Haematology - Anaemia: IDA, Thalassemia, Megaloblastic anemia, Polycythemia Flashcards

Question

Causes of ineffective erythropoiesis (erythroid hyperplasia)

Answer 1

 Megaloblastic anaemia  α and β-thalassaemia (\*usu ↑reticulocyte count)  Myelodysplastic syndromes  Sideroblastic anaemia and lead poisoning  Congenital dyserythropoietic anaemia (CDA)

Answer 2

**Intrinsic RBC defects:** □ Enzyme deficiencies, eg. G6PD def □ Hb defects, eg. thalassemia, Hb-pathy □ Membrane defects, eg. hereditary spherocytosis, elliptocytosis **Extrinsic RBC defects:** □ Mechanical, eg. mechanical heart valve □ Infections, eg. malaria □ Immune: warm- or cold-reacting, drug-induced, alloimmune □ Microangiopathic haemolytic anaemia (MAHA), eg. DIC, TTP **Hypersplenism**

Answer 3

** GI bleeding (most common in general)** ** Menorrhagia (most common in young F)**  Haematuria (uncommon)  Trauma and surgery  Respiratory tract bleeding  Occult bleeding

Answer 4

 Iron deficiency anaemia  Thalassaemia intermedia and major  Anaemia of chronic disease/inflammation (some)  Sideroblastic anaemia (congenital and acquired) and lead poisoning

Answer 5

 Acute bleeding (haemodilution) and early/recovering iron deficiency anaemia  Anaemia of chronic disease/inflammation (ACD)  Marrow suppression, eg. cancer, aplastic anaemia, infection  Chronic renal insufficiency  Microcytic anaemia masked by reticulocytosis  Haemolytic anaemia (can be normal or high)

Answer 6

\*Causes of macrocytosis without anaemia include Reticulopenic, macrocytic RBC:  Hypothyroidism and liver disease due to lipid abnormalities  Chronic alcoholism  Drugs interfering with nucleic acid metabolism, eg. zidovudine, methotrexate, trimethoprim, phenytoin, TKIs) Cell swelling and water retension:  CO2 retention (e.g. COPD)

Answer 7

Polycythaemia: defined as abnormal elevation of haemoglobin and/or haematocrit in peripheral blood □ Increased haemoglobin as defined as \>16.5g/dL (M) and \>16.0g/dL (F) □ Increased haematocrit as defined as \>49% (M) and \>48% (F)

Answer 8

□ Relative polycythaemia: spurious ↑Hb/Hct due to loss of plasma volume (i.e. haemoconcentration) → Causes: diuretics, vomiting/diarrhoea, obesity, heavy smoking, Gaisbock syndrome □ Absolute polycythaemia: true ↑Hb/Hct due to ↑total body RBC mass, which can be divided into → Primary polycythaemia due to autonomous production of RBCs → Secondary polycythaemia due to ↑serum erythropoietin

Answer 9

Primary (EPO = ↓/0) **Congenital**: erythropoietin receptor mutations, congenital methaemoglobinaemia **Polycythemia rubra vera** (due to JAK2 mutation) Other **myeloproliferative neoplasms** (due to JAK2, MPL, CALR mutations)

Answer 10

Secondary (↑EPO) **Hypoxia-associated ↑EPO**: chronic pulmonary disease, cyanotic heart diseases, obstructive sleep apnoea, high altitude, chronic CO poisoning (incl heavy smoking) **Inappropriately increased erythropoietin:** Renal diseases: renal artery stenosis, hydronephrosis, cysts, post-transplant **EPO-producing tumours**: HCC, RCC, haemangioblastoma, phaeochromocytoma, uterine leiomyoma **Performance-enhancing drugs in athletes**, eg. recombinant erythropoiesis-stimulatint agents, autologous transplantation, androgens/anabolic steroids

Answer 11

Symptoms of primary myeloproliferative neoplasms: → Hyperviscosity: chest/abd pain, myalgia/weakness, fatigue, headache, ↓VA, slow mentation → Thrombosis/bleeding: thrombosis at unusual sites, excessive bleeding/bruising → PV-related: unexplained fever, sweats, weight loss, aquagenic pruritus, erythromelalgia, gout

