV; target fibrinogen >150 mg/dL; use when hypofibrinogenemia is the dominant defect
• Platelet transfusion: 1 adult dose (4-6 units) for platelets <20,000/μL or <50,000/μL with active bleeding; avoid in TTP/HIT (no benefit, may worsen)
• Antithrombin III concentrate: Consider in sepsis-associated DIC with very low AT-III levels

• Heparin: Indicated for DIC manifested primarily by thrombosis; blocks thrombin and Xa via ATIII; contraindicated in DIC with active hemorrhage; begin after blood component replacement
• Low-dose UFH 5-10 IU/kg/hr continuous infusion; or LMWH in stable chronic DIC (cancer-associated)

• Generally contraindicated in DIC (may worsen thrombosis); exception: life-threatening bleeding refractory to blood component therapy (e.g., cardiac surgery DIC) → tranexamic acid 1 g IV

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6E. Immune Thrombocytopenia (ITP)

• Corticosteroids: Prednisone 1-2 mg/kg/day PO x 2-4 weeks (then taper); dexamethasone 40 mg/day x 4 days (higher CR rate, faster response); mechanism: suppress phagocytosis and autoantibody production; response rate ~70-80% but sustained remission only ~20-30%
• IVIG (IV Immunoglobulin): 1 g/kg/day x 1-2 days; rapidly raises platelet count (within 24-48 hours); mechanism - saturates Fcγ receptors on splenic macrophages, blocking platelet destruction; also neutralizes anti-platelet antibodies; transient effect (weeks); use when rapid rise needed (pre-surgery, active bleeding)
• Anti-D immunoglobulin (WinRho): For Rh-positive, non-splenectomized patients; 50-75 mcg/kg IV; opsonizes RBCs → competes for splenic Fc receptors; risk: hemolysis (black box warning)

• Rituximab (anti-CD20 monoclonal antibody): 375 mg/m² IV weekly x 4 doses; depletes B cells → reduced autoantibody production; durable response ~40% at 1 year; risk: HBV reactivation, infusion reactions, PML (rare)
• Splenectomy: Removes primary site of platelet destruction and anti-platelet antibody production; 60-70% durable remission; use after failure of ≥1 medical therapy; vaccination required ≥2 weeks before (pneumococcal, meningococcal, Hib)
• Thrombopoietin receptor agonists (TPO-RAs) - increase platelet production:
  • Romiplostim (Nplate): Weekly SC injection; 1-10 mcg/kg; activates MPL (thrombopoietin receptor) → stimulates megakaryopoiesis; response rate ~80%; risk: marrow fibrosis, rebound thrombocytopenia if abruptly stopped
  • Eltrombopag (Promacta): Oral; 25-75 mg/day; non-peptide TPO-RA binding transmembrane domain of MPL; hepatotoxicity risk (monitor LFTs); thrombocytopenia rebounds if stopped abruptly
  • Avatrombopag and lusutrombopag: Newer oral TPO-RAs without food interaction
• Fostamatinib (Tavlisse): Oral SYK inhibitor; blocks signaling downstream of Fc receptor on macrophages → prevents phagocytosis of opsonized platelets; 100-150 mg BID; for chronic ITP after ≥2 prior therapies

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6F. HIT (Heparin-Induced Thrombocytopenia Type II)

1. STOP ALL HEPARIN (including heparin flushes, LMWH, heparin-coated catheters) - most critical step
2. Do NOT transfuse platelets (unless life-threatening bleeding or platelet count <10,000; platelet transfusions may fuel further thrombosis)
3. Start alternative anticoagulation IMMEDIATELY (even before confirmatory lab results, if clinical suspicion high)

• Argatroban: Direct thrombin inhibitor; IV infusion 2 mcg/kg/min; hepatically metabolized (preferred in renal failure); monitor aPTT (target 1.5-3× baseline); FDA approved for HIT
• Bivalirudin: Direct thrombin inhibitor; IV infusion; renally cleared; short half-life (~25 min); preferred for cardiac catheterization in HIT
• Fondaparinux: Selective anti-Xa pentasaccharide; SC injection; does not bind PF4 and does not cause HIT; 5-10 mg SC daily; off-label but widely used
• Direct oral anticoagulants (DOACs): Rivaroxaban and apixaban used once platelet count recovers >150,000
• Avoid warfarin in acute phase (until platelet count >150,000): warfarin can cause paradoxical venous limb gangrene and skin necrosis by rapidly depleting Protein C before thrombin production is controlled
• Duration: Continue alternative anticoagulation for ≥3 months (or longer with confirmed thrombosis)

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6G. TTP

• Therapeutic plasma exchange (plasmapheresis): 1-1.5 plasma volumes replaced with fresh frozen plasma (FFP) daily until remission; dual mechanism: (1) removes ADAMTS13 antibodies, (2) replenishes ADAMTS13 enzyme; must start within hours of diagnosis; reduces mortality from ~90% untreated to <20%
• Do NOT delay PEX for laboratory confirmation if clinical diagnosis is strong

• Rituximab (anti-CD20): 375 mg/m² IV weekly x 4 doses; depletes B cells producing anti-ADAMTS13 antibodies; reduces relapse rate; can be initiated with PEX
• Corticosteroids: Prednisone 1 mg/kg/day or methylprednisolone 1 g/day IV x 3 days (standard adjunct)
• Caplacizumab (Cablivi): Anti-von Willebrand factor (anti-A1 domain) nanobody - blocks interaction between ULvWF multimers and platelet GPIb receptor; SC injection daily; dramatically accelerates platelet recovery; reduces major thrombotic complications and recurrence; given with PEX until ADAMTS13 activity normalizes; FDA approved 2019

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6H. Vitamin K Deficiency / Warfarin Reversal

• Phytonadione (Vitamin K1): 5-10 mg PO/IV for warfarin reversal; IV preferred for severe bleeding (but risk of anaphylaxis - infuse slowly over 30 min); corrects PT within 6-24 hours (PO) or 2-6 hours (IV)
• High-dose IV vitamin K: 10 mg for severe/urgent reversal; repeated daily if necessary

• 4-factor Prothrombin Complex Concentrate (4F-PCC / Kcentra): Contains Factors II, VII, IX, X + Protein C, S, Z + heparin; 25-50 IU/kg IV based on INR; immediate INR reversal (minutes); preferred over FFP for urgent reversal (faster, smaller volume, no cross-match needed); FDA approved for urgent warfarin reversal
• 3-factor PCC: Contains Factors II, IX, X (low Factor VII); less effective for warfarin reversal
• Fresh Frozen Plasma: 10-15 mL/kg; slower, requires large volumes; use when PCC unavailable

• Idarucizumab (Praxbind): Monoclonal antibody fragment; specific reversal of dabigatran (direct thrombin inhibitor); 5 g IV (2×2.5 g); immediate full reversal; FDA approved 2015
• Andexanet alfa (Andexxa): Recombinant modified FXa decoy; reverses rivaroxaban, apixaban, edoxaban (anti-Xa agents); FDA approved 2018; low or high dose regimen depending on agent/dose/timing
• Tranexamic acid: Adjunct antifibrinolytic for severe DOAC-associated bleeding

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6I. Antiphospholipid Syndrome (APS)

• Acute thrombosis: Therapeutic heparin (UFH or LMWH) bridging to warfarin
• Long-term anticoagulation: Warfarin (target INR 2.0-3.0 for venous; 2.5-3.5 for arterial thrombosis or high-risk triple positive APS)
• DOACs: Inferior to warfarin in high-risk APS (especially triple-positive); rivaroxaban showed higher arterial thrombosis rate than warfarin in TRAPS trial; use only in single/double positive with venous thrombosis if warfarin not tolerated

• Low-dose aspirin 81 mg/day + Low-molecular-weight heparin (LMWH) prophylaxis throughout pregnancy and 6 weeks post-partum; aspirin alone for low-risk obstetric APS

• Triple therapy: Anticoagulation (heparin) + Glucocorticoids (methylprednisolone 500-1000 mg/day IV x 3 days) + IVIG or plasma exchange
• Rituximab or eculizumab for refractory cases

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Summary Pharmacology Table

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7. COMPLICATIONS

Hemophilia

• Hemophilic arthropathy - the dominant long-term morbidity: chronic synovitis → cartilage destruction → joint space narrowing → flexion contractures, disability; requires orthopedic intervention (synovectomy, total joint replacement)
• Intracranial hemorrhage: Occurs in 10% lifetime risk; 2% per year risk; 30% case fatality; neurologic sequelae in survivors
• Compartment syndrome: Intramuscular hematoma in closed fascial compartment → neurovascular compromise → fasciotomy required
• Retroperitoneal hemorrhage: Mimics acute abdomen; compresses femoral nerve → hip flexion deformity; life-threatening if unrecognized
• Inhibitor development: Anti-FVIII alloantibodies in 20-30% of severe Hemophilia A; dramatically increases treatment complexity and cost
• Transfusion-transmitted infections (historical): HIV and Hepatitis C transmitted through pooled factor concentrates before 1985 (viral inactivation); now extremely rare with recombinant products
• Iron deficiency anemia: From chronic recurrent bleeding

von Willebrand Disease

• Menorrhagia → iron deficiency anemia (most common presentation in women)
• Post-surgical hemorrhage if untreated
• GI bleeding (from arteriovenous malformations in Type 2A/3)
• Type 2B: Thrombocytopenia (spontaneous vWF-platelet aggregation)
• DDAVP complications: Hyponatremia/seizures (water retention), facial flushing, tachycardia
• Repeated vWF/FVIII concentrate infusion: Risk of elevated FVIII → thrombosis (rare)

DIC

• Acute organ failure:
  • Kidneys: Bilateral renal cortical necrosis (fibrin microthrombi in glomeruli) → acute renal failure
  • Adrenals: Bilateral hemorrhagic necrosis → Waterhouse-Friderichsen syndrome (acute adrenal insufficiency; classically with meningococcemia)
  • Brain: Microinfarcts → altered consciousness, seizures, coma
  • Anterior pituitary: Postpartum Sheehan syndrome (DIC + ischemic pituitary necrosis → pan-hypopituitarism)
  • Lungs: Diffuse alveolar damage → ARDS
• Diffuse hemorrhage: Oozing from IV sites, mucosal surfaces, wound sites; intracranial hemorrhage
• Mortality of acute DIC: 20-50% (heavily dependent on underlying cause)
• Purpura fulminans: Symmetric peripheral gangrene from microvascular thrombosis in skin (classically meningococcal DIC)

ITP

• Life-threatening intracranial hemorrhage (rare but most feared; risk when platelets <10,000/μL)
• Fatigue, anxiety, reduced quality of life from chronic thrombocytopenia
• Treatment complications:
  • Prolonged corticosteroids: Cushing syndrome, osteoporosis, avascular necrosis, hyperglycemia, infections, cataracts
  • Splenectomy: Lifelong risk of overwhelming post-splenectomy infection (OPSI) with encapsulated organisms (S. pneumoniae, N. meningitidis, H. influenzae) → vaccinate pre-splenectomy; lifelong penicillin prophylaxis debated
  • Rituximab: Hepatitis B reactivation, prolonged hypogammaglobulinemia, PML (rare)
  • TPO-RAs: Rebound thrombocytopenia on abrupt discontinuation; marrow reticulin fibrosis (generally reversible)
  • IVIG: Headache (aseptic meningitis), hemolysis, anaphylaxis (in IgA-deficient individuals)

HIT Type II

• Thrombosis (primary feared complication, not bleeding) - 50% of HIT patients develop thrombosis:
  • Deep vein thrombosis (DVT) and pulmonary embolism (most common)
  • Limb artery thrombosis → limb ischemia, amputation
  • Stroke, MI, mesenteric ischemia (less common)
• Venous limb gangrene and warfarin-induced skin necrosis if warfarin is started without adequate alternative anticoagulation (Protein C depletion precedes full anticoagulant effect)
• Long-term: 30-day mortality ~5-10%; 30-day thrombosis rate ~15-30% if untreated

TTP

• Without treatment: Mortality >90%; with prompt PEX: mortality <20%
• Neurological damage: Transient (reversible in most with treatment) - stroke, confusion, seizures, visual disturbances; some permanent neurological deficits in delayed/severe cases
• Renal failure: More prominent in HUS (complement-mediated) than typical immune TTP
• Cardiac involvement: Myocardial microinfarcts → arrhythmias, sudden death
• Relapse rate: ~30-40% in immune TTP (due to persistent or recurrent ADAMTS13 autoantibodies); maintenance rituximab reduces relapse
• Treatment complications of PEX: Central line complications (infection, thrombosis, pneumothorax); hypocalcemia (citrate anticoagulant → Ca²⁺ chelation); allergic reactions to FFP; volume overload

APS

• Recurrent thrombosis: 50% risk of recurrence over 5 years without anticoagulation
• Recurrent pregnancy loss and obstetric morbidity: Pre-eclampsia, placental insufficiency, intrauterine growth restriction, fetal death
• Libman-Sacks endocarditis: Non-bacterial verrucous endocarditis → valve regurgitation; embolic events
• Livedo reticularis: Mottled skin discoloration (persistent in APS)
• Cognitive impairment and white matter lesions from repeated cerebrovascular events
• Warfarin complications: Bleeding (intracranial, GI); teratogenic (warfarin embryopathy) → replace with LMWH in pregnancy
• CAPS (Catastrophic APS): Multiorgan thrombosis over <1 week; 30% mortality

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Clinical pearl: The anatomical site of bleeding guides the diagnosis:

• Skin/mucous membranes (petechiae, purpura, menorrhagia) → platelet/vascular problem (primary hemostasis)
• Joints/deep muscles, delayed bleeding → coagulation factor deficiency (secondary hemostasis)
• Both simultaneously → DIC, or severe combined disorder (VWD Type 3)

The mixing test is the single most important discriminating laboratory test: correction of prolonged PT/aPTT on 1:1 mix with normal plasma indicates factor deficiency; failure to correct indicates an inhibitor (lupus anticoagulant, acquired anti-FVIII antibody).

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Leukaemias: A Comprehensive Reference

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1. DEFINITION

• Bone marrow infiltration → displacement of normal haematopoiesis → anaemia, thrombocytopenia, neutropenia
• Peripheral blood involvement → circulating blasts/abnormal cells
• Extramedullary infiltration → lymphadenopathy, hepatosplenomegaly, CNS disease, organ infiltration

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2. TYPES / CLASSIFICATION

Primary Division: Acute vs Chronic; Myeloid vs Lymphoid

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A. Acute Myeloid Leukaemia (AML) - WHO 2022 Classification

• AML with t(8;21)(q22;q22.1) - RUNX1::RUNX1T1 (favourable)
• AML with inv(16)(p13.1q22) or t(16;16) - CBFB::MYH11 (favourable, core-binding factor AML)
• APL with t(15;17)(q24.1;q21.2) - PML::RARA (acute promyelocytic leukaemia - distinct entity)
• AML with t(9;11)(p21.3;q23.3) - MLLT3::KMT2A (intermediate)
• AML with t(6;9)(p23;q34.1) - DEK::NUP214 (adverse)
• AML with inv(3)(q21.3q26.2) or t(3;3) - GATA2, MECOM (adverse)
• AML (megakaryoblastic) with t(1;22) - RBM15::MKL1
• AML with BCR::ABL1 (provisional)
• AML with mutated NPM1 (favourable if FLT3 wild-type)
• AML with biallelic CEBPA mutations (favourable)
• Provisional: AML with mutated RUNX1 (adverse)

• AML with minimal differentiation (M0)
• AML without maturation (M1)
• AML with maturation (M2)
• Acute myelomonocytic leukaemia (M4)
• Acute monoblastic/monocytic leukaemia (M5)
• Pure erythroid leukaemia (M6)
• Acute megakaryoblastic leukaemia (M7)
• Acute basophilic leukaemia
• Acute panmyelosis with myelofibrosis

• Myeloid sarcoma (extramedullary AML)
• Myeloid proliferations in Down syndrome (trisomy 21): Transient abnormal myelopoiesis (TAM), Myeloid leukaemia of Down syndrome

• Acute undifferentiated leukaemia
• Mixed phenotype acute leukaemia (MPAL) - B/myeloid, T/myeloid, with BCR-ABL1 or KMT2A

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B. Acute Lymphoblastic Leukaemia (ALL) - WHO 2022 Classification

• B-ALL NOS
• B-ALL with t(9;22) - BCR::ABL1 (Ph+ ALL, ~25% adults, ~3% children; poor prognosis)
• B-ALL with KMT2A rearrangement (t(v;11q23.3)) - infants; poor prognosis
• B-ALL with t(12;21) - ETV6::RUNX1 (most common translocation in childhood ALL; ~25%; good prognosis)
• B-ALL with hyperdiploidy (>50 chromosomes; good prognosis, children)
• B-ALL with hypodiploidy (<44 chromosomes; adverse prognosis)
• B-ALL with t(5;14) - IL3::IGH (eosinophilia associated)
• B-ALL with t(1;19) - TCF3::PBX1
• Ph-like ALL (BCR-ABL1-like): Gene expression profile similar to Ph+ ALL but lacks BCR-ABL1; CRLF2 rearrangement most common (~50% of Ph-like); JAK-STAT pathway activated; adverse prognosis; may respond to JAK inhibitors
• B-ALL with iAMP21 (intrachromosomal amplification of chromosome 21; adverse)
• B-ALL with MEF2D, ZNF384, DUX4, PAX5 rearrangements

• ~15% of childhood ALL, ~25% of adult ALL
• Often presents with mediastinal (thymic) mass
• Express TdT, CD3, CD7; subset: Early T-cell precursor ALL (ETP-ALL) - least differentiated, poorest prognosis within T-ALL

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C. Chronic Myeloid Leukaemia (CML)

• Chronic phase (CP): >90% at diagnosis; well-tolerated for 3-5 years if untreated
• Accelerated phase (AP): WHO criteria include blasts 10-19%, basophils ≥20%, new cytogenetic abnormalities
• Blast phase/Blast crisis (BC): ≥20% blasts; myeloid (70%) or lymphoid (30%); survival <12 months untreated

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D. Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)

• Most common adult leukaemia in Western world
• Identical biology: CLL = peripheral blood/marrow predominant; SLL = lymph node predominant; same disease
• Subtype: Prolymphocytic leukaemia (PLL) - more aggressive; large cells; >55% prolymphocytes
• Richter transformation: CLL → aggressive DLBCL (~5%); very poor prognosis

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E. Other/Rare Leukaemias

• Hairy cell leukaemia (HCL): Mature B-cell, BRAF V600E mutation; splenomegaly; "dry tap" on BM aspiration
• T-cell prolymphocytic leukaemia (T-PLL): Aggressive; ATM mutations
• Large granular lymphocytic (LGL) leukaemia: T or NK cell; indolent; associated with autoimmune cytopenias
• Adult T-cell leukaemia/lymphoma (ATLL): HTLV-1 driven; aggressive
• Blastic plasmacytoid dendritic cell neoplasm (BPDCN): CD123+ CD56+; aggressive

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3. CAUSES / AETIOLOGY

Genetic/Constitutional Risk

• Down syndrome (Trisomy 21): 10-20-fold increased risk of leukaemia; near 100% TAM in neonates; myeloid leukaemia of Down syndrome; leukaemia at younger age with better outcomes
• Fanconi anaemia, ataxia-telangiectasia, Bloom syndrome, Wiskott-Aldrich syndrome: DNA repair/chromosomal instability syndromes
• Familial platelet disorder (RUNX1 mutation): Predisposition to AML
• GATA2 deficiency: Predisposition to MDS/AML
• Germline TP53 (Li-Fraumeni): Haematologic and solid tumour predisposition

Environmental and Acquired Risk Factors

• Most well-established environmental risk; atomic bomb survivors (Hiroshima/Nagasaki) had markedly increased AML, ALL, and CML risk
• Greatest risk for CML from radiation (Goldman-Cecil Medicine, Ch. 170)
• Prior radiotherapy (therapeutic doses) increases leukaemia risk years later
• No infectious agent for CML identified despite ABL presence in Abelson murine leukaemia retrovirus

• Benzene (industrial solvent): Most established chemical cause of AML; occupational exposure in shoe manufacturing, petroleum, rubber industries
• Pesticides and herbicides: Agricultural workers
• Hair dyes (historical risk with older formulations)

• Alkylating agents (cyclophosphamide, melphalan, chlorambucil, busulfan): Typical latency 5-7 years post-exposure; chromosome 5 and 7 deletions dominant
• Topoisomerase II inhibitors (etoposide, doxorubicin, teniposide): Latency 1-3 years; MLL/KMT2A (11q23) rearrangements; often AML M4/M5 phenotype
• Radiotherapy: Particularly myelosuppressive field

• HTLV-1 (Human T-Lymphotropic Virus Type 1): Adult T-cell leukaemia/lymphoma (ATLL); endemic Japan, Caribbean, parts of Africa
• Epstein-Barr virus (EBV): Burkitt lymphoma/ALL; post-transplant lymphoproliferative disorders
• HIV: Increased risk of ALL, aggressive B-cell lymphomas via immunosuppression

• Myelodysplastic syndrome → secondary AML (10-40% over lifetime)
• Myeloproliferative neoplasms → blast transformation
• PNH → AML (rare)
• Aplastic anaemia → MDS/AML clonal evolution

• Obesity (increased ALL and AML risk)
• Smoking (modest AML risk increase)
• Age: AML incidence rises sharply with age (median ~68 years); ALL bimodal (peak childhood 2-5 years, second peak elderly); CLL predominantly elderly (median >70 years); CML median 65 years

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4. PATHOLOGY / PATHOPHYSIOLOGY

Normal Haematopoiesis and the Leukaemic Block

1. Block differentiation (acute leukaemias): blasts accumulate unable to mature
2. Confer proliferative advantage (all leukaemias): increased cell division
3. Confer survival advantage (all leukaemias): resistance to apoptosis

• Class I mutations: Activate signalling pathways → proliferation (e.g., FLT3-ITD, BCR-ABL, RAS, JAK2)
• Class II mutations: Block differentiation (e.g., CEBPA, RUNX1-RUNX1T1, NPM1, PML-RARA)

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AML Pathophysiology

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ALL Pathophysiology

• ETV6-RUNX1 (t12;21): Disrupts RUNX1 (CBF) → moderate differentiation block; hypersensitive to L-asparaginase; excellent prognosis
• BCR-ABL1 (Ph+): Constitutive tyrosine kinase → same as CML but more aggressive in ALL context; activates STAT5, RAS, PI3K
• Hyperdiploidy: Extra chromosomes amplify genes for metabolic pathways (folate, purine) → hypersensitivity to antimetabolites → excellent prognosis in children
• KMT2A rearrangements (MLL): Found in infant ALL (<1 year); often t(4;11); very high relapse rate

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CML Pathophysiology

• RAS/MAPK → proliferation
• JAK-STAT (STAT5) → anti-apoptosis, proliferation
• PI3K/AKT → survival
• MYC → cell cycle progression

• M-BCR → p210 (>95% CML, also ~50% Ph+ ALL)
• m-BCR → p190 (~half of Ph+ ALL, rare CML)
• μ-BCR → p230 (rare CML, chronic neutrophilic leukaemia variant)

