Comprehensive study resource covering erythropoiesis, anaemia, white cell disorders, myeloproliferative neoplasms, acute leukaemia, lymphoma, plasma cell disorders, coagulation, thrombosis, transfusion medicine, bone marrow transplantation, and haematologic emergencies. Every pathway, every drug, every high-yield pearl you need to know.
RBC Development • Iron Metabolism • Microcytic • Macrocytic • Normocytic • Haemolytic Anaemias
RBC Development: Pluripotent HSC → BFU-E → CFU-E → proerythroblast → basophilic erythroblast → polychromatic erythroblast → orthochromatic erythroblast → reticulocyte → mature RBC. Reticulocytes remain in marrow 1-2 days, then released into circulation, maturing in 1 day. Erythropoietin (EPO): Produced by peritubular interstitial cells in kidney (90%) and liver (10%, fetal). Stimulated by hypoxia (HIF-1α stabilization). Levels increase in anaemia, decrease in CKD. Recombinant EPO (epoetin alfa, darbepoetin alfa) used for anaemia of CKD, chemotherapy-induced anaemia. RBC lifespan: ~120 days. Senescent RBCs removed by splenic macrophages (extravascular hemolysis). Hb broken down: heme → biliverdin → bilirubin → conjugated in liver → excreted in bile. Iron recycled to transferrin.
Absorption: Duodenum/jejunum. Heme iron (animal sources) absorbed via heme transporter. Non-heme Fe3+ reduced to Fe2+ by duodenal cytochrome b (DcytB), then transported via DMT1 into enterocyte. Exported via ferroportin (basolateral). Hephaestin oxidizes Fe2+ to Fe3+ for transferrin binding. Transport: Transferrin carries Fe3+ in plasma. Transferrin-bound iron taken up by erythroid precursors via transferrin receptor 1 (TfR1). Storage: Ferritin (water-soluble, in cytosol) and hemosiderin (insoluble aggregates, in macrophages). Ferritin levels correlate with total body iron stores. Hepcidin Regulation: Hepcidin (liver hormone) binds ferroportin → internalization/degradation → blocks iron export from enterocytes, macrophages, and hepatocytes. Increased hepcidin: iron overload, inflammation (IL-6, IL-1β). Decreased hepcidin: iron deficiency, hypoxia, erythropoiesis (via erythroferrone). Hepcidin is central to anaemia of chronic disease (inflammation → ↑ hepcidin → iron trapping in macrophages). Iron studies: Serum iron, TIBC (transferrin capacity), transferrin saturation (serum iron/TIBC × 100%), ferritin. sTfR elevated in iron deficiency (not in ACD).
Iron Deficiency Anaemia (IDA): Most common anaemia worldwide. Causes: blood loss (GI: peptic ulcer, colon cancer, angiodysplasia, hemorrhoids; menstrual), malabsorption (coeliac, gastrectomy, atrophic gastritis, H. pylori), increased demand (pregnancy, growth), poor diet (rare). Labs: ↓ ferritin (<15-30), ↑ TIBC, ↓ transferrin sat (<16%), ↑ RDW, low MCV. Bone marrow: absent stainable iron (gold standard). Treatment: oral ferrous sulfate 325mg every other day (better absorption). IV iron for intolerance, non-adherence, severe/refractory, CKD, IBD. Response: reticulocytosis in 5-10d, Hb rise ~1g/dL/week. Correct underlying cause (colonoscopy for men/postmenopausal women). Thalassaemia: Impaired globin chain synthesis. Alpha: silent carrier (1 gene deleted), trait (2 genes), HbH disease (3 genes, β4 tetramers, Heinz bodies), Hb Bart hydrops fetalis (4 genes, lethal). Beta: minor (HbA2 >3.5%), intermedia, major (Cooley anaemia, transfusion-dependent, >95% HbF). Hb electrophoresis: ↑ HbF, ↑ HbA2 in β-thal; HbH/Hb Bart in α-thal. Treatment: transfusion, iron chelation (deferasirox, deferiprone, desferrioxamine), splenectomy, HSCT, gene therapy (exagamglogene autotemcel/Casgevy). ACD: Hepcidin-mediated. Ferritin ↑/normal, TIBC ↓, sTfR normal. Sideroblastic anaemia: Ring sideroblasts. Congenital (X-linked ALA synthase, pyridoxine responsive), acquired (MDS SF3B1, alcohol, drugs, lead poisoning, copper deficiency). Basophilic stippling in lead poisoning.
Megaloblastic: Impaired DNA synthesis. B12/folate deficiency, drugs (methotrexate, hydroxyurea, 6-MP, AZT, TMP, phenytoin). Bone marrow: megaloblastic changes, giant metamyelocytes, hypersegmented neutrophils (>5 lobes). B12 (Cobalamin) Deficiency: Pernicious anaemia (autoimmune, anti-IF/parietal cell antibodies, ↑ gastric cancer risk). Other causes: ileal resection/Crohn, bacterial overgrowth, fish tapeworm, vegan diet, atrophic gastritis, gastric bypass. Stores last 3-5yr. Clinical: megaloblastic anaemia, glossitis, neuropathy (posterior column + corticospinal tract = subacute combined degeneration), dementia, depression. Diagnosis: ↓ B12, ↑ MMA, ↑ homocysteine. Anti-IF antibodies (specific). Treatment: IM hydroxocobalamin 1000μg 3x/week for 2wk then monthly. Do NOT give folate alone (neuro progression). Folate Deficiency: Causes: inadequate intake (alcoholics, elderly, malnutrition), increased demand (pregnancy, hemolysis, cancer, dialysis), malabsorption (coeliac), drugs (methotrexate, TMP, phenytoin). Stores last ~3mo. Clinical: megaloblastic anaemia (no neuro symptoms). Diagnosis: ↓ serum folate, ↑ homocysteine (normal MMA). Treatment: folic acid 1-5mg PO daily. Non-megaloblastic macrocytosis: Liver disease, alcohol, hypothyroidism, reticulocytosis, MDS, aplastic anaemia, drugs (AZT, 5-FU). MCV rarely >115 unless megaloblastic.
