Haematology Flashcards

Question

Approach to pancytopenia

Answer 1

Etiology • decrease synthesis: o “Empty factory”: AA o Raw materials: Fe, B12/folate (megaloblastic anemia) o Ineffective production: MDS o Marrow infiltration: lymphoma, myeloma, myelofibrosis, carcinoma, TB • destruction: o DIC o Hypersplenism (e.g. Felty’s syndrome) o SLE o PNH Clinical features • Fatigue (anaemia) • Recurrent infections (leukopenia) • Mucocutaneous bleeding (thrombocytopenia) Investigations • CBC, CRP/ESR, ferritin, B12/folate, TFT, clotting • PBS: hypercellular disease may show leucoerythroblastic blood picture* • Bone marrow exam: usually indicated unless splenomegaly

Answer 2

• Usual indication: unexplained pancytopenia • Site: posterior superior iliac crest (sternum if obese, tibia if infant) • Aspiration: o Cytological abnormalities o Special tests: immunophenotyping (CD), cytogenetics, immunohistochemistry (FISH), molecular study (specific gene rearrangement) • Trephine biopsy: histological abnormalities

Answer 3

Presence of myeloid precursors and nucleated RBC in PBS (i.e. something displace them out from BM): • Myelofibrosis • BM infiltration: leukemia/lymphoma, TB, metastatic cancers • Marrow stress: severe hemolysis, severe sepsis

Answer 4

Etiology • Selective neutropenia o Congenital: Kostmann’s syndrome o Acquired: - Drug-indued agranulocytosis: e.g. carbimazole, chloramphenicol, clozapine, deferiprone, co-trimoxazole, phenytoin, chlorpromazine - Immune: SLE - Infections: viral (e.g. hepatitis, HIV), fulminant bacterial infection o Benign / Cyclical • Part of pancytopenia (see above): bone marrow failure, splenomegaly Management • Check for S/S of infection, PMHx, DHx, any hepatosplenomegaly / lymphadenopathy / autoimmune features • Likely benign / cyclical: Regular monitoring (CBC), BM exam only if symptomatic / pancytopenia • Agranulocytosis: stop offending drugs, protective isolation, septic work-up, broad spectrum Abx, G-CSF

Answer 5

Definition: destruction of haematopoietic cells of bone marrow • Severe AA: BM cellularity <25% + ≥2 of 3 criteria: o Absolute reticulocyte count < 20 o Platelet < 20 o ANC < 0.5 • Very severe AA: severe + ANC < 0.2 • Non-severe AA: not fulfilling criteria for severe AA Aetiology • Congenital: o Fanconi's anaemia (AR/XR): Dx: diepoxybutane (DEB) instability test, risk of malignancy (MDS, AML) o Dyskeratosis congenita (XR usually): mutation in telomere-related genes o Schwachman-Diamond syndrome • Acquired o Idiopathic (MC) o Chemical: benzene o Drugs: chloramphenicol, sulphonamide, cytotoxic drugs o Ionizing radiation o Infection: viral hepatitis o Pregnancy Laboratory findings • CBC: pancytopenia with normocytic/macrocytic anemia, decrease reticulocytes • PBS: normal • BM biopsy: hypocellular with fat infiltration (>90%), no malignant infiltration Management of idiopathic AA • Supportive care: discontinue offending drugs, transfusion, growth factors (G-CSF), broad-spectrum antibiotics • Triple therapy immunosuppression: anti-thymocyte globulin + cyclosporin A ± eltrombopag x 6 months • Definitive treatment: allogenic HSCT (if <40yo + HLA-matched sibling) • Consider androgens • Screen for developing other clonal disorders: MDS, PNH, AML

Answer 6

Definition: heterogenous group of clonal diseases characterised by ineffective / dysmorphic haematopoiesis Clinical features • Increased incidence with age (median age ~65); M>F • Trilineage failure S/S: progressive decline in cell counts • Pre-leukaemia: may transform to acute leukaemia • NO hepatosplenomegaly Classification Principles • Number of dysplastic lineages • Percentage of ring sideroblasts (erythroid precursor, ≥5 iron granules encircling ≥1/3 of nucleus) • Percentage of blast cells in BM and PB: must be ≤20% to r/o AML • Del (5q): good prognosis Investigations • CBC: pancytopenia • PBS: oval macrocytes, basophilic stippling, Howell-Jolly bodies, hypersegmented neutrophils • Bone marrow exam (mandatory): hypercellular marrow with single / trilineage dysplasia Management No curative treatment Risk stratification by IPSS-R score • Low risk: o Asymptomatic: observe o Symptomatic: supportive care (e.g. transfusion, antibiotics) - ± EPO (e.g. darbepoietin), TPO-RA (e.g. eltrombopag), targeted therapy as below • High risk: o Medically fit: - Allogenic HSCT - Hypomethylating agents (e.g. azacitidine, 5-aza-2’ deoxycytidine): may achieve response in 50-60% through epigenetic mechanisms - Targeted therapy: e.g. lenalidomide for del(5q), luspatercept for ring sideroblasts, IDH inhibitors o Medically unfit: supportive care