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CLL Pathophysiology

• Mutated IGHV (post-germinal centre origin): More indolent, longer survival
• Unmutated IGHV (pre-germinal centre origin): More aggressive, shorter survival, higher risk of Richter transformation

• del(17p) / TP53 mutation: ~7% at diagnosis, >50% at relapse; resistance to chemoimmunotherapy; BTK inhibitors/venetoclax remain effective
• del(11q) (ATM): Adverse; bulky lymphadenopathy
• del(13q14) (only): Most common (~50%), favourable when sole abnormality
• Trisomy 12: Intermediate risk
• ZAP-70 expression, CD38 expression: Surrogate markers for unmutated IGHV

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Hairy Cell Leukaemia (HCL) Pathophysiology

• Mature B-cell neoplasm; virtually 100% have BRAF V600E activating mutation → MEK-ERK signalling → proliferation
• Cells have abundant pale cytoplasm with "hairy" cytoplasmic projections (TRAP positive)
• Splenomegaly (massive) from red pulp infiltration; "dry tap" on marrow aspiration (fibrosis)
• Pancytopenia; monocytopenia (characteristic finding not seen in most other leukaemias)

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5. CLINICAL FEATURES / PRESENTATION

Acute Leukaemias (AML and ALL)

• Anaemia: Fatigue, dyspnoea, pallor, palpitations
• Thrombocytopenia: Petechiae, purpura, bruising, epistaxis, gingival bleeding, heavy menstruation
• Neutropenia: Recurrent/severe infections, fever (febrile neutropenia), oral candidiasis

• Gingival hypertrophy and infiltration: Monocytic subtypes (M4/M5 AML)
• Skin infiltration (leukaemia cutis): Monocytic and myelomonocytic subtypes
• APL-specific: DIC with both thrombosis and haemorrhage; may present with fatal haemorrhage
• Chloroma/Myeloid sarcoma: Extramedullary tumour of myeloblasts (orbit, skin, lymph nodes)
• Leukostasis (WBC >100,000/μL): Dyspnoea, confusion, priapism, visual disturbances from sluggish flow in microvessels

• Lymphadenopathy (more prominent than AML)
• Splenomegaly and hepatomegaly (more pronounced in ALL)
• Mediastinal mass: T-ALL (thymic origin); can cause SVC syndrome
• CNS involvement: Headache, neck stiffness, cranial nerve palsies (ALL has much higher CNS risk than AML)
• Bone pain: Periosteal infiltration (especially children with ALL); most common presenting symptom in paediatric ALL
• Testicular involvement: Testes are a CNS sanctuary site; painless testicular enlargement
• Hyperuricaemia more common in ALL (high cell turnover)

CML Clinical Features

• Often asymptomatic at diagnosis (discovered incidentally on routine CBC)
• Fatigue, night sweats, weight loss (constitutional B symptoms)
• Massive splenomegaly - hallmark; left upper quadrant pain/fullness; early satiety
• Hepatomegaly (less prominent)
• Gout/hyperuricaemia from high cell turnover
• Rare: Priapism (leukostasis in penile vessels), hyperviscosity symptoms
• Blast crisis: Fever, bone pain, rapidly enlarging spleen, refractory cytopenias - mimics acute leukaemia

CLL Clinical Features

• Asymptomatic lymphocytosis (most common presentation; incidentally discovered)
• Progressive painless lymphadenopathy (cervical, axillary, inguinal)
• Splenomegaly and hepatomegaly
• Constitutional: Fatigue, night sweats, weight loss, fevers
• Recurrent infections (hypogammaglobulinaemia; functional immunodeficiency)
• Autoimmune complications: AIHA (autoimmune haemolytic anaemia - warm IgG type, Coombs positive), ITP
• "B symptoms" (fever >38°C, drenching night sweats, >10% weight loss): Feature of advanced/aggressive disease

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6. DIAGNOSTIC APPROACH

Peripheral Blood (First Step)

• Anaemia (normocytic/normochromic; non-regenerative - low reticulocyte count)
• Thrombocytopenia
• WBC count: Variable (low, normal, or very high); blast cells in differential are key
• Basophilia: Characteristic of CML (most sensitive indicator of CML on smear)
• Lymphocytosis: CLL (typically >5×10⁹/L for >3 months by 2018 iwCLL guidelines)

• AML: Blasts with Auer rods (pathognomonic for myeloid lineage); Pelger-Huët cells; hypogranular neutrophils in APL
• ALL: Blasts (no Auer rods; cytoplasm scanty/agranular); lymphoblasts indistinguishable morphologically from myeloblasts - require immunophenotyping
• CML: Myeloid "left shift" with full maturation spectrum (no maturation block); prominent basophilia and eosinophilia; reduced LAP (leukocyte alkaline phosphatase) score
• CLL: Mature small lymphocytes with "smudge cells" (fragile CLL cells disrupted on smear) - characteristic

Bone Marrow Evaluation

• Acute leukaemias: Hypercellular; ≥20% blasts in AML; ≥20% lymphoblasts in ALL (WHO 2022 defines acute leukaemia as ≥20% blasts, though certain cytogenetic subtypes of AML [t(8;21), inv(16), APL] are diagnosed regardless of blast %)
• CML: Hypercellular; markedly increased granulopoiesis with all stages; megakaryocytes increased (often small/hypolobated); blasts <10% in chronic phase
• CLL: Infiltrated by small mature lymphocytes; interstitial, nodular, or diffuse pattern
• HCL: Marrow fibrosis → "dry tap"; hairy cells on trephine sections

Immunophenotyping (Flow Cytometry) - Essential for Lineage Assignment

Cytogenetics and Molecular Testing

• Identifies: t(8;21), inv(16), t(15;17) (APL), t(9;22) (Philadelphia), del(17p), del(11q), del(13q), trisomy 12 (CLL), hyperdiploidy/hypodiploidy (ALL)
• Turnaround: 2-3 weeks; requires dividing cells

• Rapid (24-48 hours); detects specific rearrangements even in non-dividing cells
• BCR-ABL1 (CML/Ph+ALL), PML-RARA (APL), ETV6-RUNX1 (ALL)
• Used for minimal residual disease (MRD) monitoring in CML

• Detects fusion gene transcripts: BCR-ABL1 (e13a2 or e14a2 for p210); ETV6-RUNX1; PML-RARA
• Quantitative RT-PCR (qPCR/IS): Standard for CML monitoring (international scale); BCR-ABL1 ≤0.1% IS = major molecular response; BCR-ABL1 ≤0.01% IS = MR4.0
• Baseline BCR-ABL1 by qPCR must be established before starting TKI therapy (Goldman-Cecil, Ch. 170)

• AML: FLT3-ITD/TKD, NPM1, CEBPA (biallelic), IDH1/IDH2, TP53, RUNX1, ASXL1, DNMT3A, TET2, SRSF2
• ALL: IKZF1 (Ikaros deletion; Ph-like ALL marker), NOTCH1 (T-ALL), PAX5, ETV6
• CLL: IGHV mutation status, TP53/del(17p), NOTCH1, SF3B1, ATM, BIRC3

• APL emergency: PML-RARA by FISH or RT-PCR STAT; DIC screen (PT, aPTT, fibrinogen, D-dimer, FDPs) - start ATRA immediately if APL suspected clinically
• ALL: Lumbar puncture (CSF examination) in all patients (AML: LP only if CNS symptoms present - Goldman-Cecil, Ch. 168)
• LDH: Elevated in high proliferative leukaemias; prognostic marker in ALL
• Uric acid: Often markedly elevated (especially ALL); screen for tumour lysis syndrome (uric acid, K+, Ca2+, phosphate, creatinine)
• Coagulation screen: PT, aPTT, fibrinogen (DIC in APL)

CML Monitoring Response Milestones (Goldman-Cecil, Ch. 170)

CLL Staging

• 0: Lymphocytosis only
• I: + Lymphadenopathy
• II: + Splenomegaly or hepatomegaly
• III: + Anaemia (Hgb <11 g/dL)
• IV: + Thrombocytopenia (Plt <100×10⁹/L)
• Low risk (0), Intermediate (I-II), High risk (III-IV)

• A: <3 lymph node areas involved; no anaemia/thrombocytopenia
• B: ≥3 lymph node areas; no anaemia/thrombocytopenia
• C: Anaemia (Hgb <10) OR thrombocytopenia (Plt <100)

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7. MANAGEMENT AND PHARMACOLOGY

7A. AML - Fit Adults

Pre-treatment Preparation (Goldman-Cecil, Ch. 168)

• Correct thrombocytopenia with platelet transfusion (maintain >10,000/μL; >50,000/μL if DIC/active bleeding)
• Febrile neutropenia: Blood cultures → empiric broad-spectrum antibiotics (piperacillin-tazobactam or carbapenem)
• Tumour lysis syndrome prophylaxis: IV hydration + allopurinol 100-600 mg IV/PO daily; or rasburicase 0.2 mg/kg IV for very high WBC/uric acid (catalyses uric acid → allantoin; contraindicated in G6PD deficiency due to H₂O₂ accumulation)
• APL suspected: Start ATRA immediately without waiting for molecular confirmation
• Leukostasis (WBC >100,000): Aggressive cytoreductive induction therapy as soon as possible; leukapheresis role unclear

Induction Chemotherapy - "7+3" Standard Regimen

• Cytarabine (Ara-C) 100-200 mg/m²/day continuous IV infusion × 7 days (Days 1-7)
  • Mechanism: Pyrimidine analogue; incorporates into DNA → inhibits DNA polymerase α → chain termination; S-phase specific; requires intracellular phosphorylation to ara-CTP
• Daunorubicin 60-90 mg/m²/day IV × 3 days (Days 1-3)
  • OR Idarubicin 10-12 mg/m²/day IV × 3 days (preferred by many centres; superior CR rate and survival vs. daunorubicin in some trials - Katzung's, Ch. 55)
  • Mechanism: Anthracycline; intercalates DNA, inhibits Topoisomerase II → double-strand breaks; also free radical generation
• Complete remission (CR) rate: ~60-80% in adults <60 years; ~40-50% in older adults

Targeted Induction Additions (based on molecular profile)

• FLT3-mutated AML (~30%): Add midostaurin (FLT3 inhibitor) 50 mg PO BID on Days 8-21 of induction AND consolidation cycles → improved DFS and OS (RATIFY trial)
• CD33-positive, favourable/intermediate risk: Add gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate; calicheamicin payload → DNA double-strand breaks) 3 mg/m² (max 4.5 mg) on Days 1, 4, 7 → reduces relapse
• Therapy-related AML or AML with MDS-related changes: CPX-351 (liposomal cytarabine:daunorubicin in 5:1 molar ratio) 100 mg/m² cytarabine:44 mg/m² daunorubicin on Days 1, 3, 5 → superior OS vs. standard 7+3 in this subgroup
• Older/unfit adults: Venetoclax (BCL-2 inhibitor, 400 mg/day PO) + azacitidine (75 mg/m² SC/IV × 7 days) or low-dose cytarabine; FDA approved; CR rate ~37% with Ven+Aza in unfit adults; superior to HMA alone

APL - Distinct Treatment Protocol (Low/Intermediate Risk: WBC ≤10,000)

• ATRA (all-trans retinoic acid) 45 mg/m²/day PO (in 2 divided doses) + Arsenic trioxide (ATO) 0.15 mg/kg/day IV - chemotherapy-free ATRA+ATO regimen is standard of care
  • ATRA: Binds PML-RARA → co-repressor release → terminal differentiation of promyelocytes
  • ATO: Triggers PML-RARA degradation (SUMOylation pathway) + induces apoptosis in residual cells
  • CR rate >90%; 5-year OS >85-90%; most curable AML subtype
• High-risk APL (WBC >10,000): ATRA + ATO + idarubicin (or anthracycline)
• Differentiation syndrome (ATRA syndrome): Fever, weight gain, pulmonary infiltrates, pleural/pericardial effusions from differentiating promyelocytes releasing inflammatory mediators → treat immediately with dexamethasone 10 mg IV BID × ≥3 days; withhold ATRA temporarily if severe

Post-Remission (Consolidation) Therapy

• Favourable risk (CBF AML, NPM1-mutated/FLT3-ITD wild-type): High-dose cytarabine (HiDAC) 3 g/m² IV over 3 hours q12h Days 1, 3, 5 × 4 cycles ± gemtuzumab ozogamicin; no allo-HSCT in CR1 unless MRD positive
• Intermediate risk: HiDAC OR allo-HSCT if HLA-matched donor available and MRD positive
• Adverse risk: Allo-HSCT in CR1 whenever feasible; if no donor or not eligible: HiDAC as bridge, then alternative donor transplant
• FLT3-mutated: Midostaurin continued during consolidation; allo-HSCT recommended

Relapsed/Refractory AML Salvage

• IDH1-mutated: Ivosidenib (IDH1 inhibitor, 500 mg PO daily) → ~30% CR; induces differentiation
• IDH2-mutated: Enasidenib (IDH2 inhibitor, 100 mg PO daily) → ~20% CR
• FLT3-mutated relapse: Gilteritinib (FLT3/AXL inhibitor, 120 mg/day PO) → 3.5-month OS benefit vs. salvage chemo
• Allo-HSCT after achieving second remission

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7B. ALL Treatment

Three Phases (Goldman-Cecil, Ch. 168)

• Vincristine (1.5 mg/m² IV weekly; max 2 mg): Vinca alkaloid; binds β-tubulin → inhibits microtubule polymerisation → mitotic spindle arrest; peripheral neuropathy dose-limiting toxicity
• Prednisone or Dexamethasone (dexamethasone superior CNS penetration, preferred in paediatric ALL): 40-60 mg/m²/day PO; induces apoptosis in lymphoblasts via glucocorticoid receptor
• L-Asparaginase or pegaspargase (PEG-asparaginase): Hydrolyses asparagine → deprives ALL blasts of exogenous asparagine (cannot synthesise their own); IV or IM; toxicities: hypersensitivity reactions, pancreatitis, hyperglycaemia, coagulopathy (depletes fibrinogen, antithrombin III)
• Daunorubicin or doxorubicin: Added in adult protocols and high-risk paediatric ALL
• CR rate: >90% in children; ~85-90% in adults

• Intrathecal methotrexate (IT-MTX): CNS is a pharmacological sanctuary (poor drug penetration); IT-MTX prevents/treats CNS relapse; standard component of all ALL regimens
• IT cytarabine and IT hydrocortisone (triple IT therapy) in high-risk cases
• Cranial radiation: Now largely replaced by IT chemotherapy to avoid neurocognitive late effects

• Consolidation/Intensification: High-dose methotrexate (HDMTX) + leucovorin rescue; high-dose cytarabine; 6-mercaptopurine (6-MP)
• Maintenance (2-3 years): Daily 6-mercaptopurine (75 mg/m²/day PO) + weekly methotrexate (20 mg/m²/week PO); monthly vincristine + prednisone pulses; reduces relapse significantly

• TKI + chemotherapy: Dasatinib + induction chemotherapy (VDCLP); superior to imatinib (better CNS penetration); OR chemotherapy-free dasatinib + blinatumomab (GIMEMA LAL2116 trial: 2-year OS >80%)
• Blinatumomab (BiTE antibody): Bispecific T-cell engager; CD19 × CD3; brings cytotoxic T-cells to B-ALL blasts → T-cell-mediated killing; 28 mcg/day IV continuous infusion × 28 days; highly effective in relapsed/refractory ALL; FDA approved
• Allo-HSCT in CR1 for high-risk (Ph+, MRD-positive, adverse cytogenetics)

• Tisagenlecleucel (Kymriah): CD19-directed autologous CAR-T cell therapy; conditioning with cyclophosphamide + fludarabine → enhances IL-15 and CAR-T expansion; CR rate ~80% in children/young adults with relapsed B-ALL; potentially curative as bridge to allo-HSCT or standalone
• Inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate; calicheamicin): 0.8 mg/m² then 0.5 mg/m² IV weekly × 3-4 weeks per cycle; CR rate ~80% in relapsed B-ALL; toxicity: hepatic veno-occlusive disease (SOS)
• Nelarabine: Purine prodrug converted to ara-GTP; selective toxicity to T-cells → used for relapsed T-ALL
• Ponatinib or asciminib for Ph+ ALL with T315I resistance mutation

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7C. CML Treatment

• BCR-ABL1 qPCR on IS every 3 months for 2 years, then every 3-6 months
• EMR at 3 months (BCR-ABL ≤10%) is the strongest early predictor of long-term outcome
• Failure at any milestone → BCR-ABL kinase domain mutation testing → switch TKI

• Patients achieving sustained ≥2 years of MR4.5 may attempt TKI discontinuation
• ~50% maintain TFR; 50% relapse (usually in first 6 months) but respond to TKI rechallenge
• EURO-SKI trial: Duration of TKI >5.8 years and MR4.0 best predictors of TFR

• Chronic phase drug: Add or switch TKI based on mutation analysis
• Blast crisis: Treat as appropriate acute leukaemia (AML or ALL induction regimen) + TKI; bridge to allo-HSCT if second remission achieved

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7D. CLL Treatment

• Progressive marrow failure (worsening anaemia/thrombocytopenia)
• Massive (≥6 cm below costal margin) or progressive splenomegaly
• Massive (≥10 cm) or progressive lymphadenopathy
• Progressive lymphocytosis >50% over 2 months or lymphocyte doubling time <6 months
• Autoimmune anaemia or thrombocytopenia poorly responsive to steroids
• B symptoms (fever, night sweats, >10% weight loss)
• Symptomatic disease

• BTK inhibitors (preferred for most patients):
  • Ibrutinib (1st gen; 420 mg/day PO): Covalently binds Cys-481 of BTK → irreversible inhibition; blocks B-cell survival/proliferative signalling; continuous therapy until progression; risk: atrial fibrillation (~10%), hypertension, bleeding, arthralgias, fungal infections
  • Acalabrutinib (2nd gen; 100 mg BID PO): More selective BTK inhibitor; fewer cardiovascular side effects; preferred over ibrutinib for many patients
  • Zanubrutinib (3rd gen; 160 mg BID PO): Highly selective; lowest AF rate; non-inferior/superior to ibrutinib in head-to-head ALPINE trial
• Venetoclax + obinutuzumab (fixed duration, 12 cycles):
  • Venetoclax (BCL-2 inhibitor; 400 mg/day after ramp-up): Blocks BCL-2 → restores apoptosis; oral; fixed 12-month duration (in combination); CLL14 trial: superior PFS vs. chlorambucil + obinutuzumab in elderly/unfit
  • Obinutuzumab: Glycoengineered type II anti-CD20 monoclonal antibody; superior to rituximab (type I)
  • Risk of tumour lysis syndrome (TLS) during venetoclax ramp-up (especially high tumour burden/splenomegaly) → must be performed with TLS monitoring; inpatient ramp-up for high-risk patients
• FCR (Fludarabine + Cyclophosphamide + Rituximab): Now reserved for young, fit patients with mutated IGHV CLL (no del(17p)/TP53); high CR rate with potential for very long-term remissions (~30-40% remain in remission >10 years); not used for del(17p) disease

• BTK inhibitors or venetoclax-based regimens (NOT FCR or other chemoimmunotherapy - high treatment failure rate)

• Typically chemoimmunotherapy (R-CHOP-like) ± allo-HSCT
• Median survival ~1 year even with treatment
• PD-1 inhibitors under investigation

• AIHA/ITP: High-dose steroids (prednisone 1 mg/kg/day); IVIG; rituximab; cyclosporine; avoid purine analogues (fludarabine triggers autoimmune haemolysis)
• Hypogammaglobulinaemia + recurrent infections: IVIG replacement therapy

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7E. Hairy Cell Leukaemia

• Cladribine (2-CDA): Purine analogue; single course 0.09 mg/kg/day IV × 7 days; CR rate >90%; durable remissions; treatment of choice
• Pentostatin (Deoxycormycin): ADA inhibitor; 4 mg/m² IV q2 weeks × 3-6 months; similar efficacy; second option
• BRAF V600E-targeted: Vemurafenib (BRAF inhibitor) or dabrafenib for relapsed/refractory HCL; highly active

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Summary Pharmacology Table: Key Leukaemia Drugs

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8. COMPLICATIONS

Complications of Acute Leukaemia (AML/ALL)

Disease-Related

• Febrile neutropenia: Medical emergency in any patient with ANC <500/μL; 20-30% mortality if untreated empirically; gram-negative organisms (Pseudomonas, Klebsiella, E. coli), gram-positive (Staphylococcus, Streptococcus viridans), fungal (Aspergillus, Candida)
• Tumour lysis syndrome (TLS): Especially at induction; features: hyperuricaemia, hyperphosphataemia, hyperkalaemia, hypocalcaemia → acute renal failure, cardiac arrhythmias, seizures (from hypocalcaemia); Cairo-Bishop criteria for classification; prevented by hydration + allopurinol; treated with rasburicase + aggressive IV hydration; haemodialysis if renal failure
• Coagulopathy/DIC: Particularly APL (life-threatening); also seen in monocytic AML (M4/M5); requires urgent FFP, cryoprecipitate, platelets; heparin if thrombus dominant
• Leukostasis (WBC >100,000/μL): Hyperviscosity → plugging of microvasculature; respiratory failure, stroke, priapism; treat with immediate induction chemotherapy; leukapheresis controversial
• Anaemia and thrombocytopenia: From marrow replacement; manage with blood/platelet transfusions (leukoreduced, irradiated products)
• CNS leukaemia: Meningeal infiltration → headache, cranial nerve palsies, papilloedema; prophylaxis with IT MTX; treat with IT therapy ± cranial radiation

Treatment-Related Toxicities

• Anthracycline cardiomyopathy (doxorubicin/daunorubicin/idarubicin): Dose-dependent; cumulative lifetime limit (doxorubicin ~400-550 mg/m²); presents as dilated cardiomyopathy months-years later; baseline and serial echocardiography; dexrazoxane (iron chelator) for cardioprotection in high-risk patients
• APL Differentiation syndrome: Leaking differentiating promyelocytes release cytokines → capillary leak → pulmonary infiltrates, pleural/pericardial effusions, hypoxia, fever, hypotension; 5-25% incidence; treat with dexamethasone 10 mg IV BID; 90-day mortality 5-10% if delayed
• Secondary AML/MDS from prior chemotherapy (alkylating agents, topoisomerase II inhibitors) - occurs years later
• High-dose cytarabine: Cerebellar toxicity (ataxia, dysarthria, nystagmus; irreversible); ocular toxicity (conjunctivitis - use steroid eye drops prophylactically); age >60 and renal impairment are risk factors
• Methotrexate toxicity: Mucositis, myelosuppression, renal failure (high-dose → precipitates in tubules; requires hyperhydration + urinary alkalinisation + leucovorin rescue); leukoencephalopathy (with IT and high-dose MTX + cranial radiation)
• L-Asparaginase: Coagulopathy (low fibrinogen, ATIII, protein C/S → stroke, DVT, haemorrhage), pancreatitis (can be severe/fatal), hyperglycaemia (loss of insulin production), hepatotoxicity, hypersensitivity (antibody formation → switch from E. coli to Erwinia asparaginase)
• Graft-vs-Host Disease (GvHD) post allo-HSCT: Acute (skin rash, diarrhoea, jaundice) and chronic (skin sclerosis, dry eyes, mouth, liver dysfunction, recurrent infections); major cause of transplant-related mortality
• Venoocclusive disease (VOD/SOS) post allo-HSCT or inotuzumab ozogamicin: Hepatic sinusoidal obstruction; coagulopathy, tender hepatomegaly, fluid retention, hyperbilirubinaemia; severe form fatal; treat with defibrotide
• Cytokine release syndrome (CRS) from blinatumomab/CAR-T: Fever, hypotension, hypoxia; graded 1-4; treat with tocilizumab (IL-6 receptor antagonist) for grade ≥2; ICU care for severe
• Immune effector cell-associated neurotoxicity syndrome (ICANS) from CAR-T: Confusion, aphasia, seizures; treat with corticosteroids
• B-cell aplasia (from CD19/CD20-targeted CAR-T or rituximab): Prolonged hypogammaglobulinaemia → recurrent infections; IVIG replacement required