Normocytic (MCV 80-100): ACD (most common, hepcidin, treat underlying), CKD (decreased EPO, give EPO if Hb <9-10), aplastic anaemia, haemolytic anaemia, primary bone marrow disorders (MDS, leukemia, infiltration), hypothyroidism, mixed deficiency, acute blood loss. Haemolytic Anaemia: ↑ indirect bilirubin, ↑ LDH, ↓ haptoglobin, ↑ reticulocyte count. Peripheral smear: spherocytes, schistocytes, bite cells, sickle cells. Hereditary Spherocytosis (HS): Autosomal dominant. Defect in spectrin/ankyrin/band 3. Anaemia, jaundice, splenomegaly, pigment gallstones, aplastic crisis (parvovirus B19). Osmotic fragility test (↑). DAT negative. Treatment: splenectomy (vaccinate pre-op: pneumococcus, meningococcus, H. influenzae type b). Folic acid. G6PD Deficiency: X-linked recessive. Most common enzyme deficiency (~400M people). NADPH production defect → oxidative hemolysis. Triggers: drugs (primaquine, sulfonamides, dapsone, nitrofurantoin, ASA, methylene blue), fava beans, infection. Heinz bodies, bite cells. Self-limited. Diagnosis: G6PD enzyme assay (may be falsely normal during acute hemolysis). Variants: GdA+ (African, mild), GdMediterranean (severe). Treatment: avoid triggers. Sickle Cell Disease (SCD): HbS Glu6Val. HbS polymerizes when deoxygenated. HbAS = trait (asymptomatic, renal concentrating defect, exercise-related sudden death). HbSS = sickle cell anaemia. Clinical: vaso-occlusive crises, acute chest syndrome (#1 cause of death), stroke (TCD screening age 2), splenic sequestration, aplastic crisis (parvovirus B19), priapism, leg ulcers, functional asplenia. Diagnosis: Hb electrophoresis (HbS >90%). Treatment: hydroxyurea (↑ HbF, ↓ crisis/ACS), folic acid, penicillin prophylaxis (age <5), pneumococcal vaccines. Newer: L-glutamine (oral, ↓ crisis 25%), voxelotor (↑ Hb, ↓ hemolysis), crizanlizumab (anti-P-selectin, ↓ crisis 45%). Acute crisis: IV fluids, O2, opioids, incentive spirometry. Exchange transfusion for acute stroke/severe ACS/priapism. HSCT curative. Gene therapy: Casgevy (CRISPR BCL11A enhancer), LentiGlobin. Autoimmune Haemolytic Anaemia (AIHA): Warm (IgG, DAT IgG+ C3+, steroids/rituximab/splenectomy). Cold (IgM, DAT C3+ only, avoid cold, rituximab/sutimlimab). PNH: PIG-A mutation, complement-mediated, eculizumab/ravulizumab. Aplastic Anaemia: Pancytopenia + hypocellular marrow. Acquired (idiopathic, drugs, viruses) vs congenital (Fanconi, dyskeratosis congenita). Severe AA: cellularity <25% + ≥2 of: ANC <500, plt <20k, retics <1%. Treatment: HSCT (if <40yr + sibling donor) or IST (ATG + cyclosporine + eltrombopag). Supportive: transfusions (leucoreduced, irradiated, CMV-safe).
Neutrophilia • Neutropenia • Eosinophilia • Basophilia • Monocytosis • Lymphocytosis • Pancytopenia
Neutrophilia (ANC >7700): Infection (bacterial, fungal), inflammation (vasculitis, pancreatitis, trauma, MI), medications (steroids, G-CSF, lithium), stress, asplenia, CML, leukemoid reaction (>50K, left shift, toxic granulation, Dohle bodies, high LAP score, no basophilia vs CML low LAP + basophilia). Neutropenia (ANC <1500; severe <500): Risk: gram-negatives, Staph, fungal. Causes: severe congenital (Kostmann, ELANE), cyclic (ELANE, 21-day), autoimmune (Felty: RA + splenomegaly), drug-induced (chemotherapy, clozapine, carbimazole, TMP-SMX, sulfonamides, penicillins, NSAIDs, phenytoin, carbamazepine, rituximab), post-infection, benign ethnic (African/Caribbean, 1000-1500, no risk). Febrile neutropenia: emergency. Empiric broad-spectrum abx (cefepime, meropenem, piperacillin-tazobactam) +/- vancomycin. G-CSF (filgrastim, pegfilgrastim).