Answer 7

Definitions • Cytosis: increase in counts • Cythaemia: increase in counts due to primary bone marrow disorder • Erythrocytosis: Hb > 16.5 (male) or > 16 (female) Aetiology • Relative erythrocytosis (haemoconcentration): dehydration, diuretics, burns, stress • Absolute erythrocytosis: o Primary: polycythaemia rubra vera (PV) o Secondary: - Appropriate increased production of EPO —> Respiratory: COPD, sleep apnoea, pulmonary hypertension, CO poisoning —> CVS: Eisenmenger syndrome, methaemoglobinaemia - Inappropriate increased production of EPO: —> Paraneoplastic: RCC, HCC, adrenal tumors, cerebellar haemangioblastoma, uterine fibroma —> Renal: PKD, hydronephrosis Clinical features • Facial plethora • Thrombosis (DVT/ PE, stroke) or bleeding (MPN) • Hyperviscosity: headache, visual disturbance, etc Investigations • Pulse oximetry • EPO level: to differentiate primary (low) vs secondary (elevated) • If primary: JAK2 mutation, ferritin level Management • PV: see separate section • Secondary: treat underlying cause

Answer 8

Definition: platelet > 400 Aetiology • Primary: essential thrombocythaemia (ET) • Secondary/ reactive: acute phase reactant o Inflammation/ infection/ malignancy o Iron deficiency, acute bleeding o Post surgery o Rebound thrombocytosis (recovery from B12/folate deficiency or splenectomy) Investigations • Bloods: CBC, PBS, CRP/ESR, ferritin (TPO level is not widely available) • Bone marrow exam: if reactive thrombocytosis unlikely Management • Compare with previous blood results • Primary: aspirin +/- cytoreductive agents (e.g. hydroxyurea) • Reactive: treat underlying cause

Answer 9

Definition: Stem cell disorder characterised by erythrocytosis +/- increased while cell and platelet production S/S: - Facial plethora - Erythromelalgia (burning pain in hand and feet) - Aquagenic pruritis (pruritis after warm bath) - Thrombosis / bleeding - Hypeviscosity: headache, BOV - Splenomegaly CBC: - high Hb (M >16.5, F > 16), ↑WBC & Plt - high Hct (M > 49, F > 48) BM exam: - Hypercellularity with trilineage growth (panmyelosis) Genetics: - JAK2 V617F mutation (97%) - JAK2 exon 12 mutation (3%) Mx: Venesection: aim Hct <45% Low-dose aspirin (80mg) daily/BD High thrombotic risk (Hx of thrombosis / age > 60): Hydroxyurea 500mg BD Alternative: IFN / busulfan Refractory: ruxolitinib (JAKi)

Answer 10

Definition: - increased platelet production in the absence of recognisable stimulus S/S: - Vasomotor: headache, dizziness - Thrombosis: chest pain, stroke, PVD - Bleeding (non-functional platelet, acquired vWD) CBC: - increase platelet (>450) BM: - Hypercellularity with megakaryocyte lineage Genetics: JAK2 mutation (50%) CALR mutation (20%) MPL mutation (5%) Mx: Manage CV risk factors Low-dose aspirin High thrombotic risk (prior thrombosis, age > 60, JAK2 mutation): Hydroxyurea / IFN / anagrelide

Answer 11

Definition: Excessive marrow fibrosis leading to marrow failure S/S: - severe fatigue - Constitutional symptoms - Anaemic symptoms - Massive splenomegaly +/- hepatomegaly, portal HT - Bone and joint pain: osteosclerosis, gout CBC: ↓Hb, variable WBC & Plt PBS: leucoerythroblastic picture, tear drop cell BM: - Aspirate: dry tap - biopsy: megakaryocytic proliferation and atypia, fibrosis Genetics: JAK2 mutation (65%) CALR mutation (30%) MPL mutation (8%) Mx: High-risk + eligible: allogenic HSCT Symptomatic relief: Ruxolitinib (regardless of JAK2 status), fedratinib Hydroxyurea, splenectomy Transfusion, folic acid, EPO Gout prophylaxis: allopurinol *Risk stratification systems for primary myelofibrosis: IPSS (at diagnosis), DIPSS / DIPSS-Plus (at follow-up) • IPSS & DIPSS used 5 parameters à classified into low, Int-1, Int-2, high risk • DIPSS-Plus takes into account 3 more factor