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Complications of CML

• Blast crisis: Transformation to AML (~70%) or ALL (~30%); survival <12 months without aggressive treatment + allo-HSCT; acquisition of additional cytogenetic/molecular abnormalities
• Accelerated phase: Refractory cytopenias, progressive splenomegaly, fever, constitutional symptoms; intermediate prognosis
• TKI-specific complications:
  • Imatinib: Peripheral oedema, pleural effusion, muscle cramps, rash, GI intolerance; rare: severe hepatotoxicity, CHF (rare)
  • Dasatinib: Pleural effusion (most distinctive; 28% incidence; often requires thoracocentesis and temporary drug hold); pulmonary hypertension; colitis
  • Nilotinib: QTc prolongation (ECG monitoring required); peripheral arterial occlusive disease (PAD), MI, stroke - particularly concerning in patients with cardiovascular risk factors; pancreatitis; hyperglycaemia/new-onset diabetes
  • Ponatinib: Arterial thromboembolism (heart attack, stroke, PAD) in 25-35%; hypertension; liver toxicity; pancreatitis
  • Asciminib: Myelosuppression; hypertension; pancreatitis
  • All TKIs: Myelosuppression (grade 3-4 neutropenia 10-20%); teratogenic - contraception required; multiple drug interactions (CYP3A4)
• Rebound disease after TKI discontinuation (failed TFR attempt): ~50% relapse; virtually all respond to TKI rechallenge

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Complications of CLL

• Recurrent infections: Most common cause of morbidity/mortality; hypogammaglobulinaemia → bacterial infections (pneumonia, sinusitis; S. pneumoniae, H. influenzae); CMV/Pneumocystis after BTK inhibitor or chemoimmunotherapy; IVIG reduces serious bacterial infections
• Autoimmune haemolytic anaemia (AIHA): ~10-15% of CLL patients; warm IgG Coombs positive; treat with steroids, rituximab; avoid fludarabine (worsens)
• Immune thrombocytopenia (ITP): ~2-5%; distinguish from BM infiltration (marrow exam needed)
• Richter transformation: 5-10% lifetime risk; CLL → DLBCL (most common) or Hodgkin lymphoma; 50-fold increase in LDH; median OS ~1 year; aggressive chemoimmunotherapy ± allo-HSCT
• Tumour lysis syndrome with venetoclax: Requires careful dose ramp-up, hydration, uric acid monitoring, xanthine oxidase inhibitor
• Secondary cancers: Increased risk of skin cancers (SCC, BCC - aggressive behaviour in CLL), lung cancer, colorectal cancer; due to immune dysregulation
• Progressive Richter/prolymphocytic transformation
• BTK inhibitor-specific:
  • Atrial fibrillation (ibrutinib: ~10%; acalabrutinib: ~5%): Requires anticoagulation decision-making (bleeding risk vs. stroke risk)
  • Major bleeding (ibrutinib particularly; inhibits platelet GPVI collagen signalling); avoid with warfarin; consider DOAC if anticoagulation needed
  • Opportunistic infections including Pneumocystis, Aspergillus, Cryptococcus (prophylaxis recommended with TMP-SMX and antifungals in some protocols)
  • Hypertension (all BTK inhibitors)

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Key clinical pearls:

• AML requires ≥20% blasts in bone marrow or blood (except certain cytogenetic subtypes AML)
• APL is a haematological emergency: Start ATRA immediately when clinically suspected; delay = potentially fatal haemorrhage
• CML blast crisis is treated as acute leukaemia of the appropriate lineage (myeloid or lymphoid) plus a TKI
• CLL should not be treated based on lymphocyte count alone - treat only when iwCLL criteria are met
• Ph+ ALL requires TKI from day one - dasatinib preferred (superior CNS penetration); chemotherapy-sparing dasatinib + blinatumomab now standard in many centres
• T315I mutation in CML/Ph+ ALL confers resistance to all 1st/2nd generation TKIs; ponatinib or asciminib required

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Thrombocytopenia: A Comprehensive Reference

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1. DEFINITION

• <150,000/μL: Thrombocytopenia by definition; usually no bleeding unless <50,000
• 50,000-150,000/μL: Mild; bleeding unlikely spontaneously; post-traumatic bleeding possible
• 20,000-50,000/μL: Moderate; increased risk of post-traumatic or procedural bleeding
• <20,000/μL: Severe; risk of spontaneous bleeding (mucocutaneous, GI, GU)
• <5,000-10,000/μL: Very severe; significant spontaneous bleeding including CNS haemorrhage

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2. TYPES / CLASSIFICATION

A. Decreased Platelet Production (Hypoproliferative)

• Aplastic anaemia (acquired immune or inherited)
• Marrow infiltration (leukaemia, disseminated malignancy, myelofibrosis, lymphoma, granulomata)
• Myelodysplastic syndrome (MDS) - ineffective megakaryopoiesis
• Myelophthisic anaemia

• Drugs: Cytotoxic chemotherapy (most common), alcohol (direct toxic effect on megakaryocytes), thiazide diuretics, chloramphenicol
• Infections: HIV (direct suppression of megakaryocyte development), measles virus, parvovirus B19
• Nutritional deficiencies: Vitamin B12/folate deficiency (ineffective megakaryopoiesis)

• Amegakaryocytic thrombocytopenia (MPL gene mutations, absent thrombopoietin receptor)
• TAR syndrome (Thrombocytopenia Absent Radius)
• Fanconi anaemia (TAR + other anomalies)
• May-Hegglin anomaly (MYH9 mutations - giant platelets, Döhle body inclusions)
• Bernard-Soulier syndrome (GPIb deficiency - few, very large platelets)

B. Increased Platelet Destruction (Consumptive/Immune)

• Primary ITP (immune thrombocytopenia - idiopathic)
• Secondary ITP (SLE, antiphospholipid syndrome, rheumatoid arthritis, thyroid disease)
• Drug-induced immune thrombocytopenia (DITP): Quinine/quinidine, heparin (HIT Type II), GPIIb/IIIa inhibitors, beta-lactams, sulfonamides, vancomycin, digoxin, phenytoin
• Post-transfusion purpura (PTP): 5-10 days post-transfusion; anti-HPA-1a antibodies destroy donor AND patient platelets
• Neonatal alloimmune thrombocytopenia (NAIT): Maternal anti-HPA antibodies (usually anti-HPA-1a) cross placenta → destroy foetal platelets; most common cause of severe isolated thrombocytopenia in neonates
• Gestational thrombocytopenia: Mild (rarely <70,000); benign; no treatment needed; no foetal risk; resolves post-partum
• Infections: Viral (EBV, CMV, HIV, HCV, rubella, varicella), bacterial sepsis

• Thrombotic microangiopathies (TMA):
  • TTP (ADAMTS13 deficiency - immune or hereditary)
  • HUS (Haemolytic Uraemic Syndrome) - Shiga toxin (STEC-HUS) or complement dysregulation (aHUS)
  • HELLP syndrome (Haemolysis, Elevated Liver enzymes, Low Platelets - obstetric)
  • Malignant hypertension
  • Scleroderma renal crisis
• Disseminated intravascular coagulation (DIC): Platelet consumption in widespread microthrombi + secondary fibrinolysis
• Giant haemangioma (Kasabach-Merritt syndrome): Platelet trapping within vascular tumour
• Mechanical: Prosthetic heart valves, extracorporeal circulation (ECMO, CPB)

C. Platelet Sequestration

• Hypersplenism (any cause of splenomegaly): Normally spleen sequesters ~30% of platelet mass; massive splenomegaly → sequesters up to 90%
• Causes: Liver cirrhosis + portal hypertension, myeloproliferative neoplasms, haematological malignancies, Gaucher disease, tropical splenomegaly
• Platelet count rarely falls below 40,000/μL with sequestration alone; "thrombin generation" still intact

D. Dilutional Thrombocytopenia

• Massive blood transfusion (>10 units pRBC): Stored blood contains no functional platelets → progressive dilution of recipient's platelet pool; also hypofibrinogenaemia
• Large-volume crystalloid/colloid resuscitation
• Exchange transfusion in neonates

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• Newly diagnosed ITP: Up to 3 months since diagnosis
• Persistent ITP: 3-12 months since diagnosis
• Chronic ITP: Over 12 months since diagnosis
• Severe ITP: Platelet count <20,000/μL
• Refractory ITP: Failure of splenectomy + ≥1 second-line therapy

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3. CAUSES / AETIOLOGY

Primary (Idiopathic) ITP

• No identifiable cause
• Pathogenic mechanism: Autoantibodies (predominantly IgG; rarely IgM or IgA) directed against platelet surface glycoproteins - predominantly GPIIb/IIIa (fibrinogen receptor) and GPIb/IX (vWF receptor) - in ~80% of cases (Robbins Basic Pathology, Ch. 10)
• The spleen is both the major site of autoantibody production AND the primary site of IgG-coated platelet destruction (splenic macrophages via Fc-receptor-mediated phagocytosis)
• Additionally, autoantibodies impair megakaryocyte maturation and platelet production → dual mechanism (increased destruction AND decreased production)
• Children: Acute self-limited form; peak age 2-6 years; often follows viral URTI or vaccination by 1-3 weeks; >90% spontaneous remission
• Adults: Predominantly chronic form; female > male (2-3:1); insidious onset; rarely spontaneous remission without treatment

Secondary ITP Causes

Drug-Induced Thrombocytopenia (DITP)

• Innocent bystander mechanism: Quinine/quinidine → drug-antibody complex adsorbs to platelet → complement activation → intravascular platelet lysis; Platelet count can fall to <10,000/μL
• HIT Type II: Heparin + PF4 neoantigen → IgG antibodies → FcγRIIA activation → platelet consumption AND thrombosis (detailed below)
• GPIIb/IIIa inhibitors (abciximab, tirofiban, eptifibatide): ~1-4% incidence of severe acute thrombocytopenia within 24 hours; mechanism - drug-dependent antibodies against modified GPIIb/IIIa conformational epitopes
• Other agents: Vancomycin, beta-lactam antibiotics, sulfonamides, trimethoprim-sulfamethoxazole, rifampicin, carbamazepine, phenytoin, digoxin, furosemide, NSAIDs, linezolid, checkpoint inhibitors (nivolumab, pembrolizumab)

Heparin-Induced Thrombocytopenia (HIT)

• Type I (Non-immune): Direct platelet activation by heparin; mild transient thrombocytopenia (>100,000/μL); onset within 1-2 days; self-limited; clinically insignificant
• Type II (Immune-mediated): IgG antibodies directed against platelet factor 4 (PF4)-heparin complex → IgG-PF4-heparin complexes bind platelet FcγRIIA receptors → massive platelet activation → (1) platelet consumption → thrombocytopenia AND (2) paradoxical pro-thrombotic state with venous AND arterial thrombosis
• Incidence: 3-5% of patients on unfractionated heparin (UFH) for >4 days; <1% with LMWH (Robbins Basic Pathology, Ch. 10)
• Onset: 5-14 days after first heparin exposure (earlier if previously sensitised within prior 100 days)

TTP and HUS

• TTP: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) deficiency → inability to cleave ultra-large vWF multimers → spontaneous platelet aggregation in microvessels → thrombocytopenia + MAHA
  • Acquired (immune): IgG anti-ADAMTS13 inhibitors (~90% of adults)
  • Congenital (Upshaw-Schulman syndrome): Homozygous ADAMTS13 mutations
  • Triggers: Pregnancy, drugs (quinine, ticlopidine, clopidogrel), HIV, malignancy
• STEC-HUS (typical HUS): Shiga toxin (from E. coli O157:H7) → damages renal endothelium → localised thrombotic microangiopathy → renal failure predominant; most common in children <5 years; epidemic outbreaks from contaminated food
• aHUS (atypical HUS): Complement pathway dysregulation (CFH, CFI, C3, CFB, THBD mutations) → endothelial damage → TMA; recurrent; poor prognosis without treatment; eculizumab dramatically effective

HELLP Syndrome

• Severe complication of pre-eclampsia/eclampsia (third trimester or post-partum)
• Triad: Microangiopathic Haemolytic Anaemia + Elevated Liver enzymes + Low Platelets
• Pathogenesis: Placental vasculopathy → endothelial dysfunction → platelet activation and consumption

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4. PATHOLOGY / PATHOPHYSIOLOGY

Normal Platelet Physiology

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ITP Pathophysiology (Detailed)

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HIT Pathophysiology (Detailed)

1. Bind FcγRIIA receptors on platelets → platelet activation and aggregation → platelet consumption → thrombocytopenia
2. Activate endothelial cells and monocytes → tissue factor expression → thrombin generation
3. Generate microparticles → additional procoagulant surface

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TTP/HUS Pathophysiology

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DIC-Related Thrombocytopenia

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Hypersplenism Pathophysiology

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5. CLINICAL FEATURES

General Bleeding Pattern (Primary Haemostasis Defect)

• Petechiae: Pinpoint (1-3 mm) non-blanching red/purple spots; most prominent on dependent areas (lower legs), pressure sites, mucous membranes; pathognomonic for thrombocytopenia or platelet dysfunction
• Purpura: Larger confluent areas of subcutaneous bleeding (>3 mm - purpura; >1 cm - ecchymosis)
• Epistaxis (nosebleed)
• Gingival bleeding (especially after brushing)
• Menorrhagia (heavy menstrual bleeding)
• Gastrointestinal bleeding: Melaena, haematochezia
• Haematuria
• Prolonged bleeding after minor cuts or procedures

Features Suggesting Specific Causes

• ITP: No splenomegaly (uncomplicated ITP does NOT cause splenomegaly - key distinguishing feature); otherwise well patient; no anaemia or neutropenia (isolated thrombocytopenia)
• TTP: Classic pentad: Thrombocytopenia + MAHA + neurological symptoms (confusion, focal deficits, headache, seizures, altered consciousness - hallmark of TTP) + fever + renal failure; HOWEVER <5% of immune TTP have the complete pentad
• HUS: MAHA + severe acute renal failure (oliguria, haematuria, elevated creatinine) + thrombocytopenia; neurological involvement minimal; often paediatric; diarrhoea (bloody) prodrome with STEC-HUS
• HIT: History of recent heparin (5-14 days); paradoxical thrombosis (DVT, PE, arterial) despite falling platelet count; no petechiae/mucosal bleeding (HIT causes thrombosis, not bleeding)
• DIC: Concurrent bleeding from multiple sites (IV sites, wounds, mucous membranes) + features of underlying cause (sepsis, obstetric emergency, malignancy); simultaneously prolonged PT/aPTT
• Hypersplenism: Prominent splenomegaly; features of underlying liver disease (cirrhosis: palmar erythema, spider naevi, ascites, jaundice) or haematological malignancy
• Bone marrow failure: Anaemia, thrombocytopenia AND neutropenia together (pancytopenia) - suggests aplastic anaemia, MDS, leukaemia, or marrow infiltration

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6. DIAGNOSTIC APPROACH

Step 1: Confirm and Assess Severity

• CBC with differential: Platelet count; haemoglobin/MCV (anaemia?); WBC differential (neutropenia/blasts? - suggests marrow failure or leukaemia)
• Peripheral blood smear (mandatory):
  • Rule out pseudothrombocytopenia (platelet clumping from EDTA anticoagulant → repeat in citrate or heparinised tube; review smear for platelet clumps; platelets appear normal in number on smear)
  • Schistocytes (fragmented RBCs, helmet cells): Indicate TMA (TTP/HUS/DIC/HELLP) → urgent workup
  • Large/giant platelets: Bernard-Soulier, ITP (newly produced young platelets are larger), MYH9 disorders
  • Platelet clumps: Pseudothrombocytopenia
  • Blasts: Acute leukaemia
  • Hypersegmented neutrophils: B12/folate deficiency
  • Smudge cells + mature small lymphocytes: CLL
  • Evaluation for hypogranular neutrophils: MDS

Step 2: Coagulation Screen

Step 3: Targeted Tests Based on Suspected Diagnosis

Suspected ITP

• CBC, smear, coagulation screen → isolated thrombocytopenia with no other explanation
• ITP is a diagnosis of exclusion - no single test confirms it
• HIV and HCV serology (mandatory in all adults - secondary ITP causes)
• H. pylori testing (urea breath test or stool antigen - eradication can improve platelet count)
• ANA, anti-dsDNA (if SLE suspected)
• Thyroid function tests (autoimmune thyroid disease association)
• Pregnancy test (gestational thrombocytopenia, HELLP)
• Bone marrow examination: Generally NOT required for typical adult ITP; indicated if age >60, atypical features, prior to splenectomy, or unexpected failure to respond to therapy; shows increased/normal megakaryocytes (confirms peripheral destruction)

Suspected TTP

• ADAMTS13 activity (send URGENTLY before plasma exchange): <10% activity = diagnostic for immune TTP
• ADAMTS13 inhibitor antibody: Confirms immune TTP
• Direct Coombs test: Negative (microangiopathic, non-immune haemolysis)
• LDH, bilirubin (indirect), haptoglobin: LDH markedly elevated; haptoglobin absent or very low
• Creatinine: Elevated but usually less severely than HUS
• Peripheral smear: Schistocytes (≥2-4 per high-power field suggestive)

Suspected HUS

• Stool culture and Shiga toxin assay (for STEC-HUS - E. coli O157:H7)
• ADAMTS13: Normal (>10%) - distinguishes from TTP
• Complement studies: CFH, CFI, C3, CFB, CFH antibodies (for aHUS workup)
• Creatinine/BUN: Severely elevated (acute kidney injury is dominant)

Suspected HIT

• 4T Score (clinical scoring): Thrombocytopenia degree + Timing + Thrombosis + other causes of Thrombocytopenia (oTher)
  • Score 0-3: Low probability (negative predictive value >99%)
  • Score 4-5: Intermediate probability
  • Score 6-8: High probability
• Anti-PF4/heparin ELISA: Highly sensitive (>95%); a negative result rules out HIT reliably; low specificity (positive in many patients on heparin without HIT)
• Serotonin Release Assay (SRA) or HIPA (Heparin-Induced Platelet Activation): Gold standard confirmatory functional assays; high specificity; labour-intensive; not universally available
• Duplex ultrasound lower limbs: Screen for DVT (occurs in 50% of HIT)
• Platelet count: Typically drops 30-50% from baseline; absolute count usually 20,000-100,000/μL (rarely <15,000)

Suspected DIC

• ISTH DIC Score (overt DIC ≥5 points): Platelet count (2 pts <50; 1 pt 50-100) + D-dimer (3 pts strong increase; 2 pts moderate) + PT prolongation (2 pts >6s; 1 pt 3-6s) + fibrinogen (<1 g/L = 1pt)
• Peripheral smear: Schistocytes (fewer than TTP)
• Fibrinogen: Low (consumed); falling serial values most significant
• LDH, bilirubin: Mildly elevated

Suspected Bone Marrow Failure (pancytopenia)

• Bone marrow aspirate + trephine biopsy: Hypocellular (aplastic anaemia), infiltrated (leukaemia, metastatic cancer, myelofibrosis), dysplastic (MDS)
• Reticulocyte count: Low (hypoproliferative)
• Vitamin B12 and folate levels
• Flow cytometry of peripheral blood (CD55/CD59): PNH clone
• Cytogenetics and molecular panel (MDS/AML workup)

Neonatal and Pregnancy-Related Thrombocytopenia

• Gestational thrombocytopenia: Mild (>70,000/μL), no maternal or neonatal bleeding; resolves post-partum; no further workup needed if platelet count stable
• NAIT: Neonatal platelet count <50,000/μL; maternal platelet count normal; parental HPA genotyping (HPA-1a most common); maternal anti-HPA antibody testing
• HELLP: Pre-eclampsia/eclampsia in third trimester; LFTs elevated; LDH elevated; schistocytes on smear; 24-hour urine protein; AST/ALT >2× upper limit of normal

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7. MANAGEMENT AND PHARMACOLOGY

General Principles

• Treat the underlying cause whenever possible
• Bleeding threshold guides urgency of treatment
• Platelet transfusion thresholds (Rosen's Emergency Medicine):
  • Prophylactic: <10,000/μL in stable patients (primary marrow failure)
  • Before lumbar puncture: <20,000/μL
  • Before minor surgical procedures: <50,000/μL
  • Before major/neurosurgical procedures: <80,000-100,000/μL
  • Contraindicated in TTP, HIT, HUS (platelet transfusions may worsen thrombosis)
  • Of limited value in ITP (transfused platelets rapidly destroyed by autoantibodies)

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7A. ITP - Management

First-Line Therapy (Newly Diagnosed)

• Dexamethasone 40 mg/day PO or IV × 4 days (preferred for higher initial response rate and faster platelet rise)
• OR Prednisone 1-2 mg/kg/day PO × 2-4 weeks then taper over 4-6 weeks
• Mechanism: Suppresses splenic macrophage phagocytosis of opsonised platelets; reduces autoantibody production; decreases FcγR expression on macrophages; inhibits T-cell activation
• Response rate: ~70-80%; however, only ~20-30% maintain sustained remission after steroids are discontinued
• Toxicity: Hyperglycaemia, fluid retention, hypertension, insomnia, mood changes, infection susceptibility, avascular necrosis (prolonged use), osteoporosis, adrenal suppression

• 1 g/kg/day IV × 1-2 days (one dose often sufficient)
• Mechanism: (1) Saturates splenic macrophage FcγR receptors → blocks phagocytosis of opsonised platelets; (2) Accelerates autoantibody catabolism; (3) Anti-idiotypic antibodies neutralising anti-platelet IgG
• Rapid response (platelet rise within 24-48 hours) but transient (weeks only)
• Indications: Life-threatening bleeding, platelet <10,000, pre-operative rapid platelet rise required
• Dose: 1 g/kg (single dose often sufficient; 2 g/kg total for more severe cases)
• Toxicity: Headache (aseptic meningitis), haemolysis, anaphylaxis (IgA-deficient patients), renal failure (high osmolality), thromboembolic events