Eosinophilia (AEC >500): Allergic (asthma, atopic, drug), parasitic (helminths: Strongyloides, Ascaris, hookworm, Schistosoma; NOT protozoa), EGPA/Churg-Strauss (asthma + eosinophilia + ANCA/MPO), HES (>1500 + end-organ damage: Loeffler endocarditis, restrictive CMP). FIP1L1-PDGFRA fusion (imatinib-responsive). Rule out Strongyloides before steroids (hyperinfection risk). Basophilia (>200): Strongly associated with CML (~90%), also PV, PMF. Always check BCR-ABL. Monocytosis (>1000): CMML (monocytosis + dysplasia, TET2/SRSF2/ASXL1, hypomethylating agents, HSCT), TB, endocarditis, sarcoidosis, autoimmune, recovery from marrow suppression. Lymphocytosis (>4000): CLL (CD5+/CD23+, smear cells, Rai/Binet, watchful wait or FCR/venetoclax-obinutuzumab/BTKi), viral (EBV, CMV, pertussis: mature T-cell, no smear cells, self-limited), ALL (blasts, marrow failure). Pancytopenia: Bone marrow failure (aplastic, Fanconi, dyskeratosis congenita), MDS (<20% blasts, IPSS-R, lenalidomide for del5q, azacitidine/decitabine, luspatercept for ring sideroblasts, HSCT), infiltration (leukemia, lymphoma, myeloma, metastasis, myelofibrosis), hypersplenism, B12/folate, PNH, HIV, drugs, SLE. Workup: CBC, smear, reticulocyte count, B12/folate, LDH, bilirubin, haptoglobin, ANA, viral serology, bone marrow biopsy (cellularity, dysplasia, fibrosis, iron stain, cytogenetics, FISH, flow cytometry).
PV • ET • PMF • CML • JAK2 • CALR • MPL • BCR-ABL • TKI Therapy
Genetics: JAK2V617F (~95%), JAK2 exon 12 (~3%). Constitutive JAK-STAT activation. Clinical: Plethora, ruddy complexion, aquagenic pruritus (pathognomonic), erythromelalgia (burning pain hands/feet), splenomegaly (~70%), thrombosis (arterial & venous, MI, stroke, DVT/PE, Budd-Chiari), bleeding (acquired vWF deficiency), gout. Labs: ↑ Hb (>16.5 M/>16.0 F), ↑ Hct (>49%/>48%), ↓ EPO. Bone marrow: panmyelosis. Diagnosis: WHO criteria. Risk: low (age <60 + no thrombosis) vs high. Treatment: phlebotomy (target Hct <45%) + low-dose aspirin for all. High risk: hydroxyurea first-line, interferon-α (pegylated) for younger, ruxolitinib second-line (RESPONSE). Transformation: → MF (10-20% at 10-15yr) or AML (<5%).
Genetics: JAK2V617F (~50-60%), CALR (~20-25%, type 1/2, better prognosis), MPL (~3-5%), triple-negative (~10-15%). Clinical: Thrombocytosis (plt >450K). Asymptomatic or thrombosis (arterial > venous: stroke, TIA, MI, DVT, splanchnic), bleeding if extreme >1-1.5M (acquired vWD), microvascular symptoms (erythromelalgia, digital ischemia). Bone marrow: increased megakaryocytes (large, hyperlobated, clustered). Risk: age ≥60, prior thrombosis, JAK2+. Treatment: low risk → aspirin. High risk → hydroxyurea first-line, interferon-α for young/pregnancy, anagrelide second-line (less effective, ↑ fibrosis risk). Pregnancy: aspirin + LMWH if high risk. Interferon safe. Transformation to MF/AML low.
Genetics: JAK2V617F (~50-60%), CALR (~20-30%, better prognosis), MPL (~5-8%), triple-negative (~10-15%, worst). ASXL1, EZH2, SRSF2, IDH1/2 adverse. Clinical: Massive splenomegaly, constitutional symptoms (fatigue, night sweats, weight loss), portal HTN, extramedullary haematopoiesis, bone pain. Labs: ↑ LDH, leukoerythroblastosis, teardrop cells, anaemia. Bone marrow: fibrosis, osteosclerosis, atypical megakaryocytes. Prognosis: DIPSS/DIPSS-plus. Treatment: low/intermediate-1 → observe or symptom-directed. Intermediate-2/high → ruxolitinib (JAK1/2i, COMFORT-I/II, reduces spleen, symptoms, ↑ survival). Fedratinib (JAK2i, second-line, check thiamine for Wernicke). Pacritinib (JAK2/IRAK1i, for thrombocytopenic MF, PERSIST-2). Momelotinib (JAK1/JAK2/ACVR1i, for anaemic MF, MOMENTUM). Allogeneic HSCT: only curative, for high-risk/fit (TRM ~30%). Transformation to AML ~20% at 10yr.
Genetics: t(9;22) Philadelphia chromosome. BCR-ABL1 fusion (constitutive tyrosine kinase). p210 most common. Three phases: Chronic (CP, <10% blasts, ~85% at diagnosis, leukocytosis, basophilia, splenomegaly). Accelerated (AP, 10-19% blasts, basophilia >20%). Blast (BP, ≥20% blasts, myeloid ~70%, lymphoid ~20-30%). Diagnosis: CBC, smear, bone marrow (morphology + cytogenetics + FISH), qRT-PCR BCR-ABL (IS). Risk: ELTS score. Treatment: CP: first-line TKI (imatinib 400mg, dasatinib 100mg, nilotinib 600mg, bosutinib 400mg). 2G-TKIs faster/deeper responses but more side effects. ELN 2020 milestones: 3mo BCR-ABL ≤10%, 6mo ≤1%, 12mo ≤0.1% (MMR). Failure: mutation analysis. T315I resistant to imatinib/dasatinib/nilotinib/bosutinib; respond to ponatinib (high arterial risk) or asciminib (STAMP inhibitor, less toxicity). HSCT for advanced phase/multiple TKI failure. TFR: candidates with DMR ≥2yr, ~40-50% maintain. Side effects: Dasatinib: pleural effusion, PAH. Nilotinib: arterial occlusive events, hyperglycemia, pancreatitis, QTc. Ponatinib: arterial occlusion (25% at 2yr). Imatinib: fluid retention, rash. Bosutinib: diarrhea, transaminitis.