Answer 12

myelosuppression, mucocutaneous ulcer, peripheral neuropathy, teratogenicity

Answer 13

Risk factors • Genetics: Down's syndrome, Fanconi anemia, Bloom’s syndrome • Exposure to chemotherapy, radiation, benzene • Hx of pre-leukemic conditions: e.g. MDS, MPN Clinical features • Pancytopenia o Anaemia: fatigue, pallor o Thrombocytopenia: bleeding tendency, DIC (APL) o Neutropenia (despite increased WBC): infection • Organ infiltration: more in ALL o Hepatosplenomegaly o Lymphadenopathy o Orchidomegaly o Eyes: haemorrhage, Roth spots, cotton wool spots o Gum hypertrophy (AML-M5) o Mediastinal involvement (T-ALL): SVCO o CNS involvement (esp. ALL): headache, neurological S/S • Leucostasis/ hyperviscosity syndrome: headache, vision change, SOB Classification (for reference) 1. AML • AML with recurrent genetic abnormalities e.g. t(15;17), inv(16), mutated NPM1 • AML with myelodysplasia-related changes • Therapy-related AML • AML not otherwise specified (NOS) • Myeloid sarcoma • Myeloid proliferation related to Down’s syndrome 2. ALL • B-cell ALL (85%) o Not otherwise specified (NOS) o Recurrent genetic abnormalities e.g. t(9;22) • T-cell ALL (10-15%) • ALL of ambiguous lineage • AML: Prognosis depends on o Age (>60 = poor prognosis) o Genetic / molecular abnormalities o Initial response to chemotherapy (initial remission rate 70-80%, but half of them might relapse Investigations (SAQ!) • Bloods: CBC, clotting, fibrinogen/ D-dimer (DIC), RFT, LFT, CaPO4, urate, glucose, LDH (TLS), T&S X-match • Pre-treatment: G6PD (rasburicase / Septrin), viral serology (HBsAg, anti-HBc ± HBV DNA, anti-HCV, anti-HIV), anti-CMV IgG (if HSCT) • PBS and bone barrow aspiration + trephine biopsy: 1. AML - CBC: pancytopenia with blasts - PBS: myeloblast (high N:C ratio, Auer rods) AML-M3: Faggot cells (promyelocyte with multiple Auer rods) - BM exam: >20% blast Cytochemistry: MPO +ve, Sudan black +ve Immunophenotyping: CD34, HLA-DR, CD117, CD13, CD33 Cytogenetics, e.g. PML-RARA (AML-M3) Molecular genetics (e.g. FLT3-ITD/TKD, NPM1) 2. ALL - CBC: pancytopenia with blasts - PBS: Lymphoblastic (scanty cytoplasm without granules / Auer rods) - BM exam: >20% blasts Immunophenotyping: Tdt, CD3 (T-ALL), CD19, CD20 (B-ALL) Cytogenetics, e.g. Ph+ (B-ALL) Molecular genetics • Additional workup for ALL: LP (CNS involvement), CT thorax with contrast (if T-ALL: mediastinal mass) Initial Mx: 1. Blood product support • RBC if symptomatic anaemia (but C/I in leukostasis) o If HSCT is considered, give CMV-negative blood or leukodepleted blood • Platelet: if Plt ≤10 or ≤20 if fever/bleeding (keep ≥50 for APL due to high risk of DIC) • FFP if evidence of bleeding due to DIC 2. Leucostasis • Leucopharesis if WCC very high / symptomatic 3. Infection • Full septic workup • Reverse isolation +/- empirical antibiotics if evidence of infection • PCP prophylaxis (Septrin 960mg 3 days/ week) for ALL (higher risk in T cell depletion) 4. TLS prophylaxis • Aggressive fluid hydration (2-3L/day) • Allopurinol / febuxostat • Consider rasburicase in high-risk patients (C/I: G6PD) 5. Nausea and vomiting • Adequate antiemetics and analgesics prn • Consult haematologist if emergency: o Hyperleucocytosis (WBC >100): chemotherapy ± leucophoresis, avoid blood transfusion until WBC lowered o APL: early use of ATRA (refer below) • Other preparations: o HSCT: arrange HLA typing for patient's siblings o Chemo: arrange Hickmann catheter insertion Definitive management Principles (important) • Induction: high-intensity chemotherapy to destroy bulk of tumor • Consolidation: multiple courses of chemotherapy to attack residual disease • ± Maintenance (ALL): low-intensity chemotherapy to maintain remission • ± CNS prophylaxis (ALL) • ± HSCT if poor prognosis 1. AML-M3 (APL) Initiate treatment based on clinical + morphological criteria (Faggot cells), before definite cytogenetic diagnosis (t(15;17) —> PML-RARA fusion) • Correct coagulopathy and control DIC: o Aggressive platelet transfusion (target > 50) o Cryoprecipitate/ FFP (fibrinogen target > 150, PT/APTT aim normal) • Induction: Early use of ATRA (All-trans retinoic acid) 45mg/m2/day PO (promote differentiation) o Low risk (WBC ≤ 10): ATRA + arsenic trioxide (promote apoptosis of leukemic cells) o High risk (WBC > 10): ATRA + conventional chemotherapy (7+3) o Caution for ATRA differentiation syndrome (50%): cytokine release due to further differentiation of promyelocytes; S/S fever, hypotension, SOB (DDx sepsis) - Mx supportive + steroid (e.g. dexamethasone IV 10mg Q12h x ≥ 3 days) • Consolidation therapy: ATRA + ATO or ATRA + anthracycline (depend on what was used) 2. AML non-M3 Induction therapy: 7+3 regimen (Day 1-7 cytarabine continuous infusion + Day 1-3 IV anthracycline) • Cytarabine (cytosine arabinoside) 100mg/m2: S/E flu-like syndrome, myelosuppression • Anthracycline (e.g. daunorubicin) 45mg/m2: S/E cardiotoxicity, red urine • Post-Tx BM biopsy 7 days after final dose to evaluate need of 2nd induction course • Consider allogenic HSCT if high relapse risk, young patients with little comorbidities - Consolidation therapy: intermediate dose of cytarabine (IDAC) 3. ALL Induction (4-6 weeks): vincristine (weekly, S/E: neuropathy) + high-dose steroids + asparaginase • ± Rituximab (if CD20+), ± TKI (if Ph+), ± anthracycline (T-ALL) • Start CNS prophylaxis: intrathecal methotrexate / RT - Consolidation (4-8 months) ± late intensification: vincristine, steroids, other combination of drugs - Maintenance (3 years for boys, 2 years for girls): vincristine (monthly), pulse steroids, daily 6-MP Definition of remission in AML/ALL: no circulating blasts + normal PB count + <5% blasts in BM