• 50-75 mcg/kg IV for Rh(D)-positive, non-splenectomised patients only
• Mechanism: Opsonises patient's Rh(D)-positive RBCs → macrophages "busy" clearing RBCs → fewer available to destroy opsonised platelets (FcR saturation/competitive inhibition)
• Less expensive than IVIG; convenient single dose
• Contraindications: Rh(D)-negative patients; post-splenectomy (no spleen to process RBCs); Evans syndrome (concurrent AIHA); Hgb <10 g/dL
• Black box warning: Risk of severe intravascular haemolysis (rare, ~1/1000); monitor for 8 hours post-infusion

Second-Line Therapy (Persistent/Chronic ITP)

• 375 mg/m² IV weekly × 4 doses (standard dosing); or low-dose 100 mg/week × 4 doses
• Mechanism: Depletes CD20+ B lymphocytes → reduces autoantibody-producing B-cell pool → decreased anti-platelet IgG production; also depletes regulatory B cells; effects last 6-12 months until B-cell reconstitution
• Response rate: ~40-60% initial response; durable remission at 1 year ~40%; at 5 years ~20%
• Time to response: 2-8 weeks (slower than steroids/IVIG)
• Pre-treatment screening: Hepatitis B surface antigen and core antibody (HBV reactivation risk - start prophylactic entecavir if core Ab positive)
• Toxicity: Infusion reactions (pre-medicate with paracetamol, antihistamine, corticosteroid), prolonged hypogammaglobulinaemia, opportunistic infections, PML (rare, especially with concurrent immunosuppression)

• Romiplostim (Nplate):
  • SC injection, weekly; dose 1-10 mcg/kg titrated to maintain platelet count 50,000-200,000/μL
  • Peptide-Fc fusion protein ("peptibody"); binds MPL extracellular domain
  • Response rate ~85%; median platelet doubling within 2 weeks
  • Toxicity: Rebound thrombocytopenia if abruptly stopped; reticulin fibrosis in marrow (generally mild, reversible); headache; arthralgia; rare: thrombosis, progression to MDS/AML (uncertain causality)
• Eltrombopag (Promacta/Revolade):
  • Oral; 25-75 mg/day on empty stomach (food, especially Ca/Mg-rich foods, impairs absorption)
  • Non-peptide small molecule; binds transmembrane domain of MPL (distinct from TPO binding site)
  • Response rate ~75-80%
  • Toxicity: Hepatotoxicity (monitor LFTs every 2 weeks initially; monthly thereafter); cataracts (long-term); rebound thrombocytopenia on abrupt discontinuation; risk of portal vein thrombosis in patients with chronic liver disease
• Avatrombopag (Doptelet):
  • Oral; 20-40 mg/day; no food restriction (unlike eltrombopag)
  • Approved for chronic ITP; also approved for thrombocytopenia in chronic liver disease pre-procedure
  • Less hepatotoxicity than eltrombopag; thrombosis risk
• Lusutrombopag (Mulpleta):
  • Oral; specifically approved for thrombocytopenia in chronic liver disease (pre-procedure); 3 mg/day × 7 days

• Oral SYK (Spleen tyrosine kinase) inhibitor: 100-150 mg BID PO
• Mechanism: Blocks intracellular signalling downstream of FcγR on macrophages → prevents phagocytosis of opsonised platelets; also blocks BCR signalling (reduces autoantibody production)
• Approved for chronic ITP after failure of ≥2 prior therapies
• Response rate ~18% complete response; ~43% overall response
• Toxicity: Hypertension (most common; needs monitoring), diarrhoea, nausea, liver enzyme elevation, neutropenia, infection

• Surgical removal of the primary site of platelet destruction AND autoantibody production
• Laparoscopic preferred; elective when ITP is refractory to ≥1 medical therapy
• Durable complete remission: 60-70% at 5 years
• Pre-operative vaccinations (≥2 weeks before): Pneumococcal (PCV13 + PPSV23), meningococcal, H. influenzae type b (Hib) - prevents overwhelming post-splenectomy infection (OPSI)
• Pre-operative optimisation: IVIG or TPO-RA to raise platelet count >50,000 for surgery
• Contraindications: Active infection; poor surgical candidates; pregnancy (first trimester if unavoidable)
• Refractory post-splenectomy ITP: Accessory spleen (scan for scintigraphy-detectable accessory splenic tissue in 10-20%)

• Azathioprine 1-2 mg/kg/day: Inhibits purine synthesis → impairs lymphocyte proliferation; response in 40-60%; slow onset (3-6 months)
• Mycophenolate mofetil (MMF) 1-1.5 g BID: Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis → selective lymphocyte inhibition; response ~30-40%
• Cyclosporine 2.5-3 mg/kg/day: Calcineurin inhibitor; blocks IL-2 → T-cell suppression; used in refractory cases; monitor renal function, BP
• Danazol 400-800 mg/day: Androgen; reduces FcγR expression on macrophages; useful in elderly
• Dapsone 75-100 mg/day: Mechanism unclear; response ~40% in ITP

• Triple therapy (amoxicillin + clarithromycin + PPI × 14 days) or bismuth quadruple therapy
• ~50% platelet response in H. pylori-positive ITP after successful eradication; mechanism unclear (molecular mimicry or non-specific immune modulation)

• Platelet transfusion (1 adult dose) + IVIG 1 g/kg + IV methylprednisolone 1 g/day × 3 days
• rFVIIa (recombinant Factor VIIa) as rescue (off-label)
• Consider emergent splenectomy

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7B. HIT Management

1. STOP ALL heparins IMMEDIATELY: Unfractionated heparin, LMWH, heparin flushes, heparin-coated catheters
2. Start non-heparin alternative anticoagulant IMMEDIATELY (even before lab confirmation if clinical suspicion high - 4T score ≥4)
3. Do NOT transfuse platelets (may fuel thrombosis)
4. Do NOT start warfarin until platelet count recovers to baseline (warfarin → rapid protein C depletion → venous limb gangrene)
5. Evaluate for thrombosis (bilateral leg Doppler ultrasound)

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7C. TTP Management

• Must begin within hours of diagnosis; reduces mortality from ~90% to <15-20%
• 1-1.5 plasma volumes daily replaced with Fresh Frozen Plasma (FFP)
• Mechanism: (1) Removes circulating anti-ADAMTS13 antibodies; (2) Replenishes functional ADAMTS13 enzyme from donor FFP
• Continue daily until platelet count ≥150,000/μL for ≥2 consecutive days, then taper

• Corticosteroids: Methylprednisolone 1 g/day IV × 3 days OR prednisone 1 mg/kg/day PO
• Rituximab (375 mg/m² IV weekly × 4 doses, or 1 g IV × 2 doses): Reduces relapse rate when added to PEX; increasingly used upfront

• Anti-vWF nanobody (humanised single-domain antibody targeting A1 domain of vWF)
• Mechanism: Blocks interaction between ULvWF multimers and platelet GPIb receptor → prevents platelet aggregation and microthrombus formation
• Dosing: 10 mg IV bolus on day 1, then 10 mg SC daily throughout PEX and for 30 days after last PEX session
• Clinical evidence: HERCULES trial - significantly faster platelet normalisation, reduced major thromboembolic events, reduced ICU stay and recurrence
• Toxicity: Bleeding (acquired vWF deficiency - monitor), injection site reactions
• Note: Caplacizumab does NOT address the underlying antibody-mediated ADAMTS13 deficiency → must be combined with PEX + rituximab

• Acute: FFP infusions 10-15 mL/kg every 2-3 weeks to replace ADAMTS13
• Recombinant ADAMTS13 (under clinical trials)
• No need for rituximab (no antibody - hereditary enzyme deficiency)

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7D. HUS Management

• Supportive treatment (no specific therapy changes outcomes significantly)
• Aggressive fluid management and electrolyte correction
• Dialysis (required in ~50% of paediatric STEC-HUS; 25-30% adults)
• Antihypertensives (ACE inhibitors/ARBs long-term for hypertension)
• Avoid antibiotics in STEC-HUS (may increase Shiga toxin release from E. coli → worsen HUS - evidence controversial but most guidelines advise avoidance)
• Avoid antimotility agents (diphenoxylate, loperamide)
• Platelet transfusions: Avoid unless severe haemorrhage
• Prognosis: 85-90% full recovery in children; higher morbidity in adults

• Eculizumab (Soliris): Anti-C5 monoclonal antibody; blocks terminal complement → prevents MAC formation → dramatically reduces TMA; 900 mg IV weekly × 4 weeks, then 1200 mg every 2 weeks; life-changing therapy; FDA-approved for aHUS
• Ravulizumab (Ultomiris): Long-acting anti-C5; every 8-week dosing; non-inferior to eculizumab
• Plasma exchange: Used as bridge until complement inhibitor available; less effective than in TTP
• Meningococcal vaccination MANDATORY before eculizumab (terminal complement inhibition → risk of Neisseria meningitidis)

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7E. Gestational and Neonatal Thrombocytopenia

• No treatment required; monitor platelet count
• Platelet count rarely <70,000; resolves within 6 weeks post-partum
• Foetal/neonatal platelet count normal

• Antenatal (if previously affected sibling): IVIG to mother 1 g/kg/week ± prednisone from weeks 20-32 to prevent foetal/neonatal thrombocytopenia
• Neonatal treatment: IVIG 1 g/kg IV (raises platelet count within 24-48 hours); or HPA-1a-compatible/washed random platelets; steroids; serial platelet monitoring until recovery
• Severe bleeding: Intracranial haemorrhage risk → immediate HPA-compatible platelet transfusion

• Oral prednisone or IVIG (safe in pregnancy); TPO-RAs and rituximab generally avoided
• Target platelet count: >30,000/μL in first/second trimester; >80,000/μL at delivery (vaginal); >50,000/μL for neuraxial anaesthesia; >80,000/μL for caesarean section
• Check neonatal platelet count after delivery (autoantibodies cross placenta → neonatal thrombocytopenia in ~10%; severe <50,000 in ~5%)

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7F. Drug-Induced Thrombocytopenia (DITP)

• Stop the offending drug - single most important step; platelet count typically recovers in 7-14 days
• IVIG (1 g/kg × 1-2 days) if platelet count <10,000 or active bleeding (accelerates recovery)
• Platelet transfusion only for life-threatening haemorrhage
• Quinine/quinidine-induced DITP: Avoid re-challenge (anaphylaxis risk); document allergy

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7G. Bone Marrow Failure-Related Thrombocytopenia

• Aplastic anaemia: Horse ATG + cyclosporine + eltrombopag ± allo-HSCT (see hematopoietic disorders section)
• Leukaemia/MDS: Treat underlying disease; prophylactic platelet transfusions (keep >10,000/μL during treatment)
• Chemotherapy-induced: Self-limited; platelet transfusion as per thresholds; dose modifications if severe and recurrent; oprelvekin (IL-11) and romiplostim may be considered to reduce depth/duration of nadir

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Summary Pharmacology Table

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8. COMPLICATIONS

Haemorrhagic Complications

• Intracranial haemorrhage (ICH): Most feared complication; occurs in <1% of ITP but catastrophic when it does; risk sharply increases at platelet counts <10,000/μL; associated with 20-50% mortality in ITP; requires immediate IVIG + platelet transfusion + methylprednisolone + emergent neurosurgical evaluation
• Retinal haemorrhage: Visual impairment or blindness; occurs with severe thrombocytopenia
• Gastrointestinal haemorrhage: Can be life-threatening; exacerbated by concurrent NSAID use or underlying GI pathology
• Pulmonary haemorrhage: Diffuse alveolar haemorrhage with severe thrombocytopenia
• Genitourinary bleeding: Haematuria; menorrhagia (leading to iron deficiency anaemia in women)

Thrombotic Complications

• HIT-related thrombosis (HITT): Deep vein thrombosis (~50% of HIT), pulmonary embolism, arterial thrombosis (limb ischaemia, stroke, myocardial infarction, mesenteric ischaemia); 30-day mortality ~10% in untreated HITT; limb amputation risk 5-10%
• TTP-related organ ischaemia: Neurological damage (stroke, persistent cognitive impairment), myocardial microinfarcts, renal impairment
• Warfarin-induced skin necrosis and venous limb gangrene: In HIT when warfarin started before adequate alternative anticoagulation; caused by rapid depletion of Protein C before full anticoagulation effect; skin necrosis typically over fatty areas (breast, abdomen, thigh)

Treatment-Related Complications

• Overwhelming Post-Splenectomy Infection (OPSI): Most feared long-term complication; risk ~1-5% lifetime; mortality when OPSI occurs ~50%; caused by encapsulated bacteria (S. pneumoniae, N. meningitidis, H. influenzae); presents as rapid onset sepsis; prevention with vaccination and patient education (carry penicillin, seek urgent medical care for any febrile illness)
• Portal vein thrombosis (5-10% post-splenectomy; prophylaxis with anticoagulation)
• Subphrenic abscess, pancreatic tail injury, post-splenectomy thrombocytosis (reactive; rarely thrombotic)
• Increased risk of atherosclerosis long-term (platelet count elevation after splenectomy)

• Cushing's syndrome, diabetes mellitus, osteoporosis with vertebral/hip fractures
• Avascular necrosis of femoral/humeral head
• Cataracts, glaucoma
• Susceptibility to opportunistic infections (PCP, fungal, Strongyloides)
• Adrenal insufficiency on abrupt discontinuation
• Hypertension, hyperlipidaemia

• HBV reactivation (risk for up to 24 months post-treatment) → fulminant hepatitis if not prophylaxed with entecavir
• Prolonged hypogammaglobulinaemia → recurrent bacterial infections → IVIG replacement may be needed
• PML (progressive multifocal leukoencephalopathy) from JC virus reactivation (rare; higher risk with concurrent immunosuppression)
• Serum sickness (delayed infusion reaction; arthralgias, urticaria, fever 1-2 weeks post-infusion)
• Impaired vaccine responses (B-cell aplasia for 6-12 months)

• Rebound thrombocytopenia on abrupt discontinuation (platelet count may fall below pretreatment levels); taper gradually
• Marrow reticulin fibrosis with romiplostim (generally grade 1-2, reversible; rare progression to collagen fibrosis)
• Thrombosis (portal vein thrombosis, DVT, PE) especially in liver disease patients taking avatrombopag/lusutrombopag
• Eltrombopag: Hepatotoxicity (ALT >3× ULN in ~5%), cataracts (long-term)

• Anaphylaxis in IgA-deficient patients (premedicate; use IgA-depleted product)
• Haemolytic anaemia (rare; due to blood group antibodies in IVIG)
• Aseptic meningitis (headache, neck stiffness 12-48 hours post-infusion; self-limited)
• Renal failure (with high-osmolality sucrose-containing preparations)
• Hyperviscosity (rarely)

• Meningococcal meningitis/septicaemia (terminal complement inhibition blocks bacterial killing; mandatory meningococcal vaccination AND prophylactic penicillin until vaccine immunity established)
• Other encapsulated bacterial infections
• Infusion reactions

• Alloimmunisation: Anti-HPA and anti-HLA antibodies → platelet refractoriness (post-transfusion count increment <10,000/μL 1-hour post-transfusion); cross-matched or HLA-matched platelets required; leukoreduction reduces HLA alloimmunisation
• Febrile non-haemolytic transfusion reactions
• Bacterial contamination (platelets stored at room temperature → higher bacterial risk than RBCs)
• Transfusion-associated circulatory overload (TACO), TRALI (transfusion-related acute lung injury)
• Transfusion-transmitted infections (CMV, HIV, HBV - very rare with current screening)

Chronic ITP Complications

• Significant impairment of quality of life: Fatigue, anxiety, lifestyle restriction, fear of bleeding
• Iron deficiency anaemia (from chronic mucosal blood loss)
• Failure to respond to multiple therapies → increasing immunosuppressive burden → cumulative toxicity
• Pregnancy complications: Neonatal thrombocytopenia, obstetric bleeding risk

TTP Complications

• Relapse rate: 30-40% with immune TTP; ongoing monitoring of ADAMTS13 activity required; maintenance rituximab may reduce relapse
• Exacerbation: Platelet count falls after initial response to PEX (occurs in ~30%); requires extended PEX + escalated immunosuppression
• Long-term neurological sequelae: Cognitive impairment, depression, fatigue (in up to 50% of survivors)
• Renal impairment (less prominent than HUS but possible with severe/delayed TTP)
• PEX-related complications: Central venous line complications (infection, DVT, pneumothorax), citrate-induced hypocalcaemia (tetany, arrhythmias), allergic reactions to FFP, transfusion reactions, volume overload

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Key clinical pearls:

• Pseudothrombocytopenia (EDTA-induced platelet clumping) must always be excluded first by reviewing the peripheral smear or repeating CBC in a citrate tube - it requires NO treatment
• The peripheral blood smear is the single most important test after the CBC: schistocytes indicate TMA (TTP/HUS/DIC) and require urgent workup; the absence of schistocytes combined with isolated thrombocytopenia and normal coagulation strongly favours ITP
• ITP does NOT cause splenomegaly in uncomplicated cases; splenomegaly in a thrombocytopenic patient suggests a different diagnosis (lymphoma, haematological malignancy, portal hypertension, SLE, TTP)
• HIT is a thrombotic disorder, not primarily a bleeding disorder: the correct response to falling platelet count in a heparinised patient is NOT platelet transfusion, but immediate cessation of heparin and initiation of alternative anticoagulation
• TTP is a haematological emergency: once suspected (thrombocytopenia + schistocytes + neurological symptoms, even without full pentad), do NOT wait for ADAMTS13 result before starting plasma exchange

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Disorders of the Bone Marrow: A Comprehensive Reference

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1. DEFINITION

1. Failure disorders - insufficient production of normal blood cells (aplastic anaemia, MDS, pure red cell aplasia)
2. Infiltrative/replacement disorders - normal marrow replaced by abnormal cells (leukaemia, metastatic malignancy, myelofibrosis, granulomata)
3. Clonal proliferative disorders (non-leukaemic) - myeloproliferative neoplasms (polycythaemia vera, essential thrombocythaemia, primary myelofibrosis), multiple myeloma
4. Vascular disorders - avascular necrosis, Gaucher disease storage
5. Reactive/Inflammatory - secondary to systemic infection, inflammation, nutritional deficiency

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2. TYPES / CLASSIFICATION

A. Bone Marrow Failure Syndromes

• Acquired (immune-mediated): Idiopathic, post-viral, drug-induced, pregnancy-associated, PNH-associated
• Inherited (Constitutional/IBMFS):
  • Fanconi anaemia
  • Dyskeratosis congenita (telomere biology disorder)
  • Diamond-Blackfan anaemia (pure red cell aplasia variant)
  • Shwachman-Diamond syndrome
  • GATA2 deficiency
  • RUNX1 familial platelet disorder

• Thymoma-associated
• Parvovirus B19 (in immunocompromised/haemolytic background)
• Drug-induced (phenytoin, azathioprine, isoniazid)
• Anti-erythropoietin antibodies
• Lymphoid malignancy-associated

• Cyclic neutropenia (ELANE mutations)
• Severe congenital neutropenia (Kostmann syndrome)
• Amegakaryocytic thrombocytopenia

B. Myelodysplastic Syndromes (MDS)

C. Myeloproliferative Neoplasms (MPN)

D. Bone Marrow Infiltrative Disorders (Myelophthisic Disease)

• Haematological malignancies: Leukaemia (AML, ALL, CLL, CML blast phase), multiple myeloma, lymphoma (BM involvement)
• Metastatic solid tumours: Breast, prostate, lung, neuroblastoma, renal cell carcinoma
• Granulomatous disease: TB, sarcoidosis, fungal infection (histoplasma, cryptococcus)
• Storage diseases: Gaucher disease (glucocerebrosidase deficiency), Niemann-Pick disease
• Myelofibrosis (primary or secondary)

E. Multiple Myeloma / Plasma Cell Neoplasms

• MGUS (Monoclonal Gammopathy of Undetermined Significance): Precursor; <10% clonal plasma cells; M-protein present but below thresholds; 1% per year progression risk
• Smouldering Multiple Myeloma (SMM): 10-60% plasma cells or M-protein ≥30 g/L; no end-organ damage; observation only
• Multiple Myeloma: ≥10% clonal plasma cells + CRAB criteria (end-organ damage) or SLiM-CRAB myeloma-defining events
• Waldenström Macroglobulinaemia: IgM-secreting lymphoplasmacytic lymphoma; MYD88 L265P mutation; BM involvement
• Plasmacytoma: Single plasma cell tumour (solitary osseous or extramedullary)

F. Vascular and Structural Disorders

• Avascular necrosis (AVN) of femoral head: Sickle cell disease, steroid use, alcohol, radiation
• Osteoporosis/Osteopetrosis - bone density disorders affecting marrow space
• Gaucher disease: Glucocerebroside-laden macrophages replace marrow

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3. CAUSES / AETIOLOGY

Aplastic Anaemia - Causes (Harrison's 22E, Ch. 107; Goldman-Cecil, Ch. 151)

• Idiopathic (no identifiable cause; presumed autoimmune) - most common (~70-80% of acquired AA)
• Pregnancy-associated
• PNH (paroxysmal nocturnal haemoglobinuria) - PIG-A mutation in stem cell; related syndrome

• Drugs: Chloramphenicol (most notorious; idiosyncratic; dose-independent), NSAIDs, gold salts, D-penicillamine, sulfonamides, antiepileptics (phenytoin, carbamazepine), chemotherapy (predictable, dose-dependent)
• Viral infections: Seronegative hepatitis (most common viral cause; ~5% of AA; young men; severe; likely immune-mediated despite unknown pathogen), EBV, CMV, HIV, hepatitis B/C, dengue
• Radiation: Dose-dependent; therapeutic, accidental, or occupational
• Chemicals: Benzene, insecticides, solvents (industrial/agricultural exposure)
• Autoimmune diseases: SLE, autoimmune hepatitis
• Thymoma (rare; more often causes PRCA)

• Fanconi Anaemia: Autosomal recessive; 23 FA complementation groups (FANCA most common); DNA interstrand cross-link repair defect; café-au-lait spots, radial/thumb/renal anomalies, short stature; diagnosis by chromosomal fragility test (DEB/MMC)
• Dyskeratosis Congenita: Telomere biology disorder; triad of leukoplakia + dystrophic nails + skin hyperpigmentation; DKC1 (X-linked), TERT/TERC (autosomal dominant); telomere length short (<1st percentile)
• Diamond-Blackfan Anaemia: Ribosomopathy (RPS19 most common); selective red cell aplasia; congenital anomalies; elevated erythrocyte adenosine deaminase (eADA)
• Shwachman-Diamond Syndrome: SBDS mutation; neutropenia + exocrine pancreatic insufficiency; bone dysostosis
• GATA2 Deficiency: MYD88 L265P-independent B/NK cell lymphopenia; susceptibility to viral/mycobacterial/fungal infections; MonoMAC syndrome; high AML/MDS risk

MDS - Causes

• Age (median ~70 years; most important risk factor; somatic mutation accumulation in aging marrow)
• Prior chemotherapy/radiation (therapy-related MDS/AML): Alkylating agents (del 5/7; latency 5-7 years); topoisomerase II inhibitors (11q23/KMT2A; latency 1-3 years)
• Benzene and other chemical exposures
• Somatic mutations in ~100 genes: SF3B1 (splicing; ring sideroblasts; favourable), TET2, DNMT3A (epigenetic), ASXL1, EZH2 (chromatin), TP53, RUNX1 (adverse prognosis), SRSF2, U2AF1 (splicing), STAG2 (cohesin complex)
• Cytogenetic abnormalities: Del(5q) [most favourable], -7/del(7q) [adverse], del(20q), +8 (trisomy 8), complex karyotype [most adverse]