AML • APL • ALL • WHO Classification • ELN Risk • Targeted Therapy • HSCT
WHO Classification (2016/2022): AML with recurrent cytogenetic abnormalities: APL t(15;17) PML-RARA, CBFB-MYH11 inv(16) / RUNX1-RUNX1T1 t(8;21), NPM1 mutation, CEBPA biallelic mutation, KMT2A rearrangements. AML with myelodysplasia-related changes. Therapy-related AML (t-AML, from prior chemo/radiation). AML NOS (FAB subtypes M0-M7). FAB Classification: M0 (minimally differentiated, MPO-), M1 (myeloblastic without maturation), M2 (myeloblastic with maturation, t(8;21)), M3 (APL, t(15;17)), M4 (myelomonocytic, inv(16)), M5 (monocytic, KMT2A 11q23), M6 (erythroleukemia), M7 (megakaryoblastic, often Down syndrome). Clinical: Bone marrow failure (anaemia, neutropenia, thrombocytopenia), fever/infection, bleeding/bruising, fatigue, DIC (especially APL), gingival hypertrophy (M4/M5), chloroma/granulocytic sarcoma (extramedullary mass). Diagnosis: bone marrow biopsy with ≥20% blasts (or ≥5% in blood with recurrent cytogenetic abnormality). AML ELN 2022 Risk: Favorable: t(8;21), inv(16), NPM1 mut (no FLT3-ITD), biallelic CEBPA mut. Intermediate: NPM1 mut + FLT3-ITD, wild-type NPM1 + FLT3-ITD (low allelic ratio), KMT2A rearranged. Adverse: monosomal karyotype, complex karyotype, TP53 mut, ASXL1 mut, RUNX1 mut, FLT3-ITD high allelic ratio. Treatment: Fit patients (<75yr): Intensive induction 7+3 (cytarabine 100-200mg/m2 IV continuous 7d + anthracycline [daunorubicin 60-90mg/m2 or idarubicin 12mg/m2] IV 3d). CPX-351 (liposomal cytarabine/daunorubicin) for therapy-related AML or AML-MRC. Midostaurin (FLT3i) added to 7+3 for FLT3-mutated AML. Gemtuzumab ozogamicin (GO, anti-CD33 ADC) added to 7+3 for CD33+ favorable/intermediate. HIDAC consolidation (cytarabine 3g/m2 q12h days 1,3,5 for 3-4 cycles). Allogeneic HSCT for intermediate/adverse risk in CR1. Older/unfit patients: Hypomethylating agents (azacitidine, decitabine) + venetoclax (BCL2 inhibitor, ↑ response rate, ↑ OS). Ivosidenib (IDH1i), enasidenib (IDH2i) for IDH-mutated AML. Gilteritinib (FLT3i) for relapsed/refractory FLT3-mutated AML. Relapsed/refractory: Clinical trial, alternative salvage (MEC: mitoxantrone/etoposide/cytarabine, FLAG-IDA: fludarabine/Ara-C/G-CSF + idarubicin), targeted therapy, HSCT. Side effects: cardiomyopathy (anthracyclines, cumulative dose limit daunorubicin 550mg/m2, idarubicin 150mg/m2), tumor lysis syndrome, prolonged cytopenia, infections.
Genetics: t(15;17) PML-RARA. Retinoic acid receptor fusion block differentiation. Clinical: DIC at presentation (high risk of fatal hemorrhage, the most important emergency in haematology). Auer rods (bundles = faggot cells). Treatment: ATRA (all-trans retinoic acid) 45mg/m2 PO divided BID until CR + arsenic trioxide (ATO) 0.15mg/kg IV (differentiation therapy, not cytotoxic). ATRA + ATO is standard for low/intermediate-risk (WBC ≤10K). High-risk (WBC >10K): ATRA + ATO + idarubicin (gemtuzumab ozogamicin alternative). Differentiation Syndrome: ATRA/ATO → cytokine release → fever, dyspnea, weight gain, pleural/pericardial effusions, pulmonary infiltrates, hypotension. Treatment: dexamethasone 10mg IV BID until resolution, hold ATRA/ATO temporarily. Prevention: prophylactic steroids for high-risk. Supportive: aggressive platelet transfusion to maintain >30-50K, cryoprecipitate for fibrinogen <150. Monitoring: CBC, DIC panel, ECG (QTc with ATO). ATO prolongs QTc → monitor Mg/K+. Post-remission: ATRA + ATO consolidation. CNS prophylaxis (IT methotrexate) if high-risk.
