{"title": "Chapter 8: Haematological Disorders", "flashcards": [{"q": "Define the WHO criteria for polycythaemia vera (PV).", "a": "Major criteria: (1) Hb >16.5 g/dL in men (>16 g/dL in women) or raised RCM; (2) BM biopsy showing panmyelosis; (3) JAK2 V617F or exon 12 mutation. Minor: subnormal serum erythropoietin. Diagnosis requires all 3 major, or 2 major + 1 minor. Treatment: venesection ± hydroxycarbamide; aspirin for thrombosis prevention."}, {"q": "What distinguishes iron deficiency anaemia from anaemia of chronic disease?", "a": "Iron deficiency: low ferritin (<30 µg/L), low serum iron, high TIBC, microcytic hypochromic picture. Anaemia of chronic disease (ACD): normal or HIGH ferritin (acute phase reactant), low serum iron, low or normal TIBC, normocytic (or mild microcytosis). sTfR/log ferritin index helps in overlap. Both coexist in IBD, renal disease, malignancy."}, {"q": "Name three features of megaloblastic anaemia on blood film.", "a": "Oval macrocytes (macro-ovalocytes); hypersegmented neutrophils (≥5 lobes in >5% of neutrophils — pathognomonic); pancytopaenia in severe cases; teardrop cells; red cell fragments. Causes: B12 deficiency (pernicious anaemia, vegan diet, ileal disease) and folate deficiency (poor diet, alcohol, methotrexate, trimethoprim, phenytoin)."}, {"q": "What is heparin-induced thrombocytopaenia (HIT) and how is it managed?", "a": "HIT is an immune-mediated reaction: PF4-heparin complexes elicit IgG antibodies that activate platelets via FcγRIIa receptors, causing platelet consumption AND paradoxical thrombosis. Diagnosed using 4T score (thrombocytopaenia, timing, thrombosis, alternatives). Manage: stop ALL heparin immediately; switch to non-heparin anticoagulant (argatroban, fondaparinux, bivalirudin). NEVER give platelet transfusions."}, {"q": "Name the Philadelphia chromosome translocation and its clinical significance.", "a": "t(9;22)(q34;q11) creates BCR-ABL1 fusion gene encoding a constitutively active tyrosine kinase. Present in >95% of CML and ~25–30% of adult B-cell ALL. Imatinib (first-generation TKI) revolutionised CML prognosis (85% CCyR at 12 months). Second-generation TKIs (dasatinib, nilotinib) used for resistance or accelerated/blast phase."}, {"q": "What is the mechanism of action of rituximab?", "a": "Rituximab is a chimeric anti-CD20 monoclonal antibody. CD20 is expressed on all B cells from pre-B to mature B cell stage (not on stem cells or plasma cells). Rituximab causes B cell depletion via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and direct apoptosis induction. Used in B-cell NHL, CLL, DLBCL, and autoimmune conditions."}, {"q": "What are the diagnostic criteria for multiple myeloma?", "a": "CRAB criteria: hyperCalcaemia (>2.75 mmol/L); Renal impairment (creatinine >177 µmol/L or CrCl <40 mL/min); Anaemia (Hb <100 g/L); Bone lesions (lytic, osteoporosis, or pathological fracture). Plus: bone marrow clonal plasma cells ≥10% or confirmed plasmacytoma. Serum M-protein on electrophoresis confirms the clone."}, {"q": "Define thrombotic thrombocytopaenic purpura (TTP) and its mechanism.", "a": "TTP: MAHA + thrombocytopaenia + (classically) neurological symptoms, fever, and renal impairment. Caused by ADAMTS13 deficiency (congenital or acquired via IgG autoantibody), allowing ultra-large vWF multimers to cause platelet aggregation in microvasculature. ADAMTS13 activity <10% is diagnostic. Treatment: plasma exchange (removes antibody, replaces ADAMTS13) + prednisolone ± rituximab. Caplacizumab (anti-vWF nanobody) for acute episode."}, {"q": "What are the four main types of thalassaemia and their haematological features?", "a": "Alpha-thalassaemia trait (2 gene deletions): mild microcytic hypochromic anaemia or carrier; HbH disease (3 deletions): moderate haemolytic anaemia, HbH (β4 tetramers); Hydrops fetalis (4 deletions): fatal in utero. Beta-thalassaemia trait: mild microcytic hypochromic, normal Hb or mild anaemia, elevated HbA2; Beta-thalassaemia major (transfusion-dependent): severe anaemia, extramedullary haematopoiesis, hepatosplenomegaly."