Haematology JC048: Family History Of Anaemia: Inherited Causes Of Anaemia, Haemolytic Anaemia, Aplastic Anaemia Flashcards

Question

Disorders of RBC metabolism (Enzymopathy)

Answer 1

aka ***Congenital non-spherocytic haemolytic anaemia (∵ no spherocytes vs Hereditary spherocytosis / Immune-mediated haemolysis) 1. ***G6PD deficiency 2. ***Pyruvate kinase deficiency 3. Deficiency of other glycolytic pathway enzymes (rare) G6PD deficiency: - important in generation of reducing power: GSH —> needed to withstand oxidative stress (esp. RBC always in contact with O2) Glycolytic enzyme deficiency: - RBC nucleus expelled in BM before in circulation —> no protein synthesis —> rely on existing enzymes to generate energy to maintain protein integrity / osmolality —> deficiency in enzymes —> no ATP generated —> RBC susceptible to haemolysis

Answer 2

- ***X-linked recessive - Incidence in HK: 4.5% in males, 0.5% in females - >100 variants associated with enzyme deficiency - Type B refers to Wild-type Classified based on severity (residual enzyme activity): Class 1: Severe ***<2%, Santiago de Cuba (Gly447Arg) —> Haemolytic anaemia (***unprovoked chronic haemolysis), acute exacerbation Class 2: ***<10%, Canton (Arg45Leu), Mediterranean (Ser188Phe) —> Favism, Acute IV haemolysis (drug induced), Neonatal Jaundice Class 3: Moderate ***<60%, A- (Val68Met, Asn126Asp) —> No clinical effect Class 4: ***100%, Type B (wild type), Type A (Asn126Asp) —> No clinical effect Clinical features: 1. Intravascular Haemolysis with Haemoglobinuria (acute / chronic) (not common) 2. Precipitated by infection, acute medical illness, drugs, fava beans (most of the time) - drugs: Sulphonamides, Rasburicase, Primaquine Investigation: 1. Blood film - Polychromasia - ***Ghost / Hemi-ghost cells (∵ oxidative changes) —> ghost: no Hb in cell (can only see membrane) (得返個殼) Diagnosis: 1. ***G6PD assay for enzyme level - may be ***normal during acute phase (i.e. acute haemolysis) as young RBC and reticulocytes may have normal G6PD levels Treatment: 1. Supportive 2. ***Blood transfusion 3. ***Folate supplement 4. Stop + Avoid offending agents

Answer 3

Destruction of RBC accelerated —> shortened RBC life span - may not have anaemia in presence of adequate marrow compensation —> compensated haemolysis Extravascular haemolysis: Spleen: Macrophage clearing up damaged/defective RBC, Warm AIHA Intravascular haemolysis: G6PD deficiency, Microangiopathic haemolytic anaemia, Cold AIHA Causes: - Intrinsic / Extrinsic (See previous note) - Acquired / Inherited Acquired 1. Immune-mediated - Ab to RBC surface antigens —> Spherocytes + ***positive DAT 2. Microangiopathic - mechanical disruption of RBC in circulation —> Red cell fragmentation syndromes —> Schistocytes 3. Infection - Malaria, Clostridium —> cultures, serologies Hereditary 1. Enzymopathies - G6PD deficiency —> Low G6PD activity 2. Membranopathies - Hereditary spherocytosis —> Spherocytes, family history, ***negative DAT (vs Warm AIHA) 3. Hemoglobinopathies - Thalassaemia, Sickle cell disease —> Hemoglobin electrophoresis, genetic studies Laboratory findings: 1. Increased Haemoglobin breakdown (↑ Total + Unconjugated Bilirubin) 2. Red cell damage - ***Spherocytes (Hereditary spherocytosis / Warm AIHA) - ***Schistocytes (Microangiopathic haemolytic anaemia) - Sickle cell (Sickle cell anaemia) 3. Reticulocytosis (Polychromasia) 4. Circulating nucleated RBC 5. Erythroid hyperplasia (in BM) 6. Intravascular haemolysis RBC damaged in circulation —> release free Hb (↑ plasma Hb) —> Free Hb bind to Haptoglobin first (↓ Haptoglobin) —> Haptoglobin used up —> Hb bind to Albumin (↑ Methaemalbumin, +ve Schumm’s test) —> Excess Hb: 1. Haemoglobinaemia 2. Filter in glomerulus (Haemoglobinuria —> Dark urine) 3. Iron deposition in renal tubules (Haemosiderin) —> re-excreted in urine inside dislodged cells (Haemosiderinuria: Sign of chronic intravascular haemolysis)