B-ALL (75-80%): Precursor B cells. Subtypes: with recurrent genetic abnormalities (BCR-ABL1 Ph+ ~25% adults, KMT2A rearranged, ETV6-RUNX1 t(12;21) good prognosis, hyperdiploidy >50 good, hypodiploidy poor, TCF3-PBX1 t(1;19), IKZF1 deletion). BCR-ABL1-like ALL (Ph-like, kinase activating alterations, poor prognosis, respond to TKIs). T-ALL (20-25%): More common in adolescents/young adults. Mediastinal mass (thymic), higher WBC, CNS involvement more frequent. NOTCH1, TAL1, LMO2. Clinical: Bone marrow failure, lymphadenopathy, splenomegaly, mediastinal mass (T-ALL), CNS involvement, testicular involvement. Diagnosis: bone marrow ≥20% lymphoblasts (MPO-, PAS+, TdT+, CD19/CD79a/CD10 for B; CD3/CD7/CD2 for T). Cytogenetics, FISH, molecular (BCR-ABL, KMT2A). Treatment (adult): Pediatric-inspired protocols (hyper-CVAD, CALGB 10403, GRAALL-2005) have improved outcomes in AYA. Phases: induction (vincristine, steroids, anthracycline, L-asparaginase, +/- rituximab for CD20+ B-ALL), consolidation, maintenance (oral 6-MP + MTX). CNS prophylaxis (IT methotrexate/cytarabine, cranial irradiation if high-risk). Targeted/Immunotherapy: Blinatumomab (BiTE, anti-CD3 + anti-CD19, for MRD+ or relapsed/refractory B-ALL). Inotuzumab ozogamicin (anti-CD22 ADC for relapsed/refractory B-ALL). CAR-T (tisagenlecleucel, brexucabtagene autoleucel for R/R B-ALL). Dasatinib + prednisone for Ph+ ALL (or ponatinib + blinatumomab). Nelarabine (T-ALL/T-LBL, CNS-penetrating purine analog). HSCT: Allogeneic in CR1 for high-risk (Ph+, KMT2A rearranged, hypodiploid, MRD+ post-induction, WBC >30K at diagnosis). TKI maintenance after HSCT for Ph+ ALL. Prognosis: AYA better than older adults. Ph+ ALL with TKI has improved dramatically. MRD monitoring by flow or NGS guides treatment intensity.
NHL • DLBCL • FL • MCL • Burkitt • Hodgkin • T-Cell • Staging • Treatment
Classification (WHO): B-cell (85-90%): DLBCL, FL, MCL, MALT, Burkitt, CLL/SLL, lymphoplasmacytic (Waldenstrom), marginal zone. T-cell (10-15%): PTCL-NOS, ALCL (ALK+/-), AITL, ENKTL (nasal), cutaneous T-cell (mycosis fungoides, Sezary syndrome). Staging: Ann Arbor (I-IV), Cotswolds modification. PET-CT (Deauville score 1-5) is standard for staging and response assessment. Bone marrow biopsy if PET-CT negative but high suspicion (FL, MCL). Lugano classification: limited (I-II) vs advanced (III-IV). B symptoms: fever >38°C, night sweats, weight loss >10% over 6mo. IPI (International Prognostic Index): Age >60, LDH >ULN, ECOG ≥2, Ann Arbor stage III-IV, extranodal sites >1. 0-1 low, 2 low-intermediate, 3 high-intermediate, 4-5 high. FLIPI for follicular lymphoma.
Most common NHL (~30-40%). Aggressive, rapidly enlarging lymph nodes or extranodal mass (GI, bone, CNS, testicular, thyroid). Cell-of-origin: GCB (germinal center B-cell, better prognosis) vs ABC (activated B-cell, worse). Double-hit lymphoma: MYC + BCL2 and/or BCL6 rearrangements (high-risk, intensive therapy). Treatment: R-CHOP (rituximab 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, vincristine 1.4mg/m2 [max 2mg], prednisone 100mg x5d) q21d x 6 cycles. DA-EPOCH-R (dose-adjusted etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin + rituximab) for double-hit lymphoma. R-EPOCH for high-risk. CNS prophylaxis (IT methotrexate or high-dose IV MTX) for high-risk (testicular, breast, renal, adrenal, double-hit, HIV, high IPI). Relapsed/refractory: salvage chemo (R-ICE, R-DHAP, R-GDP) + autologous HSCT (if chemo-sensitive). CAR-T (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) for R/R DLBCL after 2+ lines. Polatuzumab vedotin (anti-CD79b ADC) + bendamustine + rituximab for transplant-ineligible R/R.
Indolent (low-grade) B-cell NHL. t(14;18) BCL2 rearrangement in ~80-90%. CD10+, BCL6+, BCL2+, CD5-. Grades 1-2 (low grade) vs 3A vs 3B (higher grade, treat like DLBCL). FLIPI (age, stage, Hb, LDH, nodal sites). Management: Low tumor burden (asymptomatic, normal LDH, <3 nodal sites, <7cm): watchful wait (no OS difference vs immediate treatment). Symptomatic/high burden: R-bendamustine (non-inferior to R-CHOP, less toxicity), R-CHOP, R-CVP. Rituximab maintenance after induction ↑ PFS but not OS. Obinutuzumab (anti-CD20 type II) + bendamustine for rituximab-refractory. Lenalidomide + rituximab (R2 regimen). PI3K inhibitors (idelalisib, copanlisib, duvelisib, umbralisib) for multiply relapsed (toxicity: colitis, pneumonitis, infections). CAR-T (tisagenlecleucel, axicabtagene ciloleucel) for R/R FL. Allogeneic HSCT for young, multiply relapsed. Transformation to DLBCL (risk ~2-3% per year).
t(11;14) CCND1-IGH, cyclin D1 overexpression, CD5+, CD10-, CD23-. Usually presents with advanced stage (lymph nodes, spleen, bone marrow, GI (lymphomatous polyposis). Blastoid/pleomorphic variants = aggressive. Treatment: Young/fit: intensive (R-hyperCVAD alternating with R-MTX/Ara-C, or R-CHOP + R-DHAP, or Nordic regimen) + autologous HSCT in CR1. Rituximab maintenance ↑ PFS. Older/unfit: R-bendamustine + rituximab, or R-CHOP. BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) very active in R/R and now frontline (BR + ibrutinib shows PFS benefit). Venetoclax (BCL2i) + BTKi for R/R. CAR-T (brexucabtagene autoleucel approved for R/R MCL).
t(8;14) MYC-IGH (most common), MYC rearrangement. High proliferation (>95% Ki-67). Starry sky appearance (tingible body macrophages). Endemic (African, EBV+ in >95%, jaw mass, children). Sporadic (non-African, EBV+ ~20%, ileocecal mass). Immunodeficiency-associated (HIV, EBV+). Treatment: High-intensity regimens: CODOX-M/IVAC (cyclophosphamide/vincristine/doxorubicin/MTX alternating with ifosfamide/Ara-C/etoposide), R-hyperCVAD, DA-EPOCH-R (effective, less toxicity). CNS prophylaxis. Tumor lysis syndrome common (high LDH, high burden). Allopurinol/rasburicase + aggressive hydration. HIV-associated: treat with HAART concurrently.