Answer 14

Definitions • Clonal proliferation of granulocytic cell line • Defined by Philadelphia (Ph) chromosome t(9,22) causing production of BCR-ABL1 fusion protein Clinical features • Massive splenomegaly: infiltrative disease • Hypercatabolism: bone pain, weight loss, fever, fatigue, sweating • Hyperleukostasis: blurred vision, SOB, chest pain Clinical phases - Chronic phase (3-4 years) —> Blast < 10% —> 90% of patients at any time point Asymptomatic - Accelerated phase (18 months) —> Blast 10-19% —> Acquisition of additional molecular lesions, Increasing symptoms - Blast crisis (1-2 months) —> Blast ≥ 20% —> Acute leukaemia (2/3 AML > 1/3 ALL) Investigations • CBC d/c: decrease Hb, increase WBC (basophilia, myelocyte > metamyelocyte), N/ increase Plt • Peripheral blood film: complete spectrum of myeloid cells (left shift) • BM biopsy: o Hypercellular with granulopoietic predominance o Cytogenetic study: Ph chromosome o FISH study / PCR: BCR-ABL fusion protein Management • Tyrosine kinase inhibitor (TKI) o 1st gen: imatinib o 2nd gen: nilotinib, dasatinib o 3rd gen: ponatinib (for T315I mutation) o S/E: rash, ↑QT (nilotinib), pleural/pericardial effusion (dasatinib), thrombosis / dLFT (ponatinib) • Hydroxyurea ± busulfan: cytoreduction for symptomatic relief • Allogenic HSCT (if failed TKI) • Monitoring of BCR-ABL fusion level: CBC (haematological response), cytogenetics (FISH) (cytogenetic response CyR), qPCR (molecular response MR – most sensitive) o Optimal response: ≤10% at 3mo, ≤1% (CyR) at 6mo, ≤0.1% (MMR) at 12mo