Answer 4

RBC destruction mediated by Ab directed against RBC antigens - Spherocytosis (warm AIHA) - RBC agglutination (cold AIHA) 1. Autoimmune (AutoAb) - warm / cold - many idiopathic - associated with autoimmune disease (e.g. SLE), lymphoproliferative disorder, mycoplasma pneumonia, infectious mononucleosis - +ve DAT 2. Alloimmune (AlloAb) - Haemolytic transfusion disorder (ABO incompatible blood transfusion) - Haemolytic disease of newborn (Anti-D in Rh D -ve mother —> haemolysis in Rh D +ve infant) 3. Drug-induced - Hapten mechanism: Ab directed against drug-cell membrane complex - Immune complex mechanism: drug-Ab complex on RBC surface —> Complement deposition - Autoimmune

Answer 5

Hyperproliferative anaemia Genetic disorder of globin chain synthesis - ↓ synthesis of particular globin chains —> imbalance in available globin chains —> excess chains polymerise but ***unstable —> precipitate —> ***Early destruction of RBC precursors in BM (ineffective erythropoiesis) / ***Shorten RBC life span Laboratory findings: - ***Hypochromic Microcytic RBC (defective haemoglobinisation) - Abnormal globin tetramers (Hb H / Hb Barts) / Normal haemoglobin present in non-physiological amount (e.g. Hb F) —> Increased O2 affinity —> Tissue hypoxia (cannot unload O2) ***Laboratory diagnosis of Thalassaemia: 1. CBC, RBC indices 2. Peripheral blood film - ***Hypochromic, Microcytic - ***Reticulocytosis - Anisocytosis (嚴重先有) - Poikilocytosis (嚴重先有) - Normoblasts - ***Target cells 3. β-Thalassaemia —> ***Hb F, Hb A2 quantitation by chromatography / electrophoresis 4. α-Thalassaemia —> Detection of ***Hb H inclusions 5. Genotyping for complex cases / Prenatal diagnosis Prevention of Hb Bart’s hydrops fetalis and β-Thalassemia Major 1. Public health education 2. Counselling of specific target groups (couples before / soon after marriage) 3. Carrier detection 4. Antenatal, Prenatal diagnosis

Answer 6

- defective fetal + adult Hb production - Fetus: excess γ chains (Hb Bart’s: γ4) - Adult: excess β chains (Hb H: β4) —> may be masked during smear examination by concomitant β-Thalassemia —> ∵ cannot produce β-chains 1. α-Thalassaemia trait (1 / 2 gene deletion) - 1 gene deletion: clinically / haematological silent - 2 gene deletion: normal / slightly ↓ haemoglobin, ***↑ RBC count, ***Hypochromic Microcytic RBC - ***HbH inclusions: precipitated out to form blue-green granules when RBC incubated with Brilliant cresyl blue stain (哥爾夫球) 2. Hb H disease (3 gene deletion) - ***Chronic anaemia - ***Splenomegaly (to remove RBC) - ***~ALL patient have normal physical development (small proportion has thalassaemic facies) - can be Asymptomatic - generally NOT transfusion dependent - excess β chains —> Hb H (5-40% total Hb) - small amount of Hb Bart may be present - variable features - exacerbated by pregnancy / infection - Complication: Hypersplenism —> Splenectomy indicated 3. Hb Bart’s hydrops fetalis (4 gene deletion) - no α-chain found - incompatible with life (unless start vigorous treatment early in fetal life) - excess γ chains —> Hb Bart’s (γ4) - edematous fetus due to ***heart failure (a result of anaemia) and ***liver dysfunction —> condition diagnosed with ultrasonography, confirmed with prenatal genetic diagnosis Molecular genetics - 90% due to ***deletions of DNA (vast majority removal of both α-genes from α-gene cluster, single α-gene deletions less common) - 10% due to ***non-deletional type (***Hb Constant Spring, Hb Quong Sze) —> more severe S/S, complications