MPN - Causes

• JAK2 V617F mutation: Acquired somatic mutation in exon 14; constitutively activates JAK-STAT signalling; predisposition linked to JAK2 GGCC haplotype; >95% PV; ~55% ET; ~60% PMF
• CALR exon 9 mutations: ~30% ET; ~25% PMF; mutant calreticulin activates MPL (TPO receptor) via its altered C-terminus
• MPL mutations (W515L/K): <5% ET, ~10% PMF; activating mutations in thrombopoietin receptor
• Small risk from prior benzene exposure or radiation

Bone Marrow Infiltration

• Haematological malignancies (intrinsic marrow disease)
• Haematogenous metastasis: Breast (most common source of BM metastasis in women), prostate (most common in men), lung, renal, neuroblastoma (most common solid tumour in children to cause myelophthisis)
• Granulomas: TB (most important worldwide), sarcoidosis, histoplasma, cryptococcus, brucellosis

Multiple Myeloma - Causes

• Universally preceded by MGUS (clonal precursor state)
• Genetics: Primary chromosomal translocations (IgH rearrangements): t(11;14) CCND1, t(4;14) FGFR3/MMSET, t(14;16) MAF; Hyperdiploidy (odd chromosomes 3, 5, 7, 9, 11, 15, 19, 21 trisomies)
• Secondary events: RAS mutations, TP53 deletion (del17p, adverse), 1q amplification (adverse), del(13q)
• Environmental: Radiation, benzene, agricultural chemicals
• Age (median ~70 years); slightly more common in males; Black Americans have 2-3× higher incidence

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4. PATHOLOGY / PATHOPHYSIOLOGY

Aplastic Anaemia

1. An unknown trigger (drug, virus, chemical) activates oligoclonal cytotoxic CD8+ T cells with skewed Vβ T-cell receptor usage
2. Activated T cells produce IFN-γ and TNF-α - these cytokines:
   • Directly suppress haematopoiesis (induce Fas-ligand expression on HSCs → apoptosis)
   • Upregulate inducible NO synthase in marrow stromal cells
   • Create a hostile marrow microenvironment for HSC survival
3. Regulatory T cells (Tregs) are reduced → insufficient brake on cytotoxic response
4. The net result: progressive loss of HSCs → replacement of haematopoietic marrow with fat cells → pancytopenia

• Bone marrow trephine: Markedly hypocellular (<25% cellularity, often <10%); normal haematopoietic elements replaced by fat cells and stromal elements; residual haematopoietic cells morphologically normal (no dysplasia - distinguishes from MDS); no excess blasts
• Peripheral blood: Pancytopenia; normocytic normochromic anaemia; low reticulocyte count; relative lymphocytosis

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Myelodysplastic Syndrome (MDS)

1. Ineffective haematopoiesis: Cells proliferate but undergo premature apoptosis within the marrow (high cellularity despite peripheral cytopenias) - "dysplastic cells die before leaving the marrow"
2. Disordered differentiation: Aberrant morphology (dysplasia) in one or more lineages:
   • Erythroid: Nuclear budding, karyorrhexis, nuclear-cytoplasmic dyssynchrony, ring sideroblasts (iron-laden mitochondria encircling nucleus - Prussian blue stain positive)
   • Myeloid: Hypogranular neutrophils, pseudo-Pelger-Huët cells (bilobed nuclei), Auer rods (only in EB-2/AML)
   • Megakaryocytes: Hypolobated/monolobated nuclei; micromegakaryocytes; separated nuclear lobes
3. Genomic instability: Progressive accumulation of additional mutations → risk of transformation to AML (occurs in 10-40% depending on risk score)

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Myeloproliferative Neoplasms

• Trilineage haematopoietic expansion, predominantly erythroid
• JAK2 V617F → endogenous erythroid colony formation (EEC) - colonies grow without added erythropoietin (diagnostic feature)
• Loss of heterozygosity on 9p (uniparental disomy) → JAK2 V617F homozygosity (present in ~60% PV, rare in ET)
• Morphology: Hypercellular marrow; panmyelosis (expansion of all lineages); pleomorphic megakaryocytes in clusters
• Consequence: Elevated haematocrit → increased blood viscosity → thrombotic risk; large platelet mass → acquired vWD (proteolysis of HMW vWF multimers); hyperuricaemia; splenomegaly (extramedullary haematopoiesis)

• Primarily megakaryocytic expansion → thrombocytosis (platelets >450×10⁹/L)
• CALR mutations: Mutant calreticulin C-terminus has positive charge → binds MPL extracellular domain → constitutive MPL/JAK-STAT activation
• ET megakaryocytes are large, mature, and form clusters; do not show significant atypia (vs. PMF)
• Consequence: Thrombosis (microvascular = erythromelalgia, digital ischaemia; macrovascular = DVT, stroke, MI) AND paradoxical bleeding when platelets >1500×10⁹/L (acquired vWF deficiency)

• Abnormal megakaryocytes release TGF-β, PDGF, bFGF → activation of marrow fibroblasts → progressive collagen fibrosis of the marrow → "marrow fibrosis" = replacement of haematopoietic tissue with fibre tissue
• Fibrosis drives haematopoiesis to extramedullary sites → massive splenomegaly (splenic extramedullary haematopoiesis), hepatomegaly, lymphadenopathy
• Progressive marrow failure → anaemia, thrombocytopenia, worsening neutropenia
• Morphology: "Dry tap" on aspiration (fibrosis prevents marrow egress); trephine: reticulin/collagen fibrosis graded MF-0 to MF-3 (grading of British Committee for Standards in Haematology); leukoerythroblastic blood film (immature myeloid and erythroid cells in peripheral blood); teardrop cells (dacryocytes)

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Bone Marrow Infiltration (Myelophthisic Disease)

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Multiple Myeloma

• C - Hypercalcaemia: Myeloma cells produce osteoclast-activating factors (RANKL, DKK1, MIP-1α) → osteoclast activation + inhibit osteoblasts → lytic bone lesions, pathological fractures; calcium released from bone → hypercalcaemia
• R - Renal failure: Light chain casts ("myeloma kidney"/cast nephropathy) → tubular obstruction; light chain deposition disease; hypercalcaemia nephropathy; amyloid (AL amyloidosis from λ light chains)
• A - Anaemia: BM infiltration by plasma cells + IL-6-mediated suppression of erythropoiesis + anaemia of chronic inflammation; EPO-resistant anaemia
• B - Bone lesions: Lytic "punched-out" lesions predominantly axial skeleton; absent osteoblastic repair; contrast with prostate metastases (sclerotic)

• Clonal BM plasma cells ≥60%
• Serum involved:uninvolved free light chain ratio ≥100
• MRI: >1 focal lesion of ≥5 mm

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5. CLINICAL FEATURES

Aplastic Anaemia

• Anaemia symptoms: Fatigue, weakness, pallor, dyspnoea, palpitations
• Thrombocytopenia: Petechiae, purpura, epistaxis, gum bleeding, haematuria, menorrhagia
• Neutropenia: Febrile episodes, recurrent bacterial infections (oral candidiasis, skin infections, pneumonia, sepsis), perirectal abscesses
• Absence of lymphadenopathy and splenomegaly (important distinguishing feature from leukaemia/lymphoma)
• May be discovered incidentally on routine CBC in mild/moderate cases

MDS

• Anaemia dominates early course: Fatigue, weakness, pallor, dyspnoea (most common presenting symptom)
• At least 50% of patients are asymptomatic at diagnosis (incidental CBC finding)
• Fever and weight loss more common in advanced MDS evolving towards AML
• Transfusion-dependent anaemia in advanced disease
• Infections (from neutropenia and functional neutrophil defects)
• Bleeding (thrombocytopenia)

Polycythaemia Vera

• Often discovered incidentally (elevated Hb/Hct on routine CBC)
• Hyperviscosity: Headache, visual disturbances (amaurosis fugax), tinnitus, vertigo, TIAs, stroke
• Aquagenic pruritus (characteristic - intense pruritus after warm bath/shower; due to histamine release from basophils and mast cells) and erythromelalgia (burning pain in extremities due to platelet-mediated microvascular occlusion)
• Plethoric (ruddy) complexion - facial redness; congested conjunctivae
• Thrombotic events: Cerebral, cardiac (MI), mesenteric, hepatic (Budd-Chiari syndrome - classic PV complication), portal vein thrombosis
• Splenomegaly: ~70% at diagnosis
• Hypertension, hyperuricaemia (gout), peptic ulcer disease (increased histamine), epistaxis, GI haemorrhage

Essential Thrombocythaemia

• Often asymptomatic (incidental thrombocytosis on CBC)
• Vasomotor symptoms: Erythromelalgia, headache, visual disturbances, digital ischaemia, livedo reticularis (platelet-mediated microvascular thrombosis)
• Thrombosis (arterial > venous): Stroke, TIA, MI, DVT/PE
• Haemorrhage when platelets extremely elevated (>1500×10⁹/L): GI bleeding, easy bruising (acquired vWD)
• Moderate splenomegaly (~50%)

Primary Myelofibrosis

• Constitutional symptoms (B symptoms): Profound fatigue, night sweats, fever, weight loss (>10% body weight) - hallmark; reflects cytokine-driven systemic inflammation
• Massive splenomegaly: Most distressing symptom; abdominal fullness, pain, early satiety, portal hypertension (oesophageal varices, ascites); spleen may reach the pelvis
• Hepatomegaly: From extramedullary haematopoiesis
• Anaemia: Pale, fatigued; transfusion-dependent in advanced disease
• Bone pain (from marrow fibrosis and periosteal expansion of extramedullary haematopoiesis)

Multiple Myeloma

• Bone pain: Most common symptom (70%); vertebral, rib, long bone; worse with movement; pathological fractures; vertebral collapse → spinal cord compression (emergency)
• Fatigue: From anaemia
• Recurrent bacterial infections: Particularly encapsulated organisms (S. pneumoniae, H. influenzae) from functional hypogammaglobulinaemia (normal Ig suppressed by myeloma protein)
• Renal failure: Oliguria, oedema
• Hypercalcaemia symptoms: Polyuria, polydipsia, constipation, nausea, confusion ("bones, stones, groans, and psychic moans")
• Hyperviscosity (especially with IgM/IgA myeloma or high M-protein): Headache, visual blurring, bleeding from mucous membranes, stroke
• Peripheral neuropathy: From amyloid deposition or light chain neurotoxicity

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6. DIAGNOSTIC APPROACH

A. Initial Blood Tests (All Bone Marrow Disorders)

• CBC with differential: Anaemia (type: normocytic/macrocytic), thrombocytopenia, neutropenia; WBC differential (blasts?); reticulocyte count (low in production failure)
• Peripheral blood smear: Essential; morphology of red cells (dacryocytes/teardrop - myelofibrosis; hypogranular neutrophils - MDS; schistocytes - TMA); nucleated RBCs + immature granulocytes = leukoerythroblastic picture (marrow infiltration)
• Reticulocyte count: Low (hypoproliferative) in aplastic anaemia and MDS
• LDH and uric acid: Elevated in MPN/MDS from high cell turnover

B. Bone Marrow Biopsy + Aspirate (Keystone Investigation)

C. Cytogenetics and Molecular Testing

• Conventional karyotype (G-banding): Standard; del(5q), -7, +8, del(20q), complex
• IPSS-R cytogenetic risk groups:
  • Very good: del(11q), -Y
  • Good: Normal, del(5q), del(12p), del(20q), double with del(5q)
  • Intermediate: del(7q), +8, +19, i(17q), other single or double including -7/del(7q)
  • Poor: -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex (3 abnormalities)
  • Very poor: Complex >3 abnormalities
• NGS panel: SF3B1, TET2, DNMT3A, ASXL1, SRSF2, U2AF1, TP53, RUNX1, STAG2

• JAK2 V617F by allele-specific PCR (first-line for all MPN)
• JAK2 exon 12 mutations (if V617F negative but clinical PV)
• CALR exon 9 mutations (if JAK2 V617F negative)
• MPL W515L/K (if JAK2 and CALR negative)
• BCR-ABL1 RT-PCR to exclude CML

• BM cellularity <25% OR BM cellularity <50% with <30% haematopoietic cells
• Pancytopenia; marrow is hypocellular without dysplasia or excess blasts
• Flow cytometry for PNH clone (CD55/CD59 on granulocytes and RBCs)
• Cytogenetics (normal in AA; abnormal suggests MDS)
• Telomere length testing (lymphocytes by flow-FISH) → short = telomere biology disorder
• NGS for constitutional IBMFS genes (FANCA, DKC1, TERT, TERC, SBDS, GATA2)
• Chromosomal fragility test (DEB/MMC) for Fanconi anaemia

• Serum protein electrophoresis (SPEP): M-protein spike
• Serum immunofixation: IgG (52%) > IgA (21%) > Light chain only (16%) > IgD/IgM/biclonal (rare)
• Serum free light chain (sFLC) ratio (kappa/lambda): >100 (involved:uninvolved) = myeloma-defining event
• 24-hour urine protein electrophoresis + immunofixation: Bence-Jones protein
• BM biopsy: ≥10% clonal plasma cells; immunohistochemistry (CD138+, CD38+, CD19-, CD56+/-)
• Serum β2-microglobulin + albumin → R-ISS staging
• FISH panel on plasma cells: del(17p), t(4;14), t(14;16), 1q21 amplification, del(13q), hyperdiploidy → risk stratification
• Whole-body MRI or PET-CT or low-dose CT: Lytic lesions, focal BM lesions
• Creatinine, calcium, haemoglobin, LDH (R-ISS II requires LDH >upper normal)

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7. MANAGEMENT AND PHARMACOLOGY

7A. Aplastic Anaemia

Supportive Care (All Severity)

• Blood transfusions: Leukoreduced (prevents HLA alloimmunisation), CMV-negative (for potential transplant candidates), irradiated (prevents transfusion-associated GvHD); pRBC for symptomatic anaemia; platelets for counts <10,000/μL or active bleeding
• Antimicrobial prophylaxis: Antibacterial (fluoroquinolone), antifungal (voriconazole or posaconazole for severe AA), antiviral (aciclovir/valaciclovir); empiric broad-spectrum antibiotics for febrile neutropenia
• G-CSF (filgrastim): Selective use during active infection to transiently raise ANC; not routinely given
• Avoid NSAIDs, intramuscular injections, rectal thermometry (haemorrhage/infection risk)

Definitive Treatment

• First choice for patients ≤40 years with a matched sibling donor (MSD) (Harrison's 22E, Ch. 107)
• Conditioning regimen: Cyclophosphamide 200 mg/kg + horse ATG (or fludarabine-based reduced toxicity) to prevent graft rejection AND immune ablation
• GvHD prophylaxis: Cyclosporine + methotrexate
• Expected outcome: ~90% long-term survival in young adults with MSD; 75-80% with matched unrelated donor (MUD)
• HLA typing should be ordered immediately on diagnosis for all patients

• Mechanism: Polyclonal rabbit or horse immunoglobulin raised against human thymocytes → depletes T lymphocytes (cytotoxic T cells, regulatory T cells) → removes the immune attack on HSCs
• Horse ATG preferred over rabbit ATG in aplastic anaemia (RACE trial: hATG superior to rATG in AA)
• Premedicate: Methylprednisolone + antihistamine + paracetamol (serum sickness prevention)
• Monitor: Serum sickness (7-14 days post-infusion: fever, urticaria, arthralgias, rash) → treat with higher-dose methylprednisolone

• Mechanism: Calcineurin inhibitor → blocks NFAT activation → inhibits IL-2 production → T-cell suppression
• Duration: Maintain for ≥24 months; very slow taper over 12+ months (abrupt discontinuation → relapse)
• Monitor: Renal function, blood pressure, cyclosporine levels monthly; risk of nephrotoxicity, hypertension, hirsutism, gingival hyperplasia, neurotoxicity

• Mechanism: Oral non-peptide thrombopoietin receptor agonist; stimulates megakaryopoiesis AND has direct HSC-stimulating activity (acts on CD34+ progenitors)
• Added to hATG + CsA → markedly improved response rates (~85-90% 6-month overall response with triple therapy vs. ~60% with hATG + CsA alone)
• Duration: 6 months of eltrombopag
• Take without calcium-/magnesium-rich foods or antacids (chelation reduces absorption)

• Complete Response (CR): Hgb ≥10 g/dL, ANC ≥1000/μL, Platelets ≥100,000/μL
• Partial Response (PR): Transfusion independence AND no longer meeting severe AA criteria
• No response: Persistent SAA criteria at 3-6 months → second-line options

• Allo-HSCT with alternative donor (matched unrelated, haploidentical, cord blood) if IST fails
• Second course of hATG + CsA + eltrombopag
• Androgens (danazol 400-800 mg/day, or oxymetholone, nandrolone decanoate): Stimulate erythropoiesis; particularly useful in telomere biology disorders where IST less effective; mechanism: stimulate EPO production, enhance telomerase activity (danazol specifically)
• Eltrombopage for refractory thrombocytopenia

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7B. MDS

Risk Stratification First

• Very Low/Low/Intermediate (score ≤4.5): Transfusion support, EPO-stimulating agents, lenalidomide (del5q), luspatercept (RS-MDS)
• High/Very High (score >4.5): HMA therapy ± allo-HSCT

Supportive Care

• Transfusion support (pRBC for symptomatic anaemia; target Hgb ≥8 g/dL; higher if symptomatic)
• Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa or darbepoetin alpha; effective if serum EPO <500 mU/mL; reduces transfusion dependence in ~60% of lower-risk MDS
• G-CSF/GM-CSF: For recurrent severe infections from neutropenia; not for routine use (Goldman-Cecil, Ch. 162)
• Prophylactic platelet transfusions at <10,000/μL; antifibrinolytics (aminocaproic acid) for mucosal bleeding
• Iron chelation therapy: Deferasirox (oral) or deferoxamine (SC infusion) for transfusion-dependent iron overload (serum ferritin >1000 µg/L); reduces organ damage in low-risk patients expecting prolonged transfusion dependence

Disease-Modifying Therapy

• TGF-β superfamily ligand trap (activin A receptor type IIA fusion protein) → reduces SMAD2/3 signalling → removes inhibition of late-stage erythropoiesis
• 1 mg/kg SC every 3 weeks for MDS with ring sideroblasts (SF3B1 mutation); 70% of patients achieve transfusion independence (MEDALIST trial)
• FDA approved 2020; first-line for SF3B1-mutated/RS MDS (superior to ESAs per COMMANDS trial)
• Toxicity: Hypertension, fatigue, diarrhoea, injection site reactions

• Oral IMiD (immunomodulatory drug); 10 mg/day
• Specifically effective for del(5q) MDS: ~70% achieve transfusion independence; >30% achieve cytogenetic remission lasting median >2 years
• Mechanism: Induces ubiquitin-mediated degradation of casein kinase 1A1 (CSNK1A1 haploinsufficiency in del5q cells → synthetic lethality)
• Toxicity: Neutropenia, thrombocytopenia (monitor CBC weekly), DVT/PE (aspirin prophylaxis), teratogenicity (REMS programme mandatory)

• 75 mg/m² SC or IV daily × 7 days every 4 weeks; continue until progression or toxicity (minimum 4-6 cycles before assessing response)
• Mechanism: Pyrimidine nucleoside analogue; incorporates into DNA → inhibits DNA methyltransferase (DNMT) → DNA demethylation → re-expression of silenced tumour suppressor genes → terminal differentiation of dysplastic cells
• Improves OS (median 24 vs. 15 months), delays AML transformation, improves QoL (AZA-001 trial)
• FDA/EMA approved for all MDS risk groups
• Response rate: ~50% (haematologic improvement); ~15% CR
• Toxicity: Myelosuppression (worsening cytopenias in first 1-2 cycles), nausea, injection site reactions, constitutional symptoms

• 20 mg/m²/day IV × 5 days every 4 weeks; or Oral decitabine-cedazuridine (Inqovi) (fixed-dose tablet)
• Same mechanism as azacitidine (DNMT inhibitor); 30-50% response rate
• Oral formulation equally effective to IV; cedazuridine inhibits first-pass cytidine deaminase metabolism
• Toxicity: Myelosuppression, GI effects

• ~50% 3-year DFS in selected MDS patients
• Optimal timing: After achieving best response with HMA; before blast transformation; IPSS-R High/Very High = transplant now; Intermediate = case-by-case
• Reduced-intensity conditioning (RIC) extends eligibility to age 65-70+
• Decision depends on: IPSS-R score, age/fitness, donor availability, patient preference

• Magrolimab (anti-CD47 antibody; "don't eat me" signal blockade) + azacitidine: Phase 3 trial data
• Venetoclax + azacitidine: Phase 3 studies in higher-risk MDS
• Imetelstat (telomerase inhibitor): Phase 3 for lower-risk transfusion-dependent MDS (IMERGE trial: positive)

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7C. Polycythaemia Vera (PV)

• Target Hct <45% (men) and <42% (women) (CYTO-PV trial: Hct <45% reduces major cardiovascular events vs. <50%)
• 400-500 mL every 2-4 weeks until target achieved; less frequent maintenance thereafter
• Mechanism: Removes excess red cell mass; reduces blood viscosity; depletes iron → limits further erythropoiesis
• Monitor iron stores; supplemental iron NOT given (would re-stimulate erythropoiesis)

• 81 mg/day for all PV patients without bleeding contraindication
• Reduces thrombotic events (especially microvascular symptoms); not sufficient alone for high-risk patients

• Mechanism: Inhibits ribonucleotide reductase → blocks dNTP synthesis → S-phase arrest → reduces all myeloid cell lines (Hct, WBC, platelets)
• First-line cytoreductive agent; FDA-approved for PV; lowers Hct, reduces splenomegaly, reduces thrombosis risk
• Monitor CBC every 2-4 weeks until stable; reduce dose if ANC <3000 or platelets <100,000
• Toxicity: Myelosuppression, macrocytosis, mouth/leg ulcers, skin changes, secondary leukaemia risk (small but real with long-term use)

• JAK1/2 inhibitor: Blocks constitutive JAK2-STAT5 signalling → reduces erythrocyte, platelet, leucocyte overproduction
• Approved for HU-resistant or HU-intolerant PV (RESPONSE trial: superior to best available therapy)
• Reduces haematocrit, spleen size, pruritus, night sweats, constitutional symptoms
• Toxicity: Anaemia (dose-dependent), infections (including herpes zoster reactivation - aciclovir prophylaxis), dyslipidaemia, rebound JAK-STAT activation if abruptly stopped

• Pegylated interferon α; activates STAT1 → antiproliferative, prodifferentiation effects on malignant clone; may achieve deep molecular responses (JAK2 V617F allele burden reduction)
• FDA approved 2021 for PV
• Preferred in younger patients and pregnant women (safer than HU in pregnancy - HU teratogenic)
• Toxicity: Flu-like symptoms (injection-associated), depression, autoimmune thyroiditis, hepatotoxicity