Answer 15

Definitions • Most common leukemia in adults (Western >> Chinese) • Monoclonal proliferation of non-functional mature B cells (T cells very rare) • More resemble lymphoma than ALL • Pathologically equivalent to small lymphocytic lymphoma (SLL) Clinical features • Asymptomatic (MC) • B symptoms: Fatigue, weakness, fever, night sweats, weight loss, bone pain • Lymphadenopathy, hepatosplenomegaly • Anemic symptoms (AIHA, bone marrow) • Bleeding symptoms (thrombocytopenia) • Risk of “Richter transformation”: transformation of CLL/SLL into DLBCL or HL Investigations • CBC D/C: leukocytosis with↑lymphocytes ± anaemia ± thrombocytopenia • PBS (diagnostic): smear cells / smudge cells (fragile lymphocytes damaged during slide preparation) • PB flow cytometry: CD5+, CD19+, CD20+, CD23+, sIg+ • ± BM biopsy: not required for diagnosis, but useful in monitoring treatment response • ± LN biopsy • ± cytogenetics: Del 13q (55%), Del 11q (25%) Staging: RAI / Binet - RAI: 5 - Binet: A, B, C Management • Supportive care: blood products, leukapheresis for leukostasis • Close observation for early stage asymptomatic CLL (i.e. Rai 0 / Binet A) • Chemotherapy: o Indications of treatment - Advanced stage: Rai stage III/ IV - Symptomatic: Severe B symptoms, bulky lymphadenopathy / splenomegaly - Active disease progression: Lymphocytosis ≥50% increase over 2 months / doubling time ≤ 6 months - Disease-related complications: Refractory AIHA / ITP, recurrent infections, Richter’s transformation o Choice of regimen - Young patients: FCR (fludarabine, cyclophosphamide, rituximab) / bendamustine-based Tx - Old patients: chlorambucil - Newer agents: ibrutinib (BTK inhibitor), idelalisib (P13K blocker), venectoclax (BCL-2 inhibitor), rituximab / obinutuzumab (anti-CD20) - Allogenic stem cell transplant

Answer 16

Classification: histology, immunophenotyping (B/T/NK), cytogenetics / molecular genetics 1. Hodgkin’s lymphoma - 10% Reed-Sternberg (RS) cells Strong association with EBV - Classical: CD15+ CD30+ • Nodular sclerosing (MC) • Mixed cellularity • Lymphocyte-rich • Lymphocyte-depleted Nodular lymphocyte- predominant (NLP): “popcorn cells”, CD20+, best prognosis - Superficial (70% cervical LN) Contiguous spread Few extranodal disease - S/S: non-tender lymphadenopathy B symptoms, Pruritis, Alcohol-induced pain, Splenomegaly +/- hepatomegaly 2. Non-hodgkin’s lymphoma - 90% in which: • B cell neoplasm: 90% • T/NK cell neoplasm: 10% - Indolent subtypes: incurable (not chemosensitive) • Follicular lymphoma: t(14;18) • MALToma Aggressive subtypes: potentially curable • DLBCL (MC, 30%) o Germinal centre B-cell like (GCB) t(14;18) o Activated B-cell like (ABC) t(3;14) – worse Px • Mantle cell lymphoma: t(11;14) Highly aggressive subtype: potentially curable (very chemosensitive) • Burkitt's lymphoma - related to EBV/ HIV, “starry sky appearance”, t(8;14) / t(2;8) / t(8;22) - Diffuse spread Nodal +/- extranodal disease with non-contiguous spread - S/S: Non-tender lymphadenopathy "B" symptoms* Extranodal disease: GI tract (MALToma), skin, brain (e.g. headache, seizures), tonsil (e.g. sore throat, dysphagia)., etc Investigations • Bloods: CBC, clotting, RFT/ LFT, CaPO4, ESR & LDH (prognostic), urate (TLS), PBS, glucose, DAT, serum Ig, SPE • Pre-treatment: HBV, HCV, HIV, G6PD, lung function test (bleomycin), pregnancy test • Pathology: o LN: Excisional biopsy / core biopsy for histology, cytogenetics & immunophenotyping (FNA not adequate!) o BM aspiration and trephine biopsy: for staging - HL: not indicated unless unexplained pancytopenia - NHL: bilateral (∵non-contiguous spread) • Imaging: CXR, PET-CT (preferred esp. DLBCL & HL), MRI brain / LP with cytospin (if suspect CNS lymphoma) • Other investigations: e.g. Waldeyer’s ring exam, OGD for GI lymphoma Staging: Ann Arbor staging Stage 1: Single LN group Stage 2: ≥2 LN groups on same side of diaphragm Stage 3: nodal involvement on both sides of diaphragm Stage 4: extranodal involvement e.g. liver, BM (note that spleen is considered nodal) Prognosis International Prognostic Index (IPI) for aggressive NHL considers 5 factors • Age > 60 • Performance status (ECOG) ≥ 2 • LDH elevated • Extranodal sites ≥ 2 • Stage: III / IV Management • Supportive care o TLS prophylaxis: IV fluid + allopurinol (or febuxostat) o Manage complications: TLS, SVCO, cord compression, malignant hypercalcaemia • Specific management 1. Hodgkin’s lymphoma Early stage (I/II): ABVD + Involved field radiotherapy (IFRT) • Adriamycin (= Doxorubicin) • Bleomycin (S/E: pulmonary toxicity) • Vinblastine • Dacarbazine Advanced stage (III/IV): ABVD Refractory: • Salvage chemotherapy (e.g. DHAP, ICE) • High-dose chemo + autologous HSCT Novel therapy: • Brentuximab vedotin (anti-CD30) • Pembrolizumab / nivolumab (PD1 blockade) 2. Non-Hodgkin’s lymphoma Indolent NHL: watchful waiting Aggressive NHL: R-CHOP ± IFRT • Rituximab • Cyclophosphamide • Hydroxydaunorubicin = Adriamycin = doxorubicin • Oncovin/ Vincristine Sulfate • Prednisolone • ± CNS prophylaxis (IT methotrexate) Refractory: • Salvage chemotherapy (e.g. DHAP, ICE) ± rituximab • High-dose chemo + autologous HSCT

