Haematology: Non-Malignant Mr En Lin Goh, BSc (Hons), MBBS (Dist.), MRCS 25th February 2021 Introduction • ICSM Class of 2018 • Distinction in Clinical Sciences • Pathology = 94% • Wallace Prize for Pathology • Jasmine Anadarajah Prize for Immunology • Abrahams Prize for Histopathology Content 1. Anaemia 2. Haemoglobinopathies 3. Haemostasis and thrombosis 4. Obstetric haematology 5. Transfusion medicine Anaemia Background • Hb <135 g/L in males and <115 g/L in females • Causes: decreased production, increased destruction, dilution • Classified based on MCV: microcytic (<80 fL), normocytic (80-100 fL), macrocytic (>100 fL) • Arise from disease processes affecting synthesis of haem, globin or porphyrin Microcytic anaemia work-up • Key differentials • Iron deficiency anaemia • Thalassaemia • Sideroblastic anaemia • Key investigations • Peripheral blood smear • Iron studies Iron deficiency anaemia • Commonest cause is blood loss • Key features • Peripheral blood smear – pencil cells • Iron studies – ↓iron, ↓ferritin, ↑transferrin, ↑TIBC • FBC – reactive thrombocytosis • Management – investigate underlying cause, iron supplementation Thalassaemia • α-thalassaemia, β-thalassaemia, thalassaemia trait • Key features • Peripheral blood smear – basophilic stippling, target cells • Iron studies – all normal • Management – iron supplementation, regular transfusions, iron chelation Sideroblastic anaemia • Congenital or acquired • Key features • Peripheral blood smear – basophilic stippling • Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC • Bone marrow – ringed sideroblasts • Management – treat underlying cause, regular transfusions Macrocytic anaemia work-up • Key differentials • Megaloblastic anaemia: vitamin B12 deficiency, folate deficiency • Alcohol • Hypothyroidism • Key investigations • Peripheral blood smear • LFTs • TFTs Megaloblastic anaemia • Vitamin B12 or folate deficiency • How to differentiate? • Duration – months for folate deficiency, years for vitamin B12 deficiency • Clinical findings – vitamin B12 deficiency associated with neurological changes • Serum methylmalonic acid – elevated in vitamin B12 deficiency • Schilling test – positive in vitamin B12 deficiency 2º to pernicious anaemia • Drug history – phenytoin inhibits folate absorption • Management – vitamin supplementation Non-megaloblastic anaemia • Alcohol, hypothyroidism, pregnancy • How to differentiate? • History – features of hypothyroidism • Clinical findings – hepatomegaly, gynaecomastia, abdominal veins, ascites, jaundice • LFTs – ↑AST, ↑ALT, ↑GGT, AST:ALT >2:1 • TFTs – ↑TSH, ↓T3/T4, anti-thyroid peroxidase antibodies • Management – treat underlying cause Normocytic anaemia work-up • Key differentials • Haemolytic: inherited or acquired (immune-mediated, non-immune-mediated) • Non-haemolytic: anaemia of chronic disease, failure of erythropoiesis • Key investigations • Peripheral blood smear • DAT • CRP, ESR Anaemia of chronic disease • Infection, inflammation, malignancy • Key features • Inflammatory markers – raised CRP, ESR • Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC • Management – treat underlying cause SBA 1 A 65-year-old lady presents with recent onset of fatigue and dyspnoea on exertion. She reports a decrease in appetite, constipation and weight gain. Her full blood count results show: Hb = 100 g/L, MCV = 102 fL. Which of the following is the likely diagnosis? a. Underlying malignancy b. Vitamin B12 deficiency c. Hypothyroidism d. Inflammatory bowel disease e. Liver disease SBA 1 A 65-year-old lady presents with recent onset of fatigue and dyspnoea on exertion. She reports a decrease in appetite, constipation and weight gain. Her full blood count results show: Hb = 100 g/L, MCV = 102 fL. Which of the following is the likely diagnosis? a. Underlying malignancy b. Vitamin B12 deficiency c. Hypothyroidism d. Inflammatory bowel disease e. Liver disease VSA 1 A 25-year-old lady presents with a 3-month history of worsening paraesthesia in her feet. She is a life-long vegetarian. Hb = 100 g/L, MCV = 110 fL. Which vitamin is she likely deficient in? VSA 1 A 25-year-old lady presents with a 3-month history of worsening paraesthesia in her feet. She is a life-long vegetarian. Hb = 100 g/L, MCV = 110 fL. Which vitamin is she likely deficient in? Vitamin B12 Haemolytic anaemia • Inherited or acquired (immune-mediated vs non-immune-mediated) • Inherited • Hereditary spherocytosis • Glucose-6-phosphate dehydrogenase deficiency • Immune • Autoimmune: warm vs cold haemolytic anaemia • Alloimmune: ABO or Rhesus incompatibility • Non-immune • Microangiopathic vs macroangiopathic • Infection Hereditary spherocytosis • Autosomal dominant • Defect in the vertical interaction of the red cell membrane • Key features • Peripheral blood smear: spherocytes, polychromasia • Positive osmotic fragility test • Positive eosin-5-maleimide (most sensitive test) • Management – folate supplementation, splenectomy G6PD • X-linked recessive • G6PD generates NADPH via pentose phosphate pathway • Key features • Episodes of acute haemolysis following exposure to oxidative stress (e.g. fava beans, mothballs, drugs) • Peripheral blood smear: Heinz bodies, bite cells • Intravascular haemolysis: ↑unconjugated bilirubin, ↓haptoglobin, haemoglobinuria • Management – avoidance of triggers, supportive care AIHA • Immune-mediated destruction of red blood cells, DAT positive • Warm • Mediated by IgG • Associated with CLL, SLE, methyldopa • Extravascular haemolysis • Cold • Mediated by IgM • Associated with Mycoplasma, EBV, hepatitis C • Intravascular haemolysis • Management – treat underlying cause, steroids, rituximab MAHA • Non-immune-mediated, small vessel disease • Damage to endothelial cells within the vasculature à fibrin deposition and platelet aggregation à fragmentation of red blood cells • Key features • Peripheral blood smear: schistocytes, thrombocytopenia • Disorders – HUS, TTP, DIC • Distinguish from DIC with normal APTT, PT, fibrinogen • Management – treat underlying cause, supportive HUS • Commonly caused by Escherichia coli O157:H7 – Shiga-like toxin • More frequent but less severe in children • Key features • Symptoms occur after a diarrhoeal illness – do not give antibiotics to treat • Triad of MAHA, thrombocytopenia, acute renal failure – self-limiting in children • Features of MAHA on peripheral blood smear • Management – supportive care TTP • Deficiency of ADAMTS13 à decreased break down of multimers of vWF • Can be inherited or acquired • Key features • Pentad of MAHA, thrombocytopenia, acute renal failure, neurological symptoms, fever • High mortality rate • Management – supportive care, plasma exchange SBA 2 A 6-month-old African boy presents with abdominal pain, jaundice and dark urine. He was diagnosed with a urinary tract infection three days ago and was started on nitrofurantoin. He has not experienced any similar episodes in the past. Which of the following is a likely diagnosis? a. Sickle cell anaemia b. Glucose-6-phosphate dehydrogenase deficiency c. Sepsis d. β-thalassaemia major e. Autoimmune haemolytic anaemia SBA 2 A 6-month-old African boy presents with abdominal pain, jaundice and dark urine. He was diagnosed with a urinary tract infection three days ago and was started on nitrofurantoin. He has not experienced any similar episodes in the past. Which of the following is a likely diagnosis? a. Sickle cell anaemia b. Glucose-6-phosphate dehydrogenase deficiency c. Sepsis d. β-thalassaemia major e. Autoimmune haemolytic anaemia VSA 2 An 83-year-old man with a diagnosis of chronic lymphocytic leukaemia presents with worsening tiredness, dyspnoea and reduced exercise tolerance. Hb = 66 g/L, DAT positive. What is the causative antibody underlying his condition? VSA 2 An 83-year-old man with a diagnosis of chronic lymphocytic leukaemia presents with worsening tiredness, dyspnoea and reduced exercise tolerance. Hb = 66 g/L, DAT positive. What is the causative antibody underlying his condition? IgG Haemoglobinopathies Background • Genetic disorders of globin chain synthesis • Haemoglobin • HbA (α2β2) – late foetus, infant, child and adult • HbA2 (α2δ2) – infant, child and adult • HbF (α2ɣ2) – foetus, infant • Diagnosis made with Hb electrophoresis • Disorders – thalassaemia, sickle cell disease β-thalassaemia Chr 11 β-globin • Reduced synthesis of β globin chain (Chromosome 11) β-globin • Major (homozygous), intermedia and minor (heterozygous) • Key features • Major – severe anaemia requiring regular blood transfusions • Intermedia – genetically complex, moderate reduction in β globin chain production • Minor – benign but important genetically • Management – regular blood transfusions, iron chelation, folate supplementation α-thalassaemia • Reduced synthesis of α globin chain (Chromosome 16) • Hb Barts (x4), HbH (x3), trait (x2), silent (x1) Chr 16 α-globin α-globin • Key features α-globin α-globin • Hb Barts – fatal in utero, hydrops foetalis • HbH – severe anaemia in childhood, hepatosplenomegaly • Trait – mild anaemia • Silent – asymptomatic • Management – regular blood transfusions, iron chelation, folate supplementation Sickle cell disease • Autosomal recessive • Glu à Val mutation at codon 6 on the β globin chain à HbS • HbSS, HbAS, HbSC, HbSβ • Key features • Haemolytic crisis, sequestration crisis, aplastic crisis, infection (Streptococcus pneumoniae – sepsis, Salmonella sp– osteomyelitis) • Peripheral blood smear: sickle cells • Sickle solubility test positive in HbSS and HbAS • Management – vaccination, folate supplementation, hydroxyurea,