Subtypes (WHO): Nodular sclerosis (most common, ~60%, young, mediastinal mass, CD15+/CD30+, CD20-). Mixed cellularity (~25%, older, HIV/EBV+, B symptoms). Lymphocyte-rich (~5%, good prognosis). Lymphocyte-depleted (<1%, aggressive, HIV associated). Nodular lymphocyte predominant (NLPHL, CD20+, CD15-/CD30-, indolent, treat with rituximab, radiation, or watchful wait). Staging: PET-CT (Deauville score). Ann Arbor. Treatment: Limited stage (IA-IIA, no bulk): ABVD x 2 cycles + involved-site radiation (20-30Gy). Alternatively: AVD x 2-4 cycles + PET-2 adapted. Advanced stage (IIB-IV, bulk): ABVD x 6 cycles (or escalated BEACOPP in high-risk, especially in Europe). PET-2 adapted: if Deauville 1-3, continue ABVD; if 4-5, switch to escalated BEACOPP. New agents: Brentuximab vedotin (anti-CD30 ADC, active in R/R HL and now frontline with AVD for advanced HL, ECHELON-1 trial: BV-AVD > ABVD with less pulmonary toxicity but ↑ neuropathy/neutropenia). Nivolumab/pembrolizumab (anti-PD1, very active in R/R, approved for post-auto failure). Relapsed/refractory: Salvage chemotherapy (ICE, DHAP, GDP, GVD) + autologous HSCT. Brentuximab vedotin or checkpoint inhibitor for bridging. Allogeneic HSCT for relapse after auto. Long-term toxicity: Secondary malignancies (breast, lung, AML/MDS, thyroid), CV toxicity (mediastinal RT + doxorubicin), pulmonary fibrosis (bleomycin, RT), infertility, hypothyroidism.
PTCL-NOS: Most common T-cell lymphoma (~30%). Aggressive, poor prognosis. Treatment: CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone +/- etoposide) first-line. Clinical trials preferred. ALCL (Anaplastic Large Cell Lymphoma): ALK+ (young, good prognosis, treat with CHOP-like + brentuximab vedotin). ALK- (older, worse). BV-CHP (brentuximab + CHP without vincristine) approved first-line for ALCL (ECHELON-2). AITL (Angioimmunoblastic T-cell Lymphoma): Systemic symptoms, rash, polyclonal hypergammaglobulinemia, EBV+ B cells. Hypomethylating agents (azacitidine) active. ENKTL (Extranodal NK/T-cell, nasal type): Strongly EBV+, sinonasal/upper aerodigestive, angioinvasive. Radiation + L-asparaginase based chemo. Cutaneous T-cell (Mycosis Fungoides, Sezary): Skin patches/plaques/tumors. Sezary syndrome: erythroderma + circulating Sezary cells. Treatment: skin-directed (steroids, PUVA, radiation, topical chemotherapy), systemic (interferon, retinoids, HDAC inhibitors: vorinostat, romidepsin, belinostat), brentuximab (for CD30+), mogamulizumab (anti-CCR4), allogeneic HSCT. Autologous HSCT: Standard for relapsed chemo-sensitive DLBCL and HL. Allogeneic HSCT: for relapse after autologous, T-cell lymphomas, advanced FL/MCL. PTCy (post-transplant cyclophosphamide) for GVHD prophylaxis.
MGUS • Multiple Myeloma • Waldenstrom • Amyloidosis • POEMS
Definition: Serum M-protein <3g/dL, clonal plasma cells <10% in marrow, no end-organ damage (no CRAB). Prevalence ~3% in population >50yr, ~5% >70yr. Risk of progression to MM/Waldenstrom/AL amyloidosis ~1% per year. Non-IgM MGUS (IgG/IgA) → MM. IgM MGUS → Waldenstrom or IgM MM. Monitoring: SPEP + IFE + FLC at 6mo then annually if stable. Risk stratification: Mayo Clinic model (M-protein ≥1.5g/dL, non-IgG, abnormal FLC ratio).