Answer 17

Definitions - Monoclonal gammopathy: overproduction of ≥ 1 class of Ig from a single clone of plasma cells - Plasma cell dyscrasia: neoplasm that arise from clonal expansion of plasma cells Spectrum of plasma cell dyscrasias • Multiple myeloma spectrum: multiple lesions of plasma cell proliferation o Monoclonal gammopathy of undetermined significance (MGUS) – 1%/year progression to MM o Smouldering multiple myeloma – 10%/year progression to MM o Active multiple myeloma • Plasmacytoma: solitary plasma cell tumour found in skeleton (medullary) or soft tissue (extramedullary) • Waldenström macroglobulinaemia spectrum (arise from lymphoplasmacytoid cells but not plasma cells): o IgM MGUS o Smouldering WM o WM: IgM paraproteinaemia + BM shows lymphoplasmacytoid cells o Lymphoplasmacytoid lymphoma (LPL): solid tumour with LP cells • Immunoglobulin deposition disease: o Primary AL amyloidosis: organ deposition of amyloid proteins consisting of monoclonal light chains o Light chain deposition disease: organ deposition of light chains that do not form amyloid fibrils o Heavy chain deposition disease • POEMS syndrome Multiple myeloma • 95% secrete M proteins (intact Ig, free light chain only or heavy chain only), IgG most common • 5% are non-secretors Clinical features CRAB • HyperCalcaemia/ Bone lesions: active osteoclasts o Hypercalcaemia: confusion, constipation, polyuria/ polydipsia o Bone lesions (osteolytic): pain, vertebral collapse, pathological fracture, cord compression • Renal failure: important to know the cause (SAQ!) o Cast nephropathy (MC): light chain casts obstructing distal tubules o Hypercalcemia / hyperuricemia: nephrogenic DI —> dehydration —> pre-renal failure o Amyloidosis (accumulation of FLC): present with nephrotic syndrome (require renal Bx) o Other causes - Drug-induced e.g. NSAID, bisphosphonate, chemoTx - Local infiltration of tumor cells (myeloma kidney) - Fanconi syndrome - Recurrent UTI • Anaemia (NcNc) / bleeding tendency: BM infiltration + acquired vWD Other complications • Hyperviscosity syndrome: rare c.f WM • Cardiac failure: 2° to amyloidosis / anemia / hyperviscosity • Sensory ± motor neuropathy: usually 2° to amyloidosis • Recurrent infections: immunoparesis (decrease other Ig) Investigations (SAQ!) • Screening of monoclonal gammopathy: o Serum and urine protein electrophoresis (SPE & UPE) with immunofixation (fig.) - SPE: quantification of M protein - Immunofixation: characterize type of M protein, e.g. IgGkappa (most common) - Both SPE & UPE at diagnosis is mandatory: 50% LC MM is SPE -ve but UPE +ve o Serum IgG/A/M levels o Serum FLC: more sensitive for monoclonal FLC, k/l ratio (normal 0.26-1.65) also suggests monoclonal origin o 24h urine: Bence Jones protein (FLC) • Other investigations: o Bloods: CBC (decrease Hb), increase ESR, LRFT (reversed A:G ratio, increase Cr), CaPO4 (increase Ca), urate, glucose, PBS (rouleaux) o Pre-Tx: HBsAg, anti-HBc ± HBV DNA, G6PD o BM aspiration and trephine biopsy, skeletal survey (e.g. MRI whole body) o Prognostic: serum albumin, β2-microglobulin, LDH for staging (worse if higher) - Must check these markers before induction therapy MGUS vs SMM vs MM - monoclonal component: <30g/L, >30g/L, Present - Bone marrow plasma cells: <10%, 10-60%, >10% - Myeloma defining events: Absent, Absent, Present Myeloma defining events: SLiM CRAB End-organ damage: CRAB • Calcium: adjusted Ca > 2.75 • Renal insufficiency: Cr > 177 or CrCl < 40 • Anaemia: Hb < 10 • Bone disease: osteolytic “punched-out” lesions on CT / PET-CT / whole-body MRI; ALP usually normal (∵osteoblastic activity normal) Biomarkers of malignancy: SLiM • Sixty: Clonal BM plasma cell ≥ 60% • Involved/uninvolved serum free Light chain ratio > 100 • >1 focal lesions on MRI R- ISS staging Original ISS: albumin, β2- microglobulin Revised ISS: above + LDH + FISH cytogenetics Management (SAQ!) • Supportive treatment o TLS prophylaxis: IV fluid + allopurinol / febuxostat o Hypercalcaemia / Bone disease: local RT for pain relief, aggressive hydration > 3L/day, bisphosphonates e.g. pamidronate (osteoclast inhibitor), denosumab (RANKL inhibitor) o Renal failure: hydration, avoid nephrotoxin (e.g. NSAID), dialysis prn • Specific chemotherapy: only indicated in active MM o Induction: triple therapy - Proteasome inhibitor (e.g. bortezomib, carfilzomib) – S/E: peripheral neuropathy - + Immunomodulatory agents (e.g. lenalidomide / thalidomide / pomalidomide) - + Dexamethasone o Determine transplant candidate: depend on patient’s risk (age < 60, co-morbidities) - Eligible: 4 cycles of triple therapy —> high dose Melphalan + autologous HSCT - Ineligible: 8-12 cycles of triple therapy o Consolidation & maintenance therapy (lenalidomide monotherapy): ≥ 2 years o Relapse / refractory: Anti-CD38 (daratumumab, isatuximab), SLAMF7 (elotuzumab) o Immunotherapy against BCMA: Antibody-drug conjugate (ADC), Bi-specific T-cell engager (BiTE), CAR-T