}, {"q": "Name four risk factors for venous thromboembolism (VTE).", "a": "Virchow's triad: stasis (immobility, long-haul flight, hip/knee surgery, HF); endothelial damage (trauma, surgery, catheter); hypercoagulability (malignancy, inherited thrombophilia — Factor V Leiden, prothrombin G20210A; antiphospholipid syndrome; OCP; pregnancy; myeloproliferative disease; nephrotic syndrome; HIT)."}], "quiz": [{"q": "What is the first-line treatment for newly diagnosed immune thrombocytopaenic purpura (ITP) in adults?", "opts": ["Platelet transfusion", "Oral prednisolone ± IV immunoglobulin (IVIG) for bleeding or rapid platelet recovery", "Splenectomy immediately", "Rituximab first-line"], "ans": 1, "exp": "First-line ITP: oral prednisolone 1 mg/kg/day for 4 weeks (or dexamethasone 40 mg/day for 4 days). IVIG 1 g/kg is added for severe bleeding or emergency surgery for rapid but transient platelet increase. Platelet transfusions are reserved for life-threatening bleeding (ineffective as platelets are rapidly destroyed). Splenectomy and rituximab are second-line."}, {"q": "What is the mode of inheritance of sickle cell disease?", "opts": ["Autosomal dominant", "Autosomal recessive — HbSS (two copies of HbS point mutation — Glu6Val in beta-globin chain)", "X-linked recessive", "Mitochondrial"], "ans": 1, "exp": "Sickle cell disease (HbSS) is autosomal recessive: both beta-globin alleles carry the Glu6Val point mutation. Sickle cell trait (HbAS — one mutant allele) is benign in most circumstances. Heterozygous combinations with other haemoglobinopathies (HbSC, HbS-beta-thalassaemia) also cause significant disease."}, {"q": "Which test is most specific for diagnosing haemolytic anaemia?", "opts": ["Serum bilirubin", "Serum haptoglobin (low/undetectable), raised LDH, reticulocytosis, blood film schistocytes, positive DAT (autoimmune)", "Haemoglobin level", "Peripheral blood film alone"], "ans": 1, "exp": "Haemolysis: low haptoglobin (consumed binding free Hb), raised LDH (released from RBCs), unconjugated hyperbilirubinaemia, reticulocytosis, and blood film changes (schistocytes in MAHA, spherocytes in AIHA/HS). DAT (Coombs) distinguishes immune-mediated from non-immune haemolysis."}, {"q": "A patient with NHL has tumour lysis syndrome. What is the most important initial management?", "opts": ["Start allopurinol and observe", "Aggressive IV hydration (2–3 L/m²/day) + allopurinol (prophylaxis) or rasburicase (established TLS), electrolyte monitoring", "Immediate dialysis", "Sodium bicarbonate alone"], "ans": 1, "exp": "TLS: massive cell lysis releases intracellular contents causing hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia, and AKI. Management: aggressive IV hydration (2–3 L/m²/day); rasburicase (uricase enzyme) converts uric acid to allantoin (preferred for established TLS or high risk); allopurinol for prophylaxis. Monitor electrolytes 6-hourly; dialysis if refractory."}, {"q": "What is the most important prognostic factor in diffuse large B-cell lymphoma (DLBCL)?", "opts": ["Tumour size", "International Prognostic Index (IPI) — age, LDH, performance status, disease stage, extranodal sites", "Gender", "Bone marrow biopsy result alone"], "ans": 1, "exp": "The IPI score (0–5: age >60, LDH >ULN, ECOG PS ≥2, Ann Arbor stage III/IV, extranodal sites ≥2) stratifies DLBCL into low, low-intermediate, high-intermediate, and high risk groups with 5-year OS ranging from 73% (low IPI) to ~26% (high IPI). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is first-line for all stages."