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7D. Essential Thrombocythaemia (ET)

• Low risk (age <60, no prior thrombosis, platelet <1500×10⁹/L): Aspirin 81 mg/day only
• High risk (age >60 OR prior thrombosis): Aspirin + cytoreductive therapy

• Hydroxyurea 500-1500 mg/day PO: First-line; reduce platelets to <400×10⁹/L
• Anagrelide 0.5-1 mg QID PO: Inhibits cyclic AMP phosphodiesterase → inhibits megakaryocyte maturation/differentiation → selective reduction of platelet production; used as second-line or in patients intolerant of HU; toxicity: headache, palpitations, fluid retention, anaemia, heart failure
• Interferon alfa (pegylated): Preferred in younger patients (<40 years) and pregnant women
• Ruxolitinib: For JAK2+ ET refractory to HU/anagrelide

• LMWH + aspirin throughout pregnancy (cytoreduction rarely needed)
• Interferon if cytoreduction required (HU contraindicated in pregnancy)

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7E. Primary Myelofibrosis (PMF)

• Low/Intermediate-1: Symptom-directed; watch and wait if asymptomatic; transfusion support; HU for splenomegaly
• Intermediate-2/High: Consider allo-HSCT (curative) OR JAK inhibitor therapy

• JAK1/2 inhibitor; reduces splenomegaly (>35% reduction by MRI in ~50% patients), dramatically improves constitutional symptoms, improves QoL; may prolong survival
• Toxicity: Anaemia (dose-limiting), thrombocytopenia, infections, peripheral neuropathy (rare), herpes zoster reactivation; aciclovir prophylaxis recommended
• Does NOT significantly reduce JAK2 allele burden or reverse marrow fibrosis

• JAK2/FLT3 inhibitor; approved for intermediate-2/high PMF and for ruxolitinib-relapsed/refractory disease
• Wernicke's encephalopathy risk (thiamine depletion) - screen and supplement thiamine before and during treatment; assess for encephalopathy at baseline and every 3 months

• JAK2/IRAK1 inhibitor; approved for cytopenic PMF (platelets <50×10⁹/L) where ruxolitinib is not tolerable
• Less myelosuppression than ruxolitinib; reduces spleen and symptoms in patients with severe thrombocytopenia

• JAK1/2/ACVR1 inhibitor; ACVR1 (ALK2) inhibition reduces hepcidin → improves anaemia
• Approved 2023 for symptomatic anaemia in PMF; MOMENTUM trial showed transfusion independence benefit
• First JAK inhibitor to address both spleen/symptom burden AND anaemia simultaneously

• Only curative treatment for PMF; ~50% 5-year DFS
• Indicated for DIPSS intermediate-2 and high-risk patients
• RIC (reduced-intensity conditioning) allows transplant up to age 70-75 in fit patients
• Major risks: Graft-versus-host disease, graft failure (engraftment difficult in severely fibrotic marrow)

• Danazol 400-600 mg/day: Stimulates erythropoiesis; ~40% response
• Prednisone/glucocorticoids: For autoimmune haemolytic component; also reduces cytokine burden
• Thalidomide + prednisone: 50-100 mg/day thalidomide; ~40% erythroid response
• EPO (erythropoietin): Ineffective if EPO >125 mU/mL; may worsen splenomegaly
• Momelotinib: Preferred for anaemic PMF (ACVR1-mediated hepcidin reduction)
• pRBC transfusions: For symptomatic anaemia; iron chelation if ferritin >1000 ng/mL

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7F. Multiple Myeloma

• C Calcium >11 mg/dL; R Creatinine >2 mg/dL or CrCl <40; A Hgb <10 g/dL; B Bone lesions (lytic or osteoporosis with fracture)
• S Clonal BM plasma cells ≥60%; Li Serum involved:uninvolved FLC ≥100; M MRI ≥2 focal lesions

1. Induction (4-6 cycles): VRd (Bortezomib + Lenalidomide + Dexamethasone) or Dara-VRd (+ Daratumumab)
   • Bortezomib (Velcade) 1.3 mg/m² SC twice weekly or weekly: Proteasome (26S) inhibitor → accumulation of misfolded ubiquitinated proteins → ER stress → apoptosis; SC administration reduces neuropathy vs. IV; herpes zoster prophylaxis required (aciclovir)
   • Lenalidomide 25 mg/day days 1-21 of 28-day cycle: IMiD; cereblon-binding → IKZF1/IKZF3 degradation → myeloma cell death; aspirin or LMWH DVT prophylaxis required
   • Dexamethasone 40 mg/week PO: Antimyeloma activity via glucocorticoid receptor; reduces oedema, nausea; glucose monitoring required
   • Daratumumab (Dara) 16 mg/kg IV (or 1800 mg SC flat dose): Anti-CD38 monoclonal antibody; complement-dependent cytotoxicity + ADCC + ADCP + immunomodulatory effects; first anti-CD38; pre-medicate to prevent infusion reactions; Dara-VRd now standard in CEPHEUS/GRIFFIN trials
2. Autologous Stem Cell Transplantation (ASCT):
   • High-dose melphalan 200 mg/m² conditioning → autologous stem cell rescue
   • Deepens response (increases VGPR/CR rates); extends PFS 4-5 years (doubles vs. no transplant)
   • Stem cells harvested with G-CSF ± plerixafor (CXCR4 antagonist → mobilises CD34+ HSCs from marrow)
3. Consolidation + Maintenance:
   • Lenalidomide maintenance 10 mg/day until progression: Improves OS (MYELOMA XI, IFM 2009 trials); increases secondary myeloid malignancy risk (small absolute risk)
   • Bortezomib maintenance (for high-risk cytogenetics: del17p, t(4;14), t(14;16)): SC weekly or fortnightly
   • Daratumumab maintenance: Post-ASCT in CASSIOPEIA trial prolonged PFS

• Dara-Rd (Daratumumab + lenalidomide + dexamethasone) - MAIA trial: PFS and OS superiority; preferred first-line in elderly/unfit
• Dara-VMP (Daratumumab + bortezomib + melphalan + prednisone): ALCYONE trial; European standard in non-transplant eligible
• VRd-lite (reduced doses): For frail elderly patients

• Carfilzomib (Kyprolis): 2nd generation irreversible proteasome inhibitor; 27 mg/m² or 56 mg/m² IV; less neuropathy than bortezomib; cardiovascular toxicity (hypertension, heart failure, MI) most concerning
• Pomalidomide (Pomalyst): 3rd generation IMiD; 4 mg/day days 1-21; for lenalidomide-refractory; cereblon-binding; DVT prophylaxis required
• Elotuzumab (Empliciti): Anti-SLAMF7/CS1 antibody; immunostimulatory (activates NK cells); with pomalidomide + dexamethasone
• Isatuximab (Sarclisa): Anti-CD38 (alternative to daratumumab); combined with carfilzomib+dex or pom+dex
• Selinexor (Xpovio): XPO1 (exportin-1) inhibitor → nuclear sequestration of tumour suppressor proteins → myeloma apoptosis; oral; nausea/anorexia dose-limiting; for penta-refractory MM
• Ide-cel (bb2121, Abecma): BCMA-directed CAR-T; complete remission in ~33%; durable responses; 1 infusion; CRS and neurotoxicity; for ≥4 prior therapies
• Cilta-cel (JNJ-4528, Carvykti): BCMA-directed CAR-T with dual epitope binding; superior efficacy; approved 2022; for ≥1 prior therapy including PI + IMiD in CARTITUDE-4 trial

• Zoledronic acid (Zometa) 4 mg IV every 4 weeks: Bisphosphonate; inhibits osteoclast mevalonate pathway → prevents skeletal-related events (SREs: fractures, spinal cord compression, hypercalcaemia); reduces all-cause mortality (NICE/ASCO recommend for all patients)
• Denosumab (Xgeva) 120 mg SC every 4 weeks: Anti-RANKL monoclonal antibody; blocks osteoclast activation; non-inferior to zoledronic acid for SRE prevention; preferred in CKD (no renal toxicity)
• Both carry risk of osteonecrosis of the jaw (ONJ) - dental review before initiation; avoid invasive dental procedures

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7G. Pure Red Cell Aplasia

• Identify and treat underlying cause: Thymectomy (if thymoma); antiviral therapy (for parvovirus B19 - IVIG 1-2 g/kg)
• Cyclosporine 5-10 mg/kg/day PO: Calcineurin inhibitor → T-cell suppression; most effective agent; ~70% response
• Prednisolone 1 mg/kg/day: Adjunct or first-line if cyclosporine not available
• EPO-antibody-mediated PRCA (from subcutaneous EPO): Withdraw EPO immediately; switch to darbepoetin (different protein backbone); cyclosporine or rituximab for antibody suppression
• Rituximab: For B-cell (antibody-mediated) or refractory PRCA
• Allo-HSCT for inherited refractory cases (Diamond-Blackfan anaemia unresponsive to corticosteroids)

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Summary Pharmacology Table

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8. COMPLICATIONS

Aplastic Anaemia Complications

• Infections (leading cause of death): Bacterial sepsis (Gram-negative: Pseudomonas, E. coli; Gram-positive: Staph aureus) and fungal infections (Aspergillus - most feared) from neutropenia; risk proportional to ANC and duration of neutropenia
• Intracranial haemorrhage from severe thrombocytopenia (<10,000/μL): Fatal 30-50% if not rapidly corrected
• Clonal evolution (10-30% of AA patients): Evolution to PNH (haemolysis, thrombosis), MDS, or AML over months-years; requires long-term haematological monitoring; related to clonal haematopoiesis and genomic instability
• Organ damage from recurrent infections and iron overload

• Serum sickness (hATG): 7-14 days post-ATG; fever, urticaria, arthralgias, rash; treat with escalated methylprednisolone
• Cyclosporine toxicity: Nephrotoxicity (dose-dependent; monitor creatinine), hypertension, tremor, hirsutism, gingival hyperplasia; long-term use → chronic kidney disease
• GvHD (post allo-HSCT): Acute (dermatitis, hepatitis, gastroenteritis) and chronic (multisystem fibrotic disease); major cause of post-transplant morbidity/mortality
• Graft failure (post allo-HSCT): 5-10% incidence; treated with second transplant or donor lymphocyte infusion
• Transfusional iron overload: Ferritin >2500 µg/L → cardiac arrhythmias (most dangerous), liver cirrhosis, endocrinopathies; requires chelation (deferasirox 14-20 mg/kg/day PO or deferoxamine 40 mg/kg SC infusion overnight)
• Relapse after IST: 30-40% relapse after hATG + CsA; most respond to second course; clonal evolution in some

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MDS Complications

• Progression to AML: 10-40% depending on IPSS-R; higher risk with excess blasts, complex karyotype, TP53 mutation
• Transfusion-dependent iron overload: Cardiac siderosis (arrhythmias, heart failure), hepatic fibrosis/cirrhosis, endocrine dysfunction (diabetes mellitus from pancreatic iron deposition); chelation required
• Infections: From neutropenia and functional neutrophil defects (hypogranular, reduced chemotaxis)
• Haemorrhage: Thrombocytopenia + qualitative platelet dysfunction from dysplastic megakaryocytes
• HMA treatment-related: Worsening cytopenias in first 1-2 treatment cycles (expected; do not switch therapy early); nausea, injection site reactions; rarely: interstitial pneumonitis (azacitidine)
• Lenalidomide DVT/PE: Especially when combined with high-dose dexamethasone; mandatory thromboprophylaxis

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MPN Complications

• Arterial and venous thrombosis (leading cause of death): Stroke, MI, DVT, PE, Budd-Chiari syndrome (particularly young women), portal/mesenteric vein thrombosis (particularly men); driven by elevated haematocrit, leukocytosis, and platelet activation by JAK2 V617F
• Haemorrhage: Paradoxically, from acquired von Willebrand disease when platelets extremely elevated (>1500×10⁹/L); also peptic ulcer disease (histamine-driven)
• Transformation to post-PV myelofibrosis (PPV-MF): 15-20% at 10 years; signalled by progressive splenomegaly, worsening anaemia, rising LDH
• Transformation to AML: 5-10% lifetime risk (higher in PPV-MF); very poor prognosis with median OS <1 year
• Hydroxyurea toxicity: Leg/mouth ulcers (discontinue HU if ulcers develop; switch to ruxolitinib), macrocytic anaemia, myelosuppression, skin changes (xerosis, hyperpigmentation), secondary leukaemia risk (small)
• Aquagenic pruritus refractory to therapy: Reduces quality of life; treat with antihistamines, SSRI (paroxetine), phototherapy, ruxolitinib

• Thrombosis (arterial: stroke, MI, digital gangrene; venous: DVT, PE, splanchnic vein thrombosis)
• Haemorrhage (extreme thrombocytosis >1500×10⁹/L → acquired vWD)
• Transformation to myelofibrosis (post-ET MF): ~5% at 10 years; ~1-3% transform to AML
• Pregnancy complications: First-trimester miscarriage (increased); need LMWH + aspirin management

• Massive splenomegaly → portal hypertension: Oesophageal varices, ascites, spontaneous bacterial peritonitis
• Leukaemic transformation (blast phase PMF): 15-20% at 10 years; 30% at 15 years; poor prognosis (median OS <1 year); treat with allo-HSCT if feasible
• Profound anaemia: Transfusion-dependence in advanced disease; iron overload from chronic transfusion
• Bone pain and extra-medullary haematopoiesis: Spinal cord compression from vertebral extramedullary haematopoiesis; hepatic failure from hepatic infiltration
• Ruxolitinib complications: Acute withdrawal syndrome if abruptly stopped (cytokine rebound → fever, sepsis-like picture); Wernicke's encephalopathy not associated with ruxolitinib but with fedratinib
• Splenic infarction (acute left upper quadrant pain + peritonism)

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Multiple Myeloma Complications

• Pathological fractures: Most commonly vertebral bodies → vertebral collapse → acute pain + kyphosis + spinal cord compression (haematological emergency); treat with urgent decompressive surgery or radiotherapy + high-dose dexamethasone
• Spinal cord compression (SCC): Acute neurological deterioration (limb weakness, sensory level, bowel/bladder dysfunction); requires immediate MRI spine + dexamethasone 16-40 mg/day IV + urgent radiotherapy or surgical decompression
• Hypercalcaemia: Confusion, drowsiness, polyuria, constipation, nausea; treat with aggressive IV saline + zoledronic acid (4 mg IV) + calcitonin (4 IU/kg SC) for rapid effect
• Hyperviscosity syndrome (IgA/IgM myeloma, high M-protein): Headache, visual blurring, stroke, bleeding; treat with plasma exchange
• AL Amyloidosis: Cardiac (restrictive cardiomyopathy, fatal arrhythmias), renal (nephrotic syndrome), hepatic, neurological (autonomic dysfunction, peripheral neuropathy), tongue (macroglossia); prognosis determined by cardiac involvement (NT-proBNP, troponin); treat underlying myeloma with bortezomib-based therapy; cardiac transplant occasionally for isolated cardiac amyloid
• Recurrent infections: Bacterial (S. pneumoniae, H. influenzae), viral (VZV), PCP; IVIG replacement for severe hypogammaglobulinaemia + recurrent infections; trimethoprim-sulfamethoxazole prophylaxis for PCP with bortezomib; aciclovir for VZV

• Peripheral neuropathy: Bortezomib (dose-dependent, dose-limiting; painful sensory > motor; partially reversible if drug held; SC route reduces risk); thalidomide (severe, often irreversible, avoid >12 months)
• DVT/PE (IMiD agents - lenalidomide, pomalidomide, thalidomide): Requires thromboprophylaxis (aspirin 81 mg/day for standard risk; LMWH or full anticoagulation for high risk)
• ONJ (Osteonecrosis of the Jaw): From bisphosphonates/denosumab; risk 1-10% with dental trauma; presents as exposed jaw bone with poor healing; mandible > maxilla; preventable with dental evaluation and avoidance of invasive dental procedures during therapy
• Secondary primary malignancies: AML/MDS risk with melphalan (ASCT conditioning) and long-term lenalidomide maintenance (2-3× increased risk; absolute risk small but real)
• Cytokine Release Syndrome (CRS) from CAR-T: Fever, hypotension, hypoxia; treat with tocilizumab + dexamethasone
• ICANS from CAR-T: Encephalopathy, aphasia, seizures; treat with corticosteroids, seizure prophylaxis
• Carfilzomib cardiovascular toxicity: Hypertension, acute heart failure, MI, stroke; baseline and serial cardiac monitoring required

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Key clinical principles:

• Bone marrow biopsy with trephine is the cornerstone investigation for all bone marrow disorders - it provides cellularity (aplastic vs. hypercellular), morphology (dysplasia in MDS, fibrosis in PMF), blast percentage (MDS vs. AML), and tissue for immunohistochemistry, cytogenetics, and molecular testing
• Aplastic anaemia and MDS can be indistinguishable on marrow morphology alone; cytogenetics and NGS are essential to distinguish them
• All MPN, MDS, and aplastic anaemia patients require long-term haematological follow-up due to risk of clonal evolution, disease transformation, and treatment toxicity
• Multiple myeloma is incurable with current therapy in most patients; treatment aims at deep remissions and prolonged PFS; CAR-T therapy is changing the landscape for heavily pre-treated patients

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Hepatobiliary Disorders: A Comprehensive Reference

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1. DEFINITION

• Metabolic functions: Carbohydrate, lipid, and protein metabolism; gluconeogenesis; glycogen storage; amino acid synthesis; urea cycle
• Synthetic functions: Coagulation factors (I, II, V, VII, VIII, IX, X, XI), albumin, complement proteins, carrier proteins (transferrin, ceruloplasmin)
• Detoxification: Drug metabolism (cytochrome P450 enzymes), bilirubin conjugation, ammonia conversion to urea
• Biliary function: Bile acid synthesis and excretion, cholesterol metabolism, excretion of bilirubin and other waste products
• Immunological function: Kupffer cells (hepatic macrophages), IgA secretion into bile

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2. TYPES / CLASSIFICATION

A. Parenchymal Liver Diseases (Hepatocellular)

1. Viral hepatitis (acute and chronic): HAV, HBV, HCV, HDV, HEV
2. Alcoholic liver disease (ALD) / Alcohol-associated liver disease: Steatosis → steatohepatitis → cirrhosis
3. Metabolic dysfunction-associated steatotic liver disease (MASLD): Previously NAFLD; encompasses steatosis, MASH (formerly NASH), fibrosis, cirrhosis
4. Drug-induced liver injury (DILI): Hepatocellular, cholestatic, or mixed pattern
5. Autoimmune hepatitis (AIH): Types 1 and 2
6. Hereditary/metabolic liver diseases: Wilson disease, haemochromatosis, alpha-1-antitrypsin deficiency
7. Cirrhosis: Final common pathway of chronic liver injury → fibrosis and architectural distortion
8. Acute liver failure (ALF) / Fulminant hepatic failure
9. Acute-on-chronic liver failure (ACLF)

B. Cholestatic / Biliary Diseases

1. Primary biliary cholangitis (PBC): Autoimmune destruction of small intrahepatic bile ducts
2. Primary sclerosing cholangitis (PSC): Fibro-inflammatory stricturing of intra- and extrahepatic ducts
3. Secondary biliary cirrhosis: From chronic biliary obstruction (stones, strictures)
4. Biliary atresia: Congenital (neonates)
5. Intrahepatic cholestasis of pregnancy (ICP)

C. Gallbladder and Extrahepatic Biliary Diseases

1. Cholelithiasis (gallstones)
2. Acute and chronic cholecystitis
3. Choledocholithiasis (common bile duct stones)
4. Acute cholangitis
5. Primary and secondary sclerosing cholangitis
6. Biliary strictures (post-surgical, post-inflammatory)
7. Gallbladder polyps and carcinoma
8. Cholangiocarcinoma (bile duct cancer): Intrahepatic, perihilar (Klatskin), distal

D. Hepatic Vascular Disorders

1. Portal hypertension (pre-hepatic, hepatic, post-hepatic)
2. Budd-Chiari syndrome (hepatic vein / IVC obstruction)
3. Portal vein thrombosis
4. Hepatic sinusoidal obstruction syndrome (SOS/VOD): From chemotherapy/HSCT
5. Congestive hepatopathy (from right heart failure)

E. Hepatic Neoplasms

1. Hepatocellular carcinoma (HCC)
2. Cholangiocarcinoma
3. Hepatic metastases (most common hepatic malignancy overall)
4. Hepatic haemangioma (most common benign tumour)
5. Focal nodular hyperplasia (FNH), hepatic adenoma

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3. CAUSES / AETIOLOGY

Viral Hepatitis

Alcoholic Liver Disease (ALD)

• Primary cause: Sustained heavy alcohol consumption (>21 units/week men; >14 units/week women)
• Pathogenic mechanisms (Harrison's 22E): Ethanol → acetaldehyde (via ADH1 and CYP2E1) → reactive oxygen species, lipid peroxidation, DNA damage; increased NADH/NAD+ ratio → impaired beta-oxidation; increased lipogenesis → steatosis; Kupffer cell activation by endotoxin (LPS) → TNF-α, IL-6, IL-8 → hepatocyte apoptosis/necrosis
• Risk factors for progression (Harrison's, block 38): Dose/duration; binge drinking; female sex (lower ADH activity, higher bioavailability); obesity/MASLD (co-factor); genetic variants (PNPLA3, MBOAT7, TM6SF2, HSD17B13); concurrent viral hepatitis or haemochromatosis; ALDH2 deficiency (common in East Asians → acetaldehyde accumulation)
• Only 10-20% of heavy drinkers develop cirrhosis

MASLD (Metabolic-Associated Steatotic Liver Disease)

• Metabolic syndrome is the central driver: Obesity (visceral adiposity), type 2 diabetes mellitus, dyslipidaemia (hypertriglyceridaemia), hypertension
• Global prevalence: 30%; highest in Latin America (44%), Middle East/North Africa (36.5%), South Asia (33.8%)
• "Two-hit" hypothesis: First hit = lipid accumulation (steatosis) from insulin resistance → increased FFA delivery to liver + de novo lipogenesis; Second hit = oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, gut microbiome dysbiosis → hepatocyte injury and inflammation → MASH
• Genetic risk: PNPLA3 I148M most important genetic determinant; TM6SF2 E167K; GCKR; HSD17B13 (protective)
• Higher risk: Hispanic and Asian ethnicities; male sex

Drug-Induced Liver Injury (DILI)

• Hepatocellular pattern (elevated ALT): Paracetamol (dose-dependent necrosis; most common cause of acute liver failure in West; depletes glutathione → N-acetylimidoquinone accumulation → Zone 3 centrilobular necrosis), isoniazid, rifampicin, methotrexate, statins, nitrofurantoin, halothane, diclofenac
• Cholestatic pattern (elevated ALP/GGT/bilirubin): Amoxicillin-clavulanate (most common cause of drug cholestasis), anabolic steroids, oral contraceptive pills, chlorpromazine, flucloxacillin, erythromycin
• Mixed pattern: Phenytoin, sulfonamides, tricyclics
• Idiosyncratic DILI (most drugs): Immune-mediated hypersensitivity reaction; dose-independent; often with fever, rash, eosinophilia