Answer 12

□ **CBC, PBS**: ↑other lineages, immature WBC, leucoerythroblastic picture → suggests MPN □ **Urinalysis, L/RFT**: for possible renal diseases and HCC □ **Pulse oximetry** for tissue hypoxia □ **Serum EPO**: low or absent serum EPO → relatively specific for MPN and PV □ **JAK2 testing for V617F mutation in PV** □ Further screen for 2o causes if JAK2 mutation negative + no clear 2o causes → **Total red cell mass (by radiolabeling RBCs)** to confirm absolute erythrocytosis → **Sleep study for OSA** → USG abdomen for **abdominal tumours (ectopic EPO)** → Lung function tests for **respiratory diseases** □ Bone marrow aspirate + trephine if suspicious of **myeloproliferative neoplasms**

Answer 13

Defects in globin synthesis: Thalassaemia Thalassaemic Hbpathies, eg. HbE Defects of iron metabolism: Iron-refractory iron deficiency anaemia DMT1 mutation Atransferrinaemia Defects in porphyrin synthesis: Inherited sideroblastic anaemia

Answer 14

**Defects in globin synthesis** Thalassaemia Thalassaemic Hbpathies, eg. HbE **Defects of iron metabolism** Iron-refractory iron deficiency anaemia DMT1 mutation Atransferrinaemia **Defects in porphyrin synthesis** Inherited sideroblastic anaemia

Answer 15

Iron deficiency anaemia (IDA) Anaemia of chronic disease (majority normocytic) Acquired sideroblastic anaemia due to lead poisoning, alcohol, drugs Copper deficiency (some) Zinc toxicity

Answer 16

□ **↑RDW**: non-specific □ **RBC count:** ↓ in Iron deficiency anaemia (IDA), N/↑ in thalassaemia □ **Iron profile and Hb studies** for IDA and thalassaemia respectively □ **Blood smear:** → Thalassaemia: marked anisopoikilocytosis (↑variation in RBC size/morphology) incl target cells, teardrop cells → Fe def: anisopoikilocytosis (↑variation in size and shape), but many have normal-looking RBCs → Anaemia of chronic disease: majority have normal sized, shape RBCs, but a subset may have microcytosis (accounts for ↓MCV) → Sideroblastic anaemia: ringed sideroblasts with a ring of iron granules surrounding nucleus → Lead poisoning: characterized by basophilic stippling (denatured RNA) □ **BM examination**: rarely necessary if isolated McHc anaemia

Answer 17

Function: Internalize ferroportin in gut lumen \>\> decrease absorption of iron from gut into blood \>\> decrease serum iron High hepcidin state: * Inflammation/ Infection \>\> inflammatory cytokines \>\> Induce hepcidin secretion from liver Low hepcidin state: * Anaemia * Hypoxia * Low iron stores

Answer 18

High hepcidin state: Infection/ Inflammatory state Low stomach acid (acid for reduction of iron): Gastrectomy, Long-term PPI use, Autoimmune gastritis Low reducing agent: e.g. low Vitamin C Iron overload Duodenum/ small intestine pathologies/ resection causing malabsorption

Answer 19

Internal cycling of iron: □ Transferrin (Tf): iron transported in plasma bound to transferrin → each Tf binds 2× Fe3+ □ Utilization: used to form erythroid precursors in BM □ RBC cycling: RBCs broken down by reticuloendothelial system (liver, spleen) and iron returned into plasma as transferrin-bound form Storage of iron: □ Form: ferritin and haemosiderin □ Site: reticulo-endothelial system (RES), i.e. macrophages of liver, bone marrow and spleen → derived almost entirely from phagocytosis of senescent erythrocytes or defective developing red cells

Answer 20

**Frank bleeding** *GI bleeding *Trauma- and surgery-related bleeding *Severe Haemoptysis *Menorrhagia **Occult bleeding/iron loss:** Iatrogenic: frequent blood donation, excessive blood taking, haemodialysis Occult/underestimated bleeding **Functional Iron deficiency - Post- EPO treatment** **Urinary and pulmonary haemosiderosis** **Malabsorption**: H. pylori-related atrophic gastritis, coeliac disease, gastrectomy/gastric bypass, autoimmune gastritis Inadequate intake (extremely rare, iron store lasts years)