Answer 18

Definition: fibrillar protein that is deposited in extracellular interstitial tissue, resulting in organ dysfunction by pressure atrophy of adjacent cells (but not evoking inflammation) Types • Systemic: o Primary AL amyloidosis: multiple myeloma o Reactive AA amyloidosis: chronic inflammation (e.g. RA, AS, IBD) o Dialysis-associated amyloidosis: long-term haemodialysis —> β2-microglobulin accumulation o Senile systemic amyloidosis: transthyretin accumulation o Hereditary amyloidosis • Localised: Alzheimer's disease [amyloid b], MTC [calcitonin] Clinical features • Kidney (MC): nephrotic syndrome • CVS: restrictive cardiomyopathy • Organomegaly: hepatomegaly, splenomegaly, macroglossia, pseudohypertrophy of muscles Diagnosis: Congo red stain under polarised light – apple-green birefringence

Answer 19

Genetic basis of transplantation • Major histocompatibility complex (MHC)/ human leukocyte antigen (HLA): important in HSCT as rejection occurs in both directions (host-versus-graft, graft-versus-host) • Minor histocompatibility antigen (MiHA) • ABO: less important in HSCT Types • Autologous: no risk of rejection or GVHD, but may contain contaminated stem cells • Allogenic: potential graft-vs-tumour effect, but risk of rejection/ GVHD Procedures • Stem cell harvest: bone marrow (pelvis) or peripheral blood (G-CSF +/- chemotherapy to stimulate HSC growth) • Conditioning regimens: o Myeloablative (irreversibly destroy the haematopoietic function of BM) o Non-myeloablative/ reduced intensity regimen (RIC): dose high enough to avoid graft rejection, and the remaining malignant cells eliminated by graft-vs-tumour effect • Post-transplant recovery: o Protective isolation, G-CSF, antibacterial/ antiviral/ antifungal prophylaxis, revaccination (infection) o Immunosuppressant, e.g. steroid (rejection) Complications • Infection risk o Early (< 100 days): neutropenia —> bacteria, Candida, Aspergillus, HSV reactivation o Late (> 100 days): encapsulated bacterial infection, VZV • Graft rejection • Graft-versus-host disease (GVHD) o Pathogenesis: T cell-mediated reaction against recipient tissues due to HLA mismatch or MiHA mismatch (even HLA fully matched) o Acute GVHD (< 100 days): skin (rash), GI (diarrhoea), liver (cholestatic hepatitis); Mx steroid o Chronic GVHD (>100 days): sclerosis, multi-organ involvement ~ autoimmune diseases; Mx steroid (poor response)