Autoimmune Hepatitis (AIH)

• Type 1: Anti-smooth muscle antibodies (ASMA) and/or ANA positive; affects females predominantly (70-80%); any age; associated with other autoimmune diseases (thyroiditis, IBD, SLE, coeliac disease)
• Type 2: Anti-LKM1 (anti-liver/kidney microsomal antibody type 1; anti-CYP2D6) positive; predominantly children and young adults; more severe course
• Pathogenesis (Sleisenger, block 23): Genetic predisposition (HLA-DR3, DR4 in Type 1; HLA-DR7, DR3 in Type 2) + environmental triggers (viral infections, drugs) → molecular mimicry → loss of T-regulatory cell tolerance → CD4+ and CD8+ T-cell-mediated hepatocyte destruction → interface hepatitis → fibrosis

Primary Biliary Cholangitis (PBC)

• Autoimmune destruction of small intrahepatic bile ducts
• Antimitochondrial antibodies (AMA) against pyruvate dehydrogenase complex E2 subunit (PDC-E2) - 95% sensitive and specific
• Strongly female predominance (9:1 F:M); peak age 40-60 years
• Associated with Sjögren's syndrome, autoimmune thyroid disease, CREST syndrome

Primary Sclerosing Cholangitis (PSC)

• Idiopathic; fibro-inflammatory stricturing of bile ducts
• Strong male predominance (2:1); median age ~40 years
• >70% have concomitant inflammatory bowel disease (predominantly ulcerative colitis; pancolitis)
• HLA-B8, DR2, DR3 genetic associations
• p-ANCA positive in ~80%; no pathognomonic antibody
• Lifetime risk of cholangiocarcinoma ~10-15% (most feared complication)

Cholelithiasis (Gallstones)

• Cholesterol stones (80-85%): Supersaturation of bile with cholesterol + nucleation factors + gallbladder hypomotility; risk factors: "5 Fs" - Fat, Female, Forty, Fertile (multiparity), Family history; additionally: rapid weight loss, OCP, TPN, Crohn's disease (terminal ileum disease → impaired bile salt reabsorption → decreased bile salt pool → cholesterol supersaturation), octreotide therapy
• Pigment stones (15-20%): Black pigment stones: Chronic haemolysis (sickle cell disease, hereditary spherocytosis, thalassaemia), cirrhosis, Gilbert syndrome - calcium bilirubinate deposits; Brown pigment stones: Biliary stasis + bacterial infection (E. coli deconjugates bilirubin) - associated with bile duct infections

Hepatocellular Carcinoma (HCC)

• Chronic HBV infection (with or without cirrhosis - HBV can cause HCC without cirrhosis; integrated viral DNA directly oncogenic)
• Cirrhosis from any cause (HCV, alcoholic, MASLD, haemochromatosis)
• Aflatoxin B1 (Aspergillus-contaminated grain in Africa/Asia; potent hepatocarcinogen; p53 mutation at codon 249)
• MASLD-associated HCC (rising incidence; can occur without cirrhosis)
• Male sex; age; diabetes; alcohol
• Risk: ~3-5% annual HCC incidence in cirrhotic HCV patients

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4. PATHOLOGY / PATHOPHYSIOLOGY

Alcoholic Liver Disease - Morphological Spectrum

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MASLD Pathophysiology

• NAFL (simple steatosis): Hepatic fat ≥5% of liver weight (without inflammation or injury) - generally benign; annual risk of progressing to MASH is ~1-2%
• MASH (Metabolic-Associated Steatohepatitis, formerly NASH): Steatosis + hepatocyte ballooning + lobular inflammation (lobular necroinflammation) ± Mallory-Denk bodies + pericellular/perisinusoidal fibrosis ("chickenwire" pattern on Masson's trichrome) - Pathognomonic location: Zone 3 (centrilobular, perivenular)
• MASLD Fibrosis → Cirrhosis: Annual rate of fibrosis progression from MASH ~1 stage/7 years; 10-15% of MASH patients develop cirrhosis over 10-15 years
• Noninvasive assessment: FIB-4 index (age × AST / [platelet count × √ALT]); NFS (NAFLD fibrosis score); liver stiffness by FibroScan (transient elastography)

• Steatosis (0-3) + Lobular inflammation (0-3) + Hepatocyte ballooning (0-2) = NAS 0-8
• NAS ≥5 = MASH; NAS <3 = likely no MASH; NAS 3-4 = borderline

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Cirrhosis - Pathophysiology

• Normally quiescent, store vitamin A as retinyl esters in cytoplasmic fat droplets
• Following injury: Activated by TGF-β1 (from Kupffer cells, platelets, portal fibroblasts) → trans-differentiation into myofibroblasts → express α-SMA → produce collagen I, III, IV, fibronectin, proteoglycans → progressive fibrosis

• Primary: Increased intrahepatic vascular resistance from fibrous bands and regenerative nodules compressing portal venule branches + activated HSC contraction + endothelin-1 excess (reduced NO bioavailability in hepatic sinusoids)
• Secondary (hyperdynamic circulation): Splanchnic vasodilation (driven by NO, prostacyclin, CO from bacterial translocation) → increased portal blood flow → further elevates portal pressure → activation of renin-angiotensin-aldosterone system (RAAS) → sodium and water retention → ascites

• Hepatic venous pressure gradient (HVPG) = wedged hepatic vein pressure - free hepatic vein pressure
• Normal HVPG <5 mmHg; Clinically significant portal hypertension (CSPH) = HVPG ≥10 mmHg (varices form); Variceal bleeding threshold HVPG ≥12 mmHg; Ascites threshold ≥10 mmHg

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Primary Biliary Cholangitis (PBC)

• AMAs target PDC-E2 on apical surface of biliary epithelial cells (BECs)
• CD4+ and CD8+ T-cells attack BEC expressing aberrant PDC-E2 on cell surface
• Florid duct lesion (pathognomonic): Granulomatous inflammation surrounding damaged small bile ducts; portal inflammation with dense lymphocytic infiltrate
• Progressive: Small bile duct destruction → bile ductopenia → cholestasis → fibrosis → cirrhosis
• Elevated ALP, GGT, conjugated bilirubin; elevated cholesterol (often very high - xanthomas); pruritus from bile acid retention

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Primary Sclerosing Cholangitis (PSC)

• "Onion-skin" periductal fibrosis around medium and large bile ducts - pathognomonic
• Progressive fibro-obliterative stricturing → segmental strictures alternating with normal calibre ("beads on a string" on MRCP) → intrahepatic cholestasis → secondary biliary cirrhosis
• Strong association with ulcerative colitis (>70%)
• Elevated ALP, GGT; IgM elevated in PBC (not PSC); MRCP is the diagnostic gold standard

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Cholelithiasis and Cholecystitis Pathophysiology

• Cholesterol stones: Cholesterol supersaturation of bile + mucin nucleation + gallbladder dysmotility → crystal nucleation → stone growth
• Pigment stones: Excess bilirubin conjugation (haemolysis) or bacterial deconjugation of bilirubin → calcium bilirubinate precipitation

• Gallstone impaction in cystic duct → obstruction → increased intraluminal pressure → venous and lymphatic occlusion → inflammation → secondary bacterial superinfection (E. coli, Klebsiella, Enterococcus in ~50%)
• Acalculous cholecystitis (5-10%): Critically ill patients (ICU, TPN, post-major surgery, burns, sepsis) → gallbladder ischaemia/stasis → wall necrosis → gangrene; higher mortality than calculous type

• Common bile duct (CBD) obstruction → obstructive jaundice (conjugated hyperbilirubinaemia)
• Ascending cholangitis (Charcot's triad: fever + jaundice + right upper quadrant pain)
• Gallstone pancreatitis

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Hepatocellular Carcinoma Pathophysiology

• Chronic inflammation → repeated cycles of hepatocyte death and regeneration → accumulation of somatic mutations
• Key molecular pathways: Wnt/β-catenin pathway (CTNNB1 mutations - most common, ~30%); TP53 mutations (aflatoxin-associated); TERT promoter mutations (telomerase reactivation, most common promoter mutation); ARID1A, AXIN1, RB1
• Chronic HBV: HBx protein transactivates host oncogenes; HBV DNA integrates into host genome → insertional mutagenesis near proto-oncogenes

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5. CLINICAL FEATURES

Acute Viral Hepatitis (All Types)

• Prodromal phase (1-2 weeks): Flu-like symptoms - fever, malaise, myalgia, anorexia, nausea, right upper quadrant discomfort, aversion to cigarette smoke (specific for hepatitis)
• Icteric phase: Jaundice (yellow sclerae, dark urine, pale stools, pruritus), tender hepatomegaly, splenomegaly (20%)
• Recovery: Jaundice and symptoms resolve; liver enzyme normalisation over 1-3 months

Chronic Hepatitis

• Often asymptomatic for years to decades
• Non-specific: Fatigue, malaise, right upper quadrant discomfort
• Advanced disease: Signs of portal hypertension + liver failure (see cirrhosis below)

Cirrhosis - Clinical Features

1. Ascites: Abdominal distension, shifting dullness and fluid thrill on examination; caused by portal hypertension + hypoalbuminaemia + RAAS activation
2. Variceal bleeding: Haematemesis or melaena; gastro-oesophageal varices rupture; may be catastrophic; portal hypertension-driven
3. Hepatic encephalopathy (HE): Altered consciousness, confusion, asterixis (hepatic flap), constructional apraxia; spectrum from Grade I (altered sleep, mild confusion) to Grade IV (coma); precipitated by: GI bleeding, infection, constipation, electrolyte disturbance, sedative drugs, high protein intake, TIPS
4. Spontaneous bacterial peritonitis (SBP): Infection of ascitic fluid without apparent intra-abdominal source; fever, abdominal pain, worsening encephalopathy; PMN >250 cells/mm³ on ascitic tap; E. coli, Klebsiella, S. pneumoniae most common

• Hepatomegaly or small shrunken liver (late cirrhosis), splenomegaly
• Spider naevi (>5 above waist = significant; oestrogen-mediated, also seen in pregnancy)
• Palmar erythema (hypothenar and thenar eminences; oestrogen-mediated)
• Leukonychia (white nails, Terry's nails)
• Caput medusae (periumbilical vein distension from portal-systemic collaterals)
• Dupuytren's contracture (particularly alcoholic liver disease)
• Gynaecomastia and testicular atrophy (impaired oestrogen metabolism)
• Fetor hepaticus (musty "mousy" breath from mercaptans and dimethylsulphide)
• Jaundice, pruritus (from bile acid retention - especially cholestatic disease)
• Parotid enlargement (especially alcoholic liver disease)
• Peripheral neuropathy, proximal myopathy (ALD)
• Bruising, petechiae (coagulopathy + thrombocytopenia)

Alcoholic Hepatitis (Severe)

• Acute-onset jaundice, fever, tender hepatomegaly
• Discriminant Function (Maddrey's DF) ≥32 = severe → consider corticosteroid therapy
• GAHS (Glasgow Alcoholic Hepatitis Score) ≥9 = severe; LILLE score at day 7 predicts response to steroids
• 28-day mortality ~30-50% in severe disease

Acute Liver Failure (ALF)

• Jaundice + coagulopathy (INR ≥1.5) + hepatic encephalopathy within 26 weeks in a previously healthy liver
• Most common causes in West: Paracetamol overdose (most common in UK/Australia), drug reactions, viral hepatitis (HAV, HBV, HEV)
• Most common worldwide: Viral hepatitis (HBV, HEV in pregnancy)
• King's College Criteria guide liver transplantation listing

Biliary Colic

• Episodic, severe, constant right upper quadrant (or epigastric) pain, radiating to right shoulder/scapula; begins 30-60 minutes after fatty meal; duration 1-6 hours; nausea and vomiting; no fever/jaundice unless complicated

Acute Cholecystitis

• Persistent RUQ pain >6 hours (vs. colicky pain of uncomplicated cholelithiasis)
• Fever, nausea, vomiting
• Murphy's sign: Inspiratory arrest on palpation of the right hypochondrium (gallbladder tender under examiner's fingers)
• Elevated WBC, CRP; mildly elevated ALP/bilirubin; if bilirubin markedly elevated → suspect choledocholithiasis

Ascending Cholangitis

• Charcot's triad (1877): Fever + Jaundice + RUQ pain (present in ~70%)
• Reynolds' pentad (severe, suppurative cholangitis): Adds mental status change + hypotension → requires urgent biliary decompression (ERCP/surgery); mortality ~10-30%

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6. DIAGNOSTIC APPROACH

Liver Function Tests (LFTs) / Liver Chemistry Panel

• FBC: Thrombocytopenia (portal hypertension → splenic sequestration); macrocytic anaemia (ALD/folate deficiency); leukocytosis (alcoholic hepatitis, cholangitis)
• Serum ammonia: Elevated in hepatic encephalopathy; not reliable for grading HE severity

Serology and Immunology

• Anti-HAV IgM: Acute HAV infection (diagnostic)
• HBsAg: HBV infection (surface antigen; present from 1-12 weeks post-exposure; persists >6 months = chronic)
• Anti-HBs: Immunity (vaccination or prior infection)
• HBeAg: Active viral replication, high infectivity
• Anti-HBe: Seroconversion; reduced replication (but HBeAg-negative chronic hepatitis important subset)
• HBV DNA (PCR): Quantifies viral load; guides treatment decisions; defines replication
• Anti-HCV (ELISA): Screening for HCV exposure (window period ~8-12 weeks)
• HCV RNA (PCR): Confirms active infection (positive within 1-2 weeks of infection); used for diagnosis and treatment monitoring (SVR = undetectable HCV RNA 12 weeks after completing treatment)
• HCV genotype: Determines treatment regimen and duration (though modern pangenotypic DAAs make this less critical)
• Anti-HDV IgM/IgG with HBV coinfection
• Anti-HEV IgM: Acute HEV infection

• ANA, ASMA (anti-smooth muscle): AIH Type 1
• Anti-LKM1 (anti-CYP2D6): AIH Type 2
• Anti-SLA/LP (anti-soluble liver antigen): AIH (Type 3; associated with severe course)
• AMA (anti-mitochondrial antibody): PBC (>95% sensitive and specific; anti-M2 = anti-PDC-E2)
• ANCA (p-ANCA): PSC (~80% positive)
• IgG levels: Elevated in AIH; IgM elevated in PBC; IgG4 elevated in IgG4-related cholangitis (mimics PSC)
• Simplified AIH score / International AIH Group (IAIHG) score for diagnosis

• Iron studies: Serum ferritin, transferrin saturation (>45% suggests haemochromatosis); HFE gene mutation (C282Y, H63D)
• Serum caeruloplasmin (low in Wilson disease <0.2 g/L); 24-hour urinary copper (elevated in Wilson); slit-lamp examination (Kayser-Fleischer rings in Wilson - copper in Descemet's membrane of cornea)
• Alpha-1-antitrypsin (A1AT) level and phenotype (PiZZ = most severe; PAS-positive diastase-resistant globules in hepatocytes on liver biopsy)

Imaging

• Cholelithiasis: Echogenic foci with posterior acoustic shadowing; sensitivity >95%
• Cholecystitis: Gallbladder wall thickening (>4 mm), pericholecystic fluid, positive sonographic Murphy's sign
• Biliary dilation: CBD >6 mm = dilated (add 1 mm per decade >60 years); suggests obstruction
• Cirrhosis: Coarsened echotexture, irregular surface, caudate lobe hypertrophy, splenomegaly, ascites
• Portal hypertension: Splenomegaly, ascites, portosystemic collaterals; hepatic vein/portal vein patency; reversal of portal flow (hepatofugal)
• HCC: Hypoechoic or mixed echogenicity nodule on background cirrhosis

• Three-phase CT (non-contrast, arterial, portal venous): HCC shows arterial phase enhancement (APHE - arterial phase hyperenhancement) with washout in portal venous phase (characteristic LI-RADS 5 pattern)
• Excellent for bile duct dilation, choledocholithiasis, biliary strictures, hepatic masses
• CT cholangiography for preoperative biliary mapping

• Gold standard non-invasive imaging of bile ducts
• PSC: "Beads on a string" appearance from alternating strictures and dilatations
• Choledocholithiasis: Filling defects in CBD
• Preferred over ERCP for diagnosis (no radiation, non-invasive, no pancreatitis risk)

• Therapeutic, not purely diagnostic (pancreatitis risk ~3-5%)
• Indications: Choledocholithiasis (stone extraction with sphincterotomy), biliary strictures (stenting), cholangitis (decompression), bile leak, PSC stenting
• Cholangiogram shows "pruned tree" in PSC; filling defects in choledocholithiasis

• Indications: Unexplained liver disease, staging of chronic hepatitis (fibrosis assessment), AIH diagnosis, suspected MASH, hereditary liver disease, rejection post-transplant
• Approaches: Percutaneous (ultrasound/CT-guided), transjugular (for coagulopathy/ascites), laparoscopic
• Histological features: Fibrosis stage (F0-F4 on METAVIR scale: F0=none; F1=portal; F2=periportal; F3=septal/bridging; F4=cirrhosis); necroinflammation grade (A0-A3); specific diagnoses (Wilson's, haemochromatosis, PBC, PSC, MASH)
• Noninvasive alternatives: FIB-4, APRI; FibroScan (transient elastography); Enhanced Liver Fibrosis (ELF) panel (HA + PIIINP + TIMP-1) - increasingly replacing biopsy for fibrosis staging

• HIDA scan (hepatobiliary iminodiacetic acid scintigraphy / cholescintigraphy): Functional imaging; gold standard for diagnosing acute cholecystitis when ultrasound equivocal; gallbladder non-visualisation at 4 hours = cystic duct obstruction = acute cholecystitis
• FDG-PET: For staging cholangiocarcinoma and HCC; limited sensitivity in early HCC

• Liver stiffness in kPa: <7 kPa = no significant fibrosis; 7-12.5 kPa = significant fibrosis; >12.5 kPa = cirrhosis; >20 kPa = CSPH (clinically significant portal hypertension)
• Increasingly used for cirrhosis diagnosis and portal hypertension assessment without biopsy

• Invasive via transjugular approach; gold standard for portal pressure measurement
• HVPG ≥10 mmHg = CSPH; ≥12 mmHg = risk of variceal bleeding; ≥16 mmHg = risk of decompensation

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7. MANAGEMENT AND PHARMACOLOGY

7A. Viral Hepatitis

Hepatitis A and E

• Supportive: Rest, adequate hydration, antipyretics (paracetamol with caution in large doses)
• Avoid alcohol and hepatotoxic drugs during recovery
• Isolation: Enteric precautions until jaundice resolves
• HAV vaccine (inactivated): 2-dose schedule; 95%+ protective; recommended for travellers, MSM, IVDU, CLD patients
• HEV in immunocompromised (chronic HEV): Ribavirin 600 mg/day × 3-6 months; reduce immunosuppression if possible

Hepatitis B - Chronic (Harrison's 22E, block 38)

• HBV DNA >2000 IU/mL + elevated ALT (>upper limit of normal)
• HBV DNA >20,000 IU/mL regardless of ALT (HBeAg-positive)
• Advanced fibrosis (F3-F4) regardless of DNA level
• Compensated or decompensated cirrhosis (any HBV DNA level)
• Immunocompromised patients receiving immunosuppression/chemotherapy (HBV reactivation prophylaxis)

• Nucleotide analogue reverse transcriptase inhibitor (NtRTI); inhibits HBV polymerase/reverse transcriptase
• 300 mg PO once daily; requires renal dose adjustment

• 99% HBV DNA suppression rate at 96 weeks; high barrier to resistance (no resistance detected in clinical trials)

• Toxicity: Nephrotoxicity (tubular dysfunction, Fanconi syndrome), decreased bone mineral density; avoid in renal impairment
• Avoid in patients with osteoporosis or renal impairment → use TAF instead

• 25 mg PO once daily; prodrug with improved cellular delivery of active metabolite → allows lower plasma levels → less renal and bone toxicity than TDF
• Equal antiviral efficacy to TDF; preferred in patients with renal impairment, osteoporosis, or elderly
• Slight increase in lipid levels vs. TDF

• Deoxyguanosine nucleoside analogue; inhibits HBV polymerase (initiation, reverse transcription, DNA synthesis)
• 0.5 mg PO once daily (treatment-naive); 1 mg PO once daily (lamivudine-experienced or resistant)
• High potency; very high barrier to resistance (resistance <1% in treatment-naive patients at 5 years)
• Avoid in patients with HIV coinfection without concomitant HIV treatment (may select ETV-resistant HIV)

• 180 mcg SC weekly × 48 weeks (fixed duration)
• Mechanism: Antiviral + immunomodulatory; may achieve HBsAg seroconversion (durable off-therapy response) in ~5-7% HBeAg-positive patients
• Advantages: Finite treatment duration; no resistance; possible HBsAg loss
• Disadvantages: Subcutaneous injection; significant side effects (flu-like, cytopenias, depression, autoimmune); contraindicated in decompensated cirrhosis
• Preferred for younger patients and those wishing finite treatment

• HBV DNA every 3-6 months during treatment; target undetectable
• HBeAg/anti-HBe (for seroconversion monitoring in HBeAg-positive)
• ALT every 3-6 months
• Renal function and bone density (TDF users)
• Treatment duration: Indefinite (lifelong) in most patients with oral antivirals unless HBsAg seroconversion (loss of HBsAg + gain of anti-HBs = functional cure)

Hepatitis C - Chronic (Direct-Acting Antivirals - DAAs)

• NS5B inhibitor (nucleotide analogue): Sofosbuvir - inhibits RNA-dependent RNA polymerase (RdRp); high barrier to resistance; pangenotypic
• NS5A inhibitor: Velpatasvir, pibrentasvir, ledipasvir - blocks NS5A protein (essential for replication complex formation and viral assembly)
• NS3/4A protease inhibitor: Glecaprevir, voxilaprevir, grazoprevir - inhibits viral protease; cleaves non-structural polyprotein; genotype-dependent NS3 inhibitors have some genetic barrier limitations

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7B. Autoimmune Hepatitis (AIH)

• Prednisolone 40-60 mg/day PO (or 1 mg/kg/day) → taper slowly over 4-6 weeks to maintenance 5-10 mg/day

• Azathioprine 50 mg/day → titrate to 1-2 mg/kg/day (add after 2-4 weeks of steroids once tolerability confirmed)
• Mechanism: Azathioprine → 6-mercaptopurine → 6-thioguanine nucleotides → inhibition of purine synthesis → T and B cell lymphopenia
• Check TPMT (thiopurine methyltransferase) activity before starting azathioprine - TPMT-deficient patients accumulate 6-TGN → severe myelosuppression
• Monitor LFTs, CBC every 3 months

• Mycophenolate mofetil (MMF) 1-2 g/day: Inosine monophosphate dehydrogenase (IMPDH) inhibitor → de novo purine synthesis blockade in lymphocytes; alternative to azathioprine; not recommended if planning pregnancy (teratogenic)
• Cyclosporine or tacrolimus: For refractory AIH or acute severe presentation; calcineurin inhibitors
• Budesonide 9 mg/day (non-cirrhotic mild-moderate AIH): Gut-first-pass metabolism (high hepatic extraction) → high local immunosuppression + lower systemic steroid side effects; less effective in cirrhosis (portosystemic shunting bypasses first-pass)
• Rituximab (anti-CD20): For truly refractory cases; depletes B cells