}, {"q": "What blood film finding is pathognomonic of haemolytic uraemic syndrome (HUS)?", "opts": ["Spherocytes", "Schistocytes (fragmented erythrocytes from mechanical shearing in microthrombi-laden vessels)", "Target cells", "Sickle cells"], "ans": 1, "exp": "Schistocytes — fragmented RBC fragments — are pathognomonic of microangiopathic haemolytic anaemia (MAHA) occurring in HUS, TTP, and DIC. They form when RBCs are mechanically sheared by fibrin strands or platelet-vWF thrombi in the microvasculature. Presence of schistocytes with thrombocytopaenia and AKI = HUS until proved otherwise."}, {"q": "What is the mechanism of action of erythropoiesis-stimulating agents (ESAs) in CKD anaemia?", "opts": ["They directly transfuse red blood cells", "Epoetin alfa/darbepoetin alfa bind the EPO receptor on erythroid progenitors, stimulating proliferation, differentiation, and preventing apoptosis — mimicking endogenous EPO deficiency in CKD", "They increase iron absorption", "They stimulate bone marrow stem cells to produce all blood lines"], "ans": 1, "exp": "CKD causes EPO deficiency from reduced renal peritubular interstitial cell EPO synthesis. ESAs (epoetin alfa, darbepoetin alfa) bind EPO receptors on erythroid progenitor cells in the bone marrow, stimulating RBC production. Target Hb is 100–120 g/L; higher targets (>130 g/L) increase cardiovascular events. IV iron must be optimised before and with ESA therapy."}, {"q": "Which staging system is used for Hodgkin lymphoma?", "opts": ["FIGO staging", "Ann Arbor staging (I–IV) modified by Lugano classification with A/B symptoms and 'bulky' designation", "TNM staging", "Binet staging"], "ans": 1, "exp": "Hodgkin lymphoma is staged by the Lugano modification of the Ann Arbor system: Stage I (single nodal region or one extranodal site); II (≥2 regions same side of diaphragm); III (both sides of diaphragm); IV (diffuse/disseminated extranodal involvement). B symptoms (fever, drenching night sweats, >10% weight loss in 6 months) confer worse prognosis."}, {"q": "What is the most common cause of polycythaemia in clinical practice?", "opts": ["Polycythaemia vera (primary)", "Apparent/relative polycythaemia from dehydration, or secondary polycythaemia from chronic hypoxia (COPD, OSA, altitude) stimulating EPO production", "JAK2 mutation", "Erythropoietin-secreting tumour"], "ans": 1, "exp": "True polycythaemia is most commonly secondary — from chronic hypoxaemia (COPD, OSA, cyanotic heart disease, high altitude) driving elevated EPO. PV (primary) is less common. Apparent (relative) polycythaemia from dehydration/plasma volume reduction is the most common cause of an elevated haematocrit found incidentally. Confirm with red cell mass measurement."}, {"q": "What is the APML-associated genetic translocation and why is it clinically critical?", "opts": ["t(9;22) BCR-ABL1", "t(15;17) PML-RARA — associated with AML-M3 (APML), sensitive to ATRA (all-trans retinoic acid) and arsenic trioxide, with risk of DIC at presentation", "t(8;14) in Burkitt lymphoma", "t(14;18) in follicular lymphoma"], "ans": 1, "exp": "AML-M3 (APML, acute promyelocytic leukaemia) carries t(15;17) creating PML-RARA fusion, blocking myeloid differentiation. APML carries risk of catastrophic DIC at diagnosis. ATRA induces differentiation of leukaemic promyelocytes and resolves DIC. ATRA + arsenic trioxide achieves >95% complete remission. It is one of the most curable adult leukaemias when treated promptly."}, {"q": "What is the mechanism of warfarin resistance in patients taking rifampicin?", "opts": ["Rifampicin reduces warfarin absorption", "Rifampicin is a potent CYP2C9 inducer, markedly increasing warfarin metabolism and reducing its anticoagulant effect — requiring substantial INR monitoring and dose adjustment", "Rifampicin increases vitamin K", "Rifampicin directly inhibits clotting factors"], "ans": 1, "exp": "Rifampicin induces hepatic CYP enzymes (CYP2C9, CYP3A4), dramatically increasing warfarin metabolism and lowering its plasma concentration and anticoagulant effect. Warfarin doses may need to increase 3–5× during rifampicin therapy. When rifampicin is stopped, doses must be rapidly reduced to avoid supratherapeutic anticoagulation. INR must be monitored very closely."