Definition: Clonal plasma cell neoplasm producing M-protein (IgG most common, IgA, light chain only, IgD, IgE, IgM/biclonal rare). CRAB criteria (end-organ damage): HyperCalcemia (Ca >11 or >1mg/dL above ULN), Renal (Cr >2 or CrCl <40), Anaemia (Hb >2g/dL below LLN or <10), Bone lesions (lytic, pathological fracture, cord compression, osteopenia). Also: SLiM (Sixty percent clonal PCs, Light chain ratio involved/uninvolved ≥100, MRI >1 focal lesion) for smoldering MM with high risk of progression. Diagnosis: SPEP (M-spike), serum FLC (kappa/lambda) & ratio, immunofixation (identify isotype), 24h urine (UPEP, UIFE). Bone marrow biopsy (clonal PCs ≥10% or ≥60% for SLiM). Skeletal survey (X-ray, whole-body low-dose CT, PET-CT, or MRI). ISS (International Staging System): β2-microglobulin + albumin. R-ISS: ISS + LDH + cytogenetics. High-risk cytogenetics: t(4;14), t(14;16), t(14;20), del(17p), p53 mutation, 1q21 gain/amplification. Standard risk: hyperdiploidy, t(11;14), t(6;14). Treatment (transplant-eligible): Induction: VRd (bortezomib 1.3mg/m2 SC days 1,4,8,11, lenalidomide 25mg PO days 1-21, dexamethasone 40mg days 1,8,15,22 q28d x 4-6 cycles). Dara-VRd (daratumumab + VRd, subcutaneous daratumumab approved, ↑ MRD negativity). KRd (carfilzomib/len/dex) alternative. Stem cell collection after induction (G-CSF +/- plerixafor). ASCT (melphalan 200mg/m2). Maintenance: lenalidomide 10-15mg daily until progression (improves OS). Daratumumab maintenance under investigation. Transplant-ineligible: D-Rd (daratumumab + lenalidomide + dex, MAIA trial, ↑ PFS/OS, new standard). VRd-lite (reduced intensity). Rd alone for frail. MPT (melphalan/prednisone/thalidomide) historical, now replaced by daratumumab-based. Relapsed: Sequential therapy: carfilzomib, pomalidomide, daratumumab (IV or SC), elotuzumab (anti-SLAMF7), selinexor (XPO1i, ↓ dose, GI/CNS toxicity). PANORAMA: panobinostat (HDACi). CAR-T: Idecabtagene vicleucel (ide-cel, anti-BCMA, KarMMa trial, R/R after 4+ lines). Ciltacabtagene autoleucel (cilta-cel, CARTITUDE-1, higher response/CR rates). Bispecific antibodies: Teclistamab (anti-BCMA x anti-CD3, MajesTEC-1, >60% ORR in triple-class exposed). Elranatamab, linvoseltamab. Supportive: Bisphosphonates (zoledronic acid 4mg IV monthly, pamidronate 90mg IV) for bone disease (reduce SREs). Monitor renal, jaw osteonecrosis (dental eval before start). Calcium, vitamin D. Kyphoplasty/vertebroplasty for painful fractures. Radiation for cord compression/painful lytic lesions. Hydration for renal protection. EPO for anaemia. Vaccination: pneumococcal, influenza, COVID-19, VZV (recombinant zoster vaccine).
Lymphoplasmacytic lymphoma with IgM monoclonal gammopathy. MYD88 L265P mutation (~90%), CXCR4 mutation (~30-40%). Clinical: Hyperviscosity (blurred vision, headache, epistaxis, coma; fundoscopy: retinal hemorrhages, venous beading/sausaging), cryoglobulinemia, cold agglutinin disease, Bing-Neel syndrome (CNS involvement, MYD88+ in CSF), neuropathy, cytopenias, splenomegaly, lymphadenopathy. Diagnosis: IgM M-spike, bone marrow (lymphoplasmacytic cells, CD19+/CD20+/CD5-/CD10-, MYD88 PCR). Treatment: Symptomatic/hyperviscosity: plasmapheresis first (remove IgM). BTKi first-line (ibrutinib 420mg, zanubrutinib 160mg BID [more selective, < cardiac toxicity, ASPEN trial], acalabrutinib). Rituximab-containing regimens (DRC: dexamethasone/rituximab/cyclophosphamide, BDR: bortezomib/dex/rituximab). Chemo-free: BTKi + rituximab. Venetoclax for CXCR4 mutant. Rituximab flare: IgM spike after rituximab (check IgM, treat with plasmapheresis if symptomatic). Watch for transformation to DLBCL (Richter transformation).
AL Amyloidosis: Misfolded immunoglobulin light chains (lambda > kappa) deposit as fibrils. Congo red stain: apple-green birefringence under polarized light. Organ involvement: Cardiac (most common cause of death): HFpEF, low voltage ECG, thickened LV wall on echo (granular sparkling), restrictive filling, elevated NT-proBNP & troponin, cardiac MRI (subendocardial LGE). Renal: nephrotic syndrome (massive proteinuria, without albumin lowering). GI: macroglossia, hepatomegaly, malabsorption. Neuropathy (peripheral/autonomic). Easy bruising (periorbital purpura = raccoon eyes). Diagnosis: tissue biopsy (abdominal fat pad, bone marrow, or involved organ) with Congo red. Serum/urine IFE + FLC for clone. Treatment: Anti-plasma cell therapy: daratumumab-CyBorD (daratumumab + cyclophosphamide 300mg/m2 + bortezomib 1.3mg/m2 + dexamethasone 20mg, ANDROMEDA trial, new standard, rapid hematologic response, ↑ OS). Autologous SCT for carefully selected (low burden, good performance, cardiac function). Organ-directed: diuretics for HF, ACEi for proteinuria. POEMS: Polyneuropathy, Organomegaly (hepatosplenomegaly, lymphadenopathy), Endocrinopathy (hypogonadism, hypothyroidism, DM, adrenal insufficiency), M-protein (IgG/IgA lambda, sclerotic bone lesions (osteosclerotic, not lytic), Skin changes (hyperpigmentation, hypertrichosis, acrocyanosis, glomeruloid hemangiomas, Raynaud, plethora). VEGF ↑ (correlates with disease activity). Castleman disease variant. Treatment: anti-myeloma regimen (lenalidomide/dex, bortezomib/dex, melphalan/dex, ASCT). Daratumumab effective. Anti-VEGF (bevacizumab) controversial.