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7C. Primary Biliary Cholangitis (PBC)

• Ursodeoxycholic acid (UDCA) 13-15 mg/kg/day PO in 2 divided doses
• Mechanism: Hydrophilic bile acid; replaces toxic hydrophobic bile acids in bile pool; cytoprotective; anti-apoptotic; stimulates biliary secretion; immunomodulatory (inhibits HLA Class II expression on BECs)
• ~50% of patients achieve full biochemical normalisation; reduces risk of cirrhosis and improves transplant-free survival
• Lifelong treatment; generally well-tolerated (loose stools, mild weight gain initially)

• ALP ≤1.5× ULN + AST ≤1.5× ULN + Bilirubin ≤17 µmol/L at 1 year
• Non-responders to UDCA (40-50%) need second-line therapy

• Obeticholic acid (OCA - Ocaliva) 5-10 mg/day PO: First-in-class FXR (farnesoid X receptor) agonist; stimulates FXR → reduces bile acid synthesis (represses CYP7A1) + promotes biliary excretion; approved by FDA 2016; toxicity: pruritus (dose-dependent, most common reason for discontinuation), hepatotoxicity (avoid in Child-Pugh B/C cirrhosis)
• Bezafibrate 400 mg/day or fenofibrate 200 mg/day: PPAR-α agonists; reduce bile acid synthesis + anti-inflammatory; second-line especially in Europe; effective for pruritus and ALP reduction
• Elafibranor (PPAR-α/δ agonist): Recently approved for inadequate UDCA responders
• Seladelpar (PPAR-δ agonist): FDA approved 2024 for PBC; effective for biochemical response and pruritus

• Pruritus: Cholestyramine (bile acid sequestrant; 4 g TID before meals; give 4 hours before/after UDCA) → rifampicin 150-300 mg/day (induces hepatic enzymes that metabolise pruritogenic bile acids; monitor LFTs; hepatotoxicity risk) → naltrexone 50 mg/day (opioid antagonist; reduces central pruritus) → sertraline → plasmapheresis (refractory)
• Fatigue: Supportive; no effective drug therapy
• Fat-soluble vitamin deficiency (A, D, E, K) from cholestasis: Supplementation; vitamin D + calcium for osteoporosis prevention

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7D. Primary Sclerosing Cholangitis (PSC)

• No disease-modifying therapy proven effective for PSC (UDCA does not improve survival in PSC; may reduce ALP but no transplant benefit at 17-23 mg/kg/day; high-dose UDCA 28-30 mg/kg/day increased adverse events in UDFK trial)
• ERCP + stenting/balloon dilation: For dominant strictures causing cholangitis or jaundice
• Regular cholangiocarcinoma surveillance: CA 19-9 every 6-12 months + MRCP annually; low threshold for brushings/EUS-FNA of strictures
• Colorectal cancer surveillance: Annual colonoscopy (due to UC association)
• Treat IBD (mesalazine, biologics for UC)
• Cholangitis episodes: Broad-spectrum antibiotics (piperacillin-tazobactam or ciprofloxacin + metronidazole) + urgent biliary decompression (ERCP/PTCD)
• Liver transplantation: Definitive treatment; 5-year survival 80-90%; recurrence in ~20-30% of grafts
• Emerging: Norursodeoxycholic acid (NorUDCA 24-norursodeoxycholic acid) - selective stimulation of hepatocellular bicarbonate secretion; Phase 2 positive data

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7E. Alcoholic Liver Disease

• Thiamine 100-200 mg IV/IM before glucose (prevents Wernicke's encephalopathy)
• Benzodiazepine-based alcohol withdrawal protocol (diazepam, chlordiazepoxide, lorazepam using CIWA-Ar scoring)
• Pharmacotherapy for alcohol use disorder: Naltrexone 50 mg/day (opioid antagonist; reduces craving/reward), acamprosate 666 mg TID (GABA-B agonist/NMDA antagonist; maintains abstinence), disulfiram 250 mg/day (inhibits ALDH2 → acetaldehyde accumulation → flushing, nausea, tachycardia), nalmefene (opioid modulator for harm reduction)

• Prednisolone 40 mg/day PO × 28 days → taper over 2 weeks (STOPAH trial: reduces 28-day mortality)
• LILLE score at day 7: <0.45 = response (continue steroids to 28 days); >0.45 = non-response (stop steroids; high mortality)
• Contraindications to steroids: Active GI bleeding, uncontrolled infection/sepsis, renal failure (CrCl <40), gastrointestinal perforation
• N-acetylcysteine (NAC) IV: As adjunct with prednisolone in severe AH (ACTA trial; improves 30-day mortality when added to prednisolone; replenishes glutathione, anti-oxidant)
• Pentoxifylline 400 mg TID: TNF-α inhibitor; inhibits phosphodiesterase; formerly used but STOPAH trial showed no survival benefit; some centres still use for hepatorenal syndrome prevention
• Nutritional support: Enteral feeding (nasogastric tube if required); minimum 35 kcal/kg/day + 1.2-1.5 g protein/kg/day
• Early liver transplantation: Selected patients with severe AH not responding to steroids (pilot studies show benefit; requires strict selection criteria and MDT decision)

• Weight loss (5-10% body weight): Reduces hepatic steatosis; 7% reduction = improvement in MASH; 10% = fibrosis regression - most effective intervention
• Dietary modification: Mediterranean diet; reduce fructose-containing beverages, refined carbohydrates
• Exercise: Aerobic exercise 30 minutes × 5 days/week reduces steatosis and inflammation
• Treat metabolic comorbidities:
  • GLP-1 receptor agonists (semaglutide, liraglutide): Significant MASH activity and fibrosis improvement; semaglutide 2.4 mg SC weekly (weight loss dose) - ESSENCE trial; semaglutide 0.4 mg SC weekly showed NASH resolution >50%
  • SGLT-2 inhibitors (empagliflozin, dapagliflozin): Reduce steatosis and inflammation; beneficial in MASLD with T2DM
  • Pioglitazone (PPAR-γ agonist): 30-45 mg/day; improves MASH histology (steatosis, necroinflammation, fibrosis) in MASH + T2DM; risk: weight gain, fluid retention, fracture risk, bladder cancer (long-term use)
  • Vitamin E 800 IU/day: Antioxidant; improves MASH histology in non-diabetic adults (PIVENS trial); not recommended in diabetics or with high cardiovascular risk; small risk of prostate cancer with long-term use
• Resmetirom (Rezdiffra): First FDA-approved pharmacotherapy for MASH (FDA March 2024); selective thyroid hormone receptor beta (THR-β) agonist (liver-targeted); 80-100 mg/day PO; Phase 3 MAESTRO-NASH trial: 26% NASH resolution without fibrosis worsening + 24% ≥1 stage fibrosis improvement vs. placebo; Approved for non-cirrhotic MASH with moderate-to-severe fibrosis (F2-F3)
• Bariatric/metabolic surgery: For BMI ≥35 with MASH; sleeve gastrectomy or Roux-en-Y gastric bypass → massive weight loss → MASH resolution; most effective long-term intervention

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7F. Cirrhosis - Complications Management

Ascites

• Dietary sodium restriction: 80-120 mmol/day (2-3 g/day salt)
• Spironolactone 100 mg/day PO → titrate up to 400 mg/day: Aldosterone antagonist; blocks distal tubule Na+ reabsorption; preferred diuretic in cirrhotic ascites; potassium-sparing; side effect: gynaecomastia (use eplerenone as alternative)
• Furosemide 40 mg/day PO → titrate up to 160 mg/day: Loop diuretic; add if spironolactone insufficient; combined spiro:furo ratio 100:40 mg (maintains potassium balance); monitor Na+, K+, creatinine closely

• Large-volume paracentesis (LVP): ≥5 L; must give IV human albumin 6-8 g per litre of ascites removed (post-paracentesis circulatory dysfunction prevention → reduces mortality)
• TIPS (Transjugular Intrahepatic Portosystemic Shunt): For refractory ascites or refractory variceal bleeding; creates portosystemic shunt → reduces portal pressure; effective but worsens hepatic encephalopathy; covered (PTFE) TIPS superior
• Terlipressin or norepinephrine: For type 1 hepatorenal syndrome (see below)

• Diagnosis: Ascites PMN ≥250 cells/mm³
• Treatment: Cefotaxime 2 g IV q8h × 5 days (third-generation cephalosporin; covers enteric Gram-negatives) + IV albumin 1.5 g/kg on day 1 and 1 g/kg on day 3 (reduces renal failure and mortality - Sort trial)
• Alternative: Piperacillin-tazobactam or quinolones (but increasing resistance)
• Primary prophylaxis (high-risk): Norfloxacin 400 mg/day PO or ciprofloxacin 500 mg/day (for ascitic protein <1.5 g/dL + CTP ≥9 or renal impairment)
• Secondary prophylaxis (post-SBP): Norfloxacin 400 mg/day PO indefinitely; reduces recurrence from 68% to 20%

Variceal Bleeding

1. Resuscitation: IV access, blood transfusion to Hgb 7-8 g/dL (restrictive transfusion reduces mortality in TRIGGER trial); avoid over-transfusion (raises portal pressure)
2. Vasoactive agents (start immediately, before endoscopy):
   • Terlipressin 2 mg IV q4h × 5 days (then 1 mg q4h): V1 receptor agonist; splanchnic vasoconstriction → reduces portal blood flow; most evidence-based vasoactive agent for variceal bleeding; reduces mortality; not available in US
   • Octreotide 50 mcg IV bolus → 50 mcg/hour infusion × 5 days: Somatostatin analogue; inhibits glucagon/VIP → splanchnic vasoconstriction; used in US instead of terlipressin
   • Somatostatin 250 mcg bolus → 250 mcg/hour infusion: Available in Europe; similar to octreotide
3. Prophylactic antibiotics (start immediately, before endoscopy): Ceftriaxone 1 g IV/day × 7 days (reduces bacterial infections and mortality; Bernardi trial); alternative: norfloxacin 400 mg BD PO if enteral route available
4. Endoscopic variceal ligation (EVL): Treatment of choice; bands applied at endoscopy; most effective haemostasis (hemostasis in ~90%); superior to injection sclerotherapy
5. Balloon tamponade (Sengstaken-Blakemore tube): Temporary bridge (maximum 24 hours) if endoscopy unavailable or fails; risk of oesophageal necrosis/rupture; superseded by self-expanding metal stents (SEMS) as bridge to TIPS
6. TIPS (covered TIPS): For refractory or recurrent variceal bleeding; pre-emptive TIPS within 72 hours in high-risk patients (Child-Pugh C10-13 or B + active bleeding) reduces 6-week mortality (GARCIA-PAGAN trial)

• Carvedilol (non-selective beta-blocker with α1-blocking properties) or propranolol/nadolol 40-80 mg BD: Reduce cardiac output + splanchnic vasoconstriction → reduce portal pressure; reduce HVPG; titrate to resting HR 55-60 bpm; start 24-48 hours after haemostasis
• EVL sessions every 2-4 weeks until obliteration of varices
• Combined β-blocker + EVL: Current standard; reduces variceal rebleeding more than either alone

Hepatic Encephalopathy (HE)

• Lactulose 15-45 mL PO TID-QID (titrate to 2-3 soft stools/day): Non-absorbable disaccharide; acidifies colon (pH <5) → NH3 → NH4+ (trapped, not absorbed); cathartic (eliminates nitrogenous waste); may be given as enema in comatose patients
• Rifaximin 550 mg PO BD: Minimally absorbed gut-specific antibiotic; reduces gut ammonia-producing bacteria; FDA-approved for prevention of recurrent HE; superior tolerability vs. neomycin/metronidazole (Harrison's, block 38)
• Zinc supplementation: 220 mg zinc sulfate PO BD; zinc deficiency common in cirrhosis; reduces ammonia by promoting urea cycle
• LOLA (L-ornithine L-aspartate) IV: Promotes urea cycle and ammonia metabolism; evidence mostly in overt HE
• Dietary protein restriction: NOT recommended (worsens malnutrition); encourage 1.2-1.5 g protein/kg/day; prefer branched-chain amino acids and vegetable/dairy protein; small frequent meals + late evening snack
• TIPS closure: For refractory HE precipitated by large TIPS shunt (TIPS reduction or occlusion)

Hepatorenal Syndrome (HRS)

• Definition: Acute kidney injury in cirrhosis with ascites, in the absence of intrinsic renal disease or shock; serum creatinine rises >26 µmol/L in 48 hours OR ≥1.5× baseline within 7 days
• Remove precipitants: SBP (treat), nephrotoxins (NSAIDs, aminoglycosides), hypovolaemia (diuretics)
• Albumin challenge: IV albumin 1 g/kg/day × 2 days (volume expand to exclude true hypovolaemia)
• HRS-1 treatment:
  • Terlipressin 0.5-2 mg IV q4-6h (or continuous infusion) + albumin 20-40 g/day IV: First-line; reverses HRS-1 in ~40%; FDA approved 2022 (CONFIRM trial); monitor for ischaemic complications (peripheral + splanchnic)
  • Norepinephrine (noradrenaline): IV infusion (0.5-3 mg/hour); splanchnic vasoconstriction; used in ICU; similar efficacy to terlipressin in recent RCTs; preferred in ICU setting
  • Midodrine 7.5-15 mg PO TID + octreotide 100-200 mcg SC TID + albumin: Outpatient/less severe HRS alternative to terlipressin
• Liver transplantation: Definitive treatment; HRS is fully reversible post-transplant; patients with HRS on waiting list often need renal support; combined liver-kidney transplant if >12 weeks of renal failure or irreversible renal damage

Hepatocellular Carcinoma (HCC) - Surveillance and Treatment

• Liver ultrasound + serum AFP every 6 months (AASLD/EASL guideline)
• Patients at very high risk (cirrhotic patients with compensated cirrhosis, HBV): Contrast-enhanced CT or MRI at 6-12 months if US equivocal

• BCLC 0/A (very early/early): Curative intent
  • Resection (solitary, preserved liver function, no portal hypertension): 5-year survival 70%
  • Liver transplantation (Milan criteria: 1 lesion ≤5 cm OR ≤3 lesions each ≤3 cm + no vascular invasion + no extrahepatic spread): Best long-term outcome; 5-year survival 75%; solves cirrhosis too
  • Radiofrequency ablation (RFA) or microwave ablation: For lesions ≤3 cm; curative intent; similar outcomes to resection for single lesions ≤3 cm
• BCLC B (intermediate, multifocal, no vascular invasion):
  • TACE (Transarterial Chemoembolisation): Intra-arterial doxorubicin/cisplatin + Lipiodol + embolic particles; selective tumour embolisation; improves survival vs. BSC; can achieve downstaging for transplant
  • TARE/Y90 (Transarterial radioembolisation with Yttrium-90 microspheres): Alternative to TACE; especially for portal vein tumour thrombus
• BCLC C (advanced, vascular invasion or extrahepatic spread):
  • Atezolizumab + bevacizumab (Tecentriq + Avastin): First-line systemic therapy; PD-L1 checkpoint inhibitor + anti-VEGF; IMbrave150 trial: superior OS (19.2 months vs. 13.4 months) and PFS vs. sorafenib; now preferred first-line
  • Durvalumab + tremelimumab (HIMALAYA trial): Anti-PD-L1 + anti-CTLA4; second first-line option
  • Sorafenib (Nexavar) 400 mg PO BD: First approved systemic therapy; multi-kinase inhibitor (VEGFR, PDGFR, RAF); improves median OS from 7.9 to 10.7 months; toxicity: hand-foot skin reaction, diarrhoea, hypertension, fatigue
  • Lenvatinib 12 mg/day PO: Multi-kinase inhibitor (VEGFR1-3, FGFR1-4, PDGFRα); non-inferior to sorafenib (REFLECT trial); second first-line option
  • Regorafenib, cabozantinib, ramucirumab: Second-line after sorafenib failure

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7G. Gallstone Disease

Biliary Colic (Uncomplicated Cholelithiasis)

• Analgesia: NSAIDs (diclofenac 75 mg IM or 50 mg PR - reduces biliary spasm + analgesic) or opioids (morphine, pethidine); antispasmodics (hyoscine butylbromide 20 mg IV/IM)
• Elective laparoscopic cholecystectomy: Definitive treatment; >95% performed laparoscopically; 30-minute procedure; 1-2 day hospital stay; mortality <0.1%
• Ursodeoxycholic acid (UDCA): 8-10 mg/kg/day PO for 12-24 months; dissolves small (<5 mm) radiolucent cholesterol stones; only if surgery contraindicated; recurrence common on stopping; largely replaced by laparoscopic surgery

Acute Cholecystitis

• IV fluids, analgesia, NBM (nil by mouth)
• Antibiotics: IV cefuroxime 1.5 g q8h + metronidazole 500 mg q8h (or amoxicillin-clavulanate, or piperacillin-tazobactam for severe); target enteric organisms (E. coli, Klebsiella, Enterococcus)
• Laparoscopic cholecystectomy: Preferred within 72 hours of diagnosis (early cholecystectomy reduces conversion to open, length of stay - ACALC, CHOLE trial data); if unfit for surgery → percutaneous cholecystostomy (drain) as bridge

Choledocholithiasis / Ascending Cholangitis

• ERCP + sphincterotomy + stone extraction: First-line definitive treatment for CBD stones; clearance rate >90%
• Urgent ERCP within 24 hours for mild-moderate cholangitis (Tokyo guidelines); emergency ERCP within 12 hours or percutaneous transhepatic cholangiogram (PTC) drainage for severe cholangitis (Reynolds' pentad/organ failure)
• Antibiotics: Broad-spectrum IV; piperacillin-tazobactam 4.5 g q8h or meropenem 1 g q8h for severe; narrow after cultures; duration: 4-7 days (or 3 days after decompression for mild)
• Subsequent cholecystectomy after recovery (if CBD stones from gallbladder origin)

Drug Therapy Summary for Hepatobiliary Disorders

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8. COMPLICATIONS

Complications of Cirrhosis and Portal Hypertension

Complications of Specific Conditions

• Acute viral hepatitis → Acute liver failure (rare; HAV 0.1%; HBV 1%; HEV in pregnancy 20%)
• Chronic HBV/HCV → Cirrhosis → HCC
• HBV reactivation during immunosuppression (chemotherapy, rituximab, steroids) → Fulminant hepatitis; prophylaxis with entecavir or tenofovir mandated
• HCV cryoglobulinaemia: Mixed type II cryoglobulinaemia → palpable purpura, arthritis, peripheral neuropathy, membranoproliferative GN (treat with DAAs ± rituximab)
• HBV extrahepatic: Polyarteritis nodosa, membranous nephropathy, aplastic anaemia

• Paracetamol overdose: Zone 3 (centrilobular) necrosis → acute liver failure; treatment window: NAC within 24 hours (ideally <8 hours); King's College Criteria for transplant listing
• Idiosyncratic DILI: Drug reaction with eosinophilia and systemic symptoms (DRESS) - vancomycin, dapsone, allopurinol; autoimmune DILI (minocycline, nitrofurantoin, statins) → can persist after drug withdrawal
• DILI outcome: Most resolve after drug cessation; ductopenic cholestasis from some drugs can cause prolonged cholestasis ("vanishing bile duct syndrome") → may progress to liver failure

• Acute cholecystitis complications: Gallbladder perforation (free perforation → biliary peritonitis; localised → pericholecystic abscess); gangrenous cholecystitis; emphysematous cholecystitis (gas-forming organisms; diabetics at risk); Mirizzi syndrome (cystic duct stone compresses CBD → jaundice)
• Choledocholithiasis complications: Ascending cholangitis (life-threatening sepsis); acute biliary pancreatitis; secondary biliary cirrhosis (from chronic CBD obstruction)
• Post-cholecystectomy syndrome: Persistent right upper quadrant pain after cholecystectomy; causes: bile duct injury, bile leak, retained CBD stones, SOD (sphincter of Oddi dysfunction), functional
• Gallstone ileus: Large stone erodes through gallbladder wall into duodenum → Rigler's triad on X-ray (pneumobilia + SBO + ectopic stone); surgical emergency

• Cholangiocarcinoma (10-15% lifetime risk; median 7 years after PSC diagnosis): Often de novo; CA 19-9 elevated; poor prognosis; surgical resection for distal/perihilar if resectable; liver transplant for perihilar in selected centres (MSKCC/Mayo criteria)
• Dominant strictures: Progressive biliary obstruction → recurrent cholangitis → secondary biliary cirrhosis
• Colorectal cancer (with UC-PSC): Higher risk than UC alone; annual colonoscopy essential; dysplasia surveillance
• Fat-soluble vitamin deficiency (ADEK), metabolic bone disease (osteoporosis), steatorrhoea

• Cerebral oedema and intracranial hypertension (Grade III-IV HE) → brain herniation (leading cause of death); manage with mannitol IV, hypertonic saline (maintain Na+ 145-155 mmol/L), head elevation, ICP monitoring in selected centres
• Multi-organ failure: AKI (hepatorenal; contrast nephropathy avoidance; continuous renal replacement therapy)
• Haemodynamic instability: Vasodilatory shock → norepinephrine infusion
• Coagulopathy + bleeding: Vitamin K, FFP/cryoprecipitate for active bleeding; PPI for stress ulcer prophylaxis
• Infection (50% develop bacterial infection, 30% fungal): Broad-spectrum antibiotics + antifungals
• Hypoglycaemia: 10% dextrose infusion; frequent glucose monitoring
• Liver transplantation (orthotopic, OLTx): Lifesaving in King's College Criteria-positive patients; must act quickly (hours to days available for decision)

• pH <7.30 after resuscitation; OR
• All 3: PT >100s + creatinine >300 µmol/L + Grade III-IV encephalopathy

• PT >100 seconds; OR
• Any 3 of: PT >50s + bilirubin >300 µmol/L + Age <10 or >40 years + Aetiology (DILI, idiopathic, Wilson) + Jaundice-to-encephalopathy interval >7 days

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Key clinical principles:

• The liver has enormous reserve capacity - symptoms of chronic liver disease appear late; by the time decompensation occurs, >80% of hepatic function is lost
• Hepatitis B and C together account for ~1.3 million deaths annually worldwide; HCV is curable in >95% with 8-12 weeks of oral therapy; HBV is controllable but rarely cured with current therapy
• MASLD (formerly NAFLD) is now the most common chronic liver disease globally (30% prevalence); resmetirom was the first FDA-approved pharmacotherapy (March 2024)
• The most important therapeutic interventions in cirrhosis are: (1) treating the underlying cause, (2) preventing and managing complications, and (3) timely referral for liver transplantation when MELD ≥15
• Bile duct obstruction requires urgent investigation - ascending cholangitis (Charcot's triad) is a medical emergency requiring immediate antibiotics + biliary decompression
• Non-selective beta-blockers (carvedilol/propranolol) and EVL are complementary strategies for variceal prophylaxis; both should be used together after a first bleed