}, {"q": "What are the diagnostic criteria for essential thrombocythaemia (ET)?", "opts": ["Platelet count >600 × 10⁹/L alone", "WHO criteria: platelet count ≥450 × 10⁹/L; BM biopsy showing megakaryocyte proliferation; exclusion of PV/CML/MF/MDS; CALR, JAK2, or MPL mutation (or ET clonal marker); ET not explained by reactive causes", "Any platelet count >450 if JAK2 positive", "Thrombocytosis + splenomegaly"], "ans": 1, "exp": "ET is a myeloproliferative neoplasm. WHO 2022 criteria: platelet ≥450 × 10⁹/L, BM showing mature megakaryocyte proliferation (large, hyperlobulated), exclusion of PV/CML/myelofibrosis/MDS, JAK2 V617F (~55%), CALR (~25%), or MPL mutation (~5%), or exclusion of reactive thrombocytosis. Treatment: low-dose aspirin for all; hydroxycarbamide for high-risk (age >60, prior thrombosis, platelet >1500, cardiovascular risk factors)."}, {"q": "What is the most common inherited thrombophilia?", "opts": ["Protein C deficiency", "Factor V Leiden (G1691A mutation in FV gene making factor Va resistant to APC cleavage) — ~5% of Europeans are carriers", "Protein S deficiency", "Antithrombin III deficiency"], "ans": 1, "exp": "Factor V Leiden is the most common inherited thrombophilia in Caucasians (~5% heterozygotes, 0.02% homozygotes). The mutation makes factor Va resistant to cleavage by activated protein C (APC resistance), maintaining a pro-coagulant state. Heterozygosity increases VTE lifetime risk ~4–8×; homozygosity ~80×. Testing is indicated after unprovoked or recurrent VTE, or thrombosis in unusual sites."}, {"q": "What blood product is used to rapidly reverse warfarin in life-threatening bleeding?", "opts": ["Fresh frozen plasma alone", "Four-factor prothrombin complex concentrate (4F-PCC — Beriplex, Octaplex) IV — immediate INR reversal in minutes; superior to FFP (faster, smaller volume, no need for blood group matching)", "Vitamin K alone", "Cryoprecipitate"], "ans": 1, "exp": "4F-PCC contains factors II, VII, IX, and X (plus proteins C and S), providing rapid (within 15–30 min), reliable, volume-efficient warfarin reversal. It is superior to FFP (which requires large volumes and longer time to prepare). IV vitamin K (5–10 mg) is always given alongside PCC to sustain reversal. FFP is used when 4F-PCC is unavailable. Protamine reverses unfractionated heparin (not warfarin)."}, {"q": "What is the Coombs test used to diagnose?", "opts": ["Iron deficiency anaemia", "Autoimmune haemolytic anaemia (AIHA) — direct Coombs (DAT) detects IgG/C3 bound to patient's RBCs; indirect Coombs detects antibodies in patient's serum reacting with test RBCs", "Thalassaemia", "Hereditary spherocytosis"], "ans": 1, "exp": "Direct antiglobulin test (DAT/direct Coombs): patient RBCs + antihuman globulin reagent → agglutination if IgG or C3 is bound to RBCs. Positive in warm AIHA (IgG — treated with steroids/rituximab), cold haemagglutinin disease (C3 — IgM binds then detaches; avoid cold), drug-induced haemolysis, HDN. Indirect Coombs: used for antibody screening in cross-matching and antenatal testing."}, {"q": "What is the most common type of non-Hodgkin lymphoma in adults?", "opts": ["Follicular lymphoma", "Diffuse large B-cell lymphoma (DLBCL) — ~30–35% of NHL", "Mantle cell lymphoma", "Burkitt lymphoma"], "ans": 1, "exp": "DLBCL is the most common NHL globally (~30–35% of cases). It is an aggressive B-cell lymphoma presenting with rapidly enlarging lymph nodes and B symptoms, often with extranodal involvement. Standard treatment: R-CHOP (6 cycles) achieving long-term remission in ~60–70% of patients. Polatuzumab vedotin added to R-CHP (pola-R-CHP — POLARIX trial) is emerging as the new standard."