Answer 7

Reduced (β+) / Absent (βo) synthesis of β-globin chain - β chain production only becomes predominant in post-natal period —> severe β-Thalassemia (β-Thalassemia major) manifest only when patient ***>= 3 months old (***大個d先見到Symptoms) 1. β-Thalassemia Trait / Minor - ***Heterozygous for βo / β+ - Asymptomatic - slightly ↓ Hb level - ***↓ MCV (Microcytic), ↓ MCH (Hypochromic) - ***↑ RBC count - ***↑ Hb A2 (MOST important diagnostic feature for heterozygous β-Thalassemia) - many have minor ↑ Hb F 2. β-Thalassemia Major (Cooley’s anaemia) - total absence / marked reduction of β-globin chains —> excessive α-globin chains precipitate out in RBC precursor cells —> extensive intramedullary destruction of RBC precursors (***Ineffective erythropoiesis) —> ***marked expansion of BM —> ***Hyperproliferative anaemia - ***↑ destruction of peripheral RBC (***Haemolytic element) - ***↑ Hb F level —> ***selective survival advantage (explain high level of Hb F) Blood film: - Marked RBC ***Anisocytosis (***↑ RDW) + ***Poikilocytosis - ***Hypochromic - ***Numerous nucleated RBC (Normoblast) Homozygous βo: - complete absence of Hb A - small amount of Hb A2 - ***HbF remainder (98%) Clinical features: 1. ***Thalassaemic facies 2. Protuberant abdomen (***Hepatosplenomegaly) 3. ***Poor musculoskeletal development 4. Complications e.g. Recurrent infections, spontaneous fractures, hypersplenism, leg ulcers, extramedullary haemopoiesis Treatment: - ***Blood transfusion - ***Iron overload —> Treat with ***Iron chelation therapy (Deferoxamine) ***3 Major genetic modifiers of disease severity (can be modified to milder clinical severity e.g. Thalassemia Intermedia): —> Nature of β-globin gene defect (whether mutation associated with severe phenotype) —> Configuration of α-globin gene locus (affect degree of α/β globin gene imbalance) —> Genetic determinants of Hb F level 3. Thalassemia Intermedia (Non-transfusion dependent Thalassemia (NTDT)) - symptomatic but milder than β-Thalassemia Major —> β-Thalassemia Intermedia —> Hb H disease —> Hb E β Thalassemia Hb E: - Haemoglobinopathy - point mutation of β gene at position 26 —> a.a. change from Glutamate to Lysine —> Abnormal Hb (Hb E) - mRNA of Hb E —> unstable —> ***underproduced abnormal Hb —> thalassaemic presentation - Heterozygous HbE —> Mild Microcytosis, No/Minimal anaemia (some have totally normal CBP) - Homozygous HbE —> Microcytosis, Mild anaemia - Compound heterozygous HbE + β-Thalassaemia —> Thalassaemia Intermedia syndrome, ***Splenomegaly, other complications Molecular genetics of β-Thalassaemia - Point mutations (NOT gene deletions) - Own unique set of mutations among different races

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Haematology JC048: Family History Of Anaemia: Inherited Causes Of Anaemia, Haemolytic Anaemia, Aplastic Anaemia Flashcards

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