Primary Haemostasis • Secondary • Fibrinolysis • vWD • Haemophilia • Factor Deficiencies
Platelet adhesion: vWF from Weibel-Palade bodies (endothelium) + α-granules binds platelet GPIb/IX/V at high shear (arterioles). Platelet activation: Shape change, granule release (ADP, TXA2 via COX-1), surface GPIIb/IIIa exposure. Platelet aggregation: GPIIb/IIIa binds fibrinogen → cross-linking → platelet plug. von Willebrand Disease (vWD): Most common inherited bleeding disorder (~1%). Type 1 (60-80%): Partial quantitative deficiency, DDAVP responsive. Type 2 (15-20%): Qualitative. 2A: loss of HMW multimers. 2B: gain-of-function, thrombocytopenia, DDAVP contraindicated. 2M: decreased platelet function. 2N: decreased FVIII binding (mimics haemophilia A). Type 3 (<5%): Severe deficiency. Diagnosis: vWF:Ag, vWF:RCo (ristocetin cofactor, best functional), FVIII, multimer analysis. Treatment: DDAVP for type 1 (test response), vWF concentrate (Humate-P) for type 3/surgery, tranexamic acid for mucosal bleeding.
Intrinsic: XII → XI → IX → VIII → X (aPTT). Extrinsic: TF + VII → X (PT/INR). Common: X → V → II (thrombin) → I (fibrinogen) → XIII (cross-link). Vitamin K-dependent: II, VII, IX, X, protein C, protein S. PT/INR: warfarin, VitK deficiency, liver, DIC, factor VII deficiency. aPTT: heparin, lupus anticoagulant, factor VIII/IX/XI/XII deficiency (haemophilia A/B). TT: thrombin time: heparin, DIC (low fibrinogen), DTIs (dabigatran). Mixing study: Corrects = factor deficiency. No correction = inhibitor (lupus antibody or factor inhibitor). Factor assays: <1% = severe deficiency.
Fibrinolysis: Plasminogen → plasmin (cleaves fibrin). tPA activates plasminogen on fibrin. PAI-1 inhibits tPA. α2-antiplasmin inhibits plasmin. D-dimer: fibrin degradation product (elevated in VTE, DIC, post-surgery, pregnancy, cancer). Anticoagulant pathways: Antithrombin (inhibits thrombin + FXa, potentiated by heparin). Protein C/S (cleaves FVa/VIIIa). TFPI (inhibits FXa and TF-FVIIa). Inherited thrombophilia: Factor V Leiden (APC resistance, most common), prothrombin G20210A, protein C/S deficiency, antithrombin deficiency. Elevated FVIII. MTHFR not significant. Timing of testing: >3mo after VTE, off anticoagulation.
Haemophilia A (FVIII def): X-linked, 1/5000 males. Severe (<1%), moderate (1-5%), mild (5-40%). Clinical: haemarthroses, muscle bleeds, intracranial hemorrhage, post-surgical bleeding. Diagnosis: isolated prolonged aPTT (corrects on mix), ↓ FVIII, normal vWF. Treatment: rFVIII (1 U/kg raises ~2%, half-life 8-12h). Prophylaxis starting age 1-2. DDAVP only for mild A. Emicizumab (bispecific, mimics FVIII) SC weekly for all haemophilia A, including inhibitors. Inhibitors: rFVIIa, FEIBA, ITI. Gene therapy: valoctocogene roxaparvovec (AAV5-hFVIII). Haemophilia B (FIX def): X-linked, 1/30,000. rFIX (half-life 18-24h, longer-acting: rFIX-Fc, albumin-fused q7-14d). Gene therapy: etranacogene dezaparvovec. Other: FXI deficiency (Ashkenazi Jews, FFP/tranexamic acid), FXIII deficiency (severe, umbilical stump bleeding, cryoprecipitate/FXIII concentrate). Factor VII deficiency (prolonged PT only, FVII concentrate).
VTE • DVT/PE • DOACs • Warfarin • APS • HIT • Thrombophilia • DOAC Reversal
Virchow triad: Stasis, endothelial injury, hypercoagulability. DVT: Unilateral leg swelling, warmth, pain. Wells score + D-dimer → CUS. PE: Dyspnea, pleuritic chest pain, hemoptysis, hypoxia. Wells + D-dimer → CTPA (or V/Q). PESI/sPESI for severity. Treatment: DOAC first-line (rivaroxaban 15mg BID x21d then 20mg daily; apixaban 10mg BID x7d then 5mg BID; edoxaban 60mg daily after 5d LMWH; dabigatran 150mg BID after 5d LMWH). Cancer-associated: LMWH or apixaban/edoxaban. Massive PE (SBP <90): thrombolysis (tPA 100mg over 2h) or catheter-directed/embolectomy. Duration: Provoked 3mo. Unprovoked ≥3mo, consider indefinite (30% recurrence at 10yr). Cancer: until resolved or indefinite. Thrombophilia testing: wait >3mo after VTE and off anticoagulation.
Antiphospholipid Syndrome (APS): Lupus anticoagulant + anticardiolipin + β2-GPI (persistent ≥12wk). Clinical: thrombosis (any site) + pregnancy morbidity. Treatment: warfarin INR 2-3 indefinitely. DOAC contraindicated (TRAPS trial). Pregnancy: LMWH + aspirin. Catastrophic APS: heparin + steroids + PEX +/- rituximab/ecculizumab. HIT: Heparin-PF4 antibodies, platelet drop >50%, thrombosis risk. 4Ts score. Diagnosis: SRA (gold standard) or ELISA. Treatment: stop all heparin, start argatroban (IV, monitor aPTT) or fondaparinux. Do not start warfarin until platelets recovered. DOAC reversal: Andexanet alfa for factor Xa inhibitors (rivaroxaban/apixaban/edoxaban). Idarucizumab 5g IV for dabigatran. PCC (4-factor, 50 U/kg) for warfarin or if specific reversal unavailable. Vitamin K 10mg IV for warfarin (slow infusion).