Answer 20

Tests on donated blood: ABO, Rh, infections (HBsAg, anti-HCV, anti-HIV, anti-HLTV, syphilis, CMV, bacterial) 1. Packed cells (250ml) / Whole blood (350ml / 450ml) - Storage: 2-6°C - Shelf life: PC: 42 days, WB: 35 days - Dosage: 1 pc = 1g/dL, Give within 4h - Indications: No single Hb value - consider rate of ongoing blood loss • Hb < 7: transfusion usually required • Hb 7-10: consider if tolerate anaemia poorly, e.g. age > 65y, CV/respiratory disease • Hb > 10: generally not required - Emergency: O- (or O+) - Packed cell preferred 2. Platelet concentrates (40-60ml) - Storage: 20-24°C - Shelf life: 5 days - Dosage: 1 unit = 7- 10x109/L ,Standard dose: 4 units (adults) - Indications: Platelet < 10 in stable patients Platelet < 20 in fever / sepsis Platelet < 50 in invasive procedures (e.g. laparotomy, LP, epidural, Bx) Platelet < 100 in eye/ CNS operation Extensive mucosal bleed or platelet dysfunction (e.g. aspirin-induced): immediate transfusion - Emergency: Any 3. Fresh frozen plasma (FFP) (200-250mL) - Storage: < -30°C (Thawed: 2-6°C) - Shelf life: 1 year (Thawed: 24h) - Dosage: 2-4 units, Give within 4h - Indications: Urgent reversal of anticoagulation Clotting factor deficiency Coagulopathy after massive transfusion DIC with bleeding - Emergency: AB 4. Cryoprecipitate* (10-40mL) - Storage: < -25°C - Shelf life: 1 year - Dosage: 10 units/dose - Indications: Fibrinogen deficiency (< 100mg/dL) or dysfunction vWD (if DDAVP or factor concentrates is inappropriate) Thrombolytic overdose Liver disease-induced coagulopathy DIC - Emergency: Any *Prepared by thawing FFP and collecting the precipitate, which is then re-frozen • Contain vWF, fibrinogen and fibronectin, factor VIII + XIII • Small volume prevents volume overload Interaction with IV fluids: • Compatible: NS, plasmalyte, gelofusin • NOT compatible: D5 (hypotonic —> hemolysis), lactated Ringer’s (calcium —> clotting)

Answer 21

Type & screen • Type: ABO & Rh typing • Screen: check patient serum against different RBC Ag by indirect Coomb's test (5min) • Crossmatch: if screen +ve; “trial transfusion” of patient's serum with donor's RBC (30-45 min) • T&S only effective for 3 days Management of adverse events (SAQ!) • Stop transfusion & spigot off the unit • Vitals & resuscitation • Recheck identity: patient, blood unit and blood form • Save blood bags and IV sets for investigations, but keep IV patent by normal saline • Workup: CBC, clotting, RFT, haemolytic screen (LDH, haptoglobin, bilirubin, urine Hb), T&S, X-match, DAT Major transfusion reaction 1. Acute haemolytic transfusion reaction (AHTR) - Fever, abdominal pain, Shock, chills, SOB, Haemoglobinuria - Blood culture: overlapping S/S with bacterial infection - Supportive: NS infusion with target of urine output of 100ml/h 2. Septic reaction - High fever (rise ≥1.5oC) - Blood (from patient and blood unit) for Gram stain & C/ST - Anti-pseudomonal antibiotics, e.g. Tazocin • Pathogens: Pseudomonas fluorescens, Yersinia 3. Anaphylaxis - Shock, bronchospasm, urticaria - IM adrenaline, steroid, antihistamine - Saline-washed RBC 4. Transfusion related Acute lung injury (TRALI) - SOB within 6h (donor anti-leucocyte Ab vs recipient WCC) - Ventilatory support - Trial of diuretics (to differentiate from fluid overload) 5. Transfusion-associated Circulatory overload (TACO) - SOB, APO - Diuretics, Ventilatory support • Delayed haemolytic transfusion reaction o Pathology: destruction of transfused red cells by antibody not detectable during type & screen - Note T&S is only valid for 3 days as new antibodies may form o Clinical features: failed increase in Hb, jaundice, haemoglobinuria o Management: supportive Mid fever or rash only: 1. Febrile non-haemolytic transfusion reaction (FNHTR) - Fever, chills, rigors Exclude AHTR & septic reaction - Paracetamol, restart infusion at a slower rate - Leucocyte-reduced blood products ± hydrocortisone prep 2. Mild allergic reaction (1-3%) - Urticaria - Exclude anaphylaxis - Antihistamine ± steroid, restart infusion at a slower rate - Saline-washed RBC if severe Complications of long-term blood transfusion • Iron overload: bronze pigmentation of skin, cardiomyopathy, cirrhosis, hypogonadism, DM • Blood-borne infections: HBV, HCV, HIV, EBV, CMV • Adverse events: allergic reactions, anaphylaxis Complications of massive transfusion (>1 total blood volume in 24h) • Electrolyte disturbances: hyperK (RBC lysis), hypoCa (EDTA takes up Ca in stored blood), acidosis • Hypothermia • Dilutional coagulopathy / thrombocytopenia

Haematology Flashcards

(47 cards)