Answer 21

Absolute deficiency: absence/severely ↓iron stores in RES Functional deficiency (iron-restricted erythropoiesis): adequate Fe for normal erythropoiesis but iron is not available for RBC, due to - ACD: ↑hepcidin → ↓ferroportin expression → ↓iron release into circulation - EPO: release into circulation not rapidly enough to respond to EPO

Answer 22

CBC: * *McHc anaemia** with ↓RBC count, ↓reticulocyte count * *Reactive thrombocytosis** due to ↑stimulation of platelet precursors by ↑EPO PBS: **hypochromic microcytic red cells with anisopoikilosis** May be dimorphic in concurrent megaloblastic anaemia or iron supplement treatment BM: not routinely done Active erythropoiesis but **poorly haemoglobinized (micronormoblastic)** Iron stain shows **↓/absent marrow iron stores**

Answer 23

Iron studies: **↓serum iron**: influenced by inflammatory state, dietary intake, diurnal variation → NOT diagnostic **↑serum transferrin/TIBC but ↓Tf saturation**: \<16% compatible with IDA (less specific than ferritin) **↓serum ferritin**: diagnostic of IDA (most Spec) - FN: acute phase reactant → FN if inflammatory state - FP: very rarely, hypothyroidism, vit C deficiency **↑soluble Tf receptor (sTfR):** reflects ↑erythropoiesis

Answer 24

□ Hx: **bleeding Hx** (GI, urine, menses, bleeding disorders), blood donation, RFs for GI cancers, drug Hx (NSAID, anticoagulants), previous scopes □ P/E: as appropriate, include PR exam □ Ix: **look for occult GI bleeding first** → **FOBT×3** if \>50y → **Stool examination** × **ova/cyst** in tropical areas → **Upper endoscopy then colonoscopy** if either IDA or FOBT+ → Consider non-GI and small bowel causes if endoscopy –ve

Answer 25

□ Treat underlying cause □ **Oral iron for majority of patients** Dosing: 150-200mg elemental iron per day until Fe profile normalized (~3-6mo) Choice: Iron sulphate tablet, ferrum hausmann chewable tablet Effect: ↑Hb by ~1g/dL every 7-10d with reticulocyte response in 1w S/E: GI S/E very common → metallic taste, dyspepsia, Nausea and vomiting, altered bowel habits, black stools □ **IV iron if refractory to oral iron, with severe ongoing blood loss or malabsorption** Choice: ferric carboxymaltose, ferric gluconate, ferumoxytol, iron sucrose, iron isomaltoside Advantage: effective, rapid correction, ensure good compliance, no GI S/E □ **Transfusion if angina, heart failure, cerebral hypoxia** or **Hb \<7g/dL**

Answer 26

Pathogenesis: result from body’s normal response to limit availability of iron for invading microbes □ Dysregulated iron homoeostasis: **Inflammation/ LPS in bacterial infection \>\> ↑ IL-6 and other cytokines \>\> Increase transcription and translation of Hepcidin in liver \>\> Hepcidin internalize ferroprotein in gut mucosa and macrophages in RES \>\> Decrease GI absorption of Fe and MQ release of Fe** □ **Immune effect on erythropoiesis:** → ↓EPO secretion by kidneys → ↓erythropoiesis → ↓RBC survival by ↑free radical formation → ↑RBC damage → ↑RBC turnover

Answer 27

□ Systemic inflammatory/ Autoimmune disease, eg. RA, SLE □ Infections: related to disease severity □ Cancer, esp haematological malignancies □ Chronic organ impairment: heart failure, COPD □ Chronic solid-organ rejection after transplant □ Chronic Kidney disease/ inflammation

Answer 28

□ CBC: Mild NcNc anaemia, can be McHc (\<1/4) with low reticulocyte count □ PBS: relatively uniform population of normocytic RBCs w/o evidence of haemolysis □ BM: iron stain shows N/↑ iron in MQ, ↓/no iron in erythroid precursors (both –ve in IDA) □ Iron studies: ↓serum iron, ↓total Tf/TIBC, ↓Tf saturation, N/↑ ferritin □ ↑CRP/ESR

Answer 29

Differentiating from or identifying concomitant Fe deficiency: → Suggestive features: MCV (↓ in IDA, Normal in ACD), Ferritin (↓ in IDA, ↑ in ACD) → Differentiating features: sTfR (↑ in IDA