}, {"q": "What is transfusion-related acute lung injury (TRALI) and when does it occur?", "opts": ["Haemolytic transfusion reaction occurring after 24 hours", "Acute hypoxic lung injury (new bilateral pulmonary infiltrates, PaO₂/FiO₂ <300, SpO₂ <90%) occurring within 6 hours of transfusion, with no alternative explanation — caused by donor antibodies (anti-HLA, anti-HNA) activating recipient neutrophils", "Allergic reaction from IgA deficiency", "Circulatory overload from excessive transfusion rate"], "ans": 1, "exp": "TRALI is the most common cause of transfusion-related mortality. Mechanism: donor antibodies (anti-HLA class I/II or anti-HNA) activate recipient neutrophils primed by an inflammatory state, causing non-cardiogenic pulmonary oedema. Occurs within 6 hours of ANY blood component transfusion. Management: stop transfusion, supportive care (oxygen, CPAP/ventilation), report to blood bank. Risk reduced by using male-predominant FFP and apheresis platelets."}, {"q": "What is the role of bone marrow biopsy in haematological malignancy?", "opts": ["Only useful for diagnosing leukaemia", "Essential for: diagnosing haematological malignancies (leukaemia, myeloma, MDS, MPN), staging lymphomas, assessing marrow infiltration in solid tumours, evaluating unexplained cytopaenias, and monitoring treatment response (minimal residual disease assessment)", "Used only when peripheral blood film is non-diagnostic", "Replaces peripheral blood film in all cases"], "ans": 1, "exp": "Bone marrow trephine biopsy provides cellularity, architecture, fibrosis grading, and immunohistochemistry. Aspirate provides cytology, immunophenotyping (flow cytometry), cytogenetics, and molecular analysis. Together they define diagnosis, subtype, prognostic category, and treatment eligibility across haematological malignancies. Site: posterior iliac crest (preferred); anterior iliac crest or sternum if inaccessible."}, {"q": "What is a 'left shift' on full blood count and what does it indicate?", "opts": ["Macrocytosis", "Presence of immature granulocytes (band forms, metamyelocytes, myelocytes) in peripheral blood, indicating high bone marrow demand for neutrophils — typically from severe infection, systemic inflammation, or leukaemoid reaction", "Thrombocytopaenia", "Lymphopaenia"], "ans": 1, "exp": "Left shift refers to release of immature neutrophil precursors from the bone marrow into peripheral blood. Normally only segmented neutrophils and a few bands are seen. Left shift with elevated WBC = leukaemoid reaction (severe infection, haemolysis, recovery from marrow suppression). Leukaemoid reactions must be distinguished from CML (leukaemia — LAP score low in CML, high in leukaemoid reactions; BCR-ABL1 negative in LR)."}, {"q": "What is the recommended indications for erythropoiesis-stimulating agents (ESAs) in myelodysplastic syndrome?", "opts": ["All MDS patients with anaemia", "Low-risk MDS (IPSS low/int-1) with symptomatic anaemia AND serum EPO <200 IU/L (or <500 IU/L with ring sideroblasts on biopsy) who do not have del(5q) — response rate ~40–60% in appropriately selected patients", "MDS patients on chemotherapy only", "ESAs are contraindicated in MDS"], "ans": 1, "exp": "ESAs (epoetin alfa/darbepoetin alfa) are used for transfusion-dependent or symptomatic anaemia in low-risk MDS. Best response predictors: low transfusion burden (<2 units/month), serum EPO <200 IU/L (<500 in RS-MDS), and no high-risk cytogenetics. MDS with del(5q): lenalidomide is the treatment of choice (transfusion independence ~70%). ESAs should not be used in higher-risk MDS or those with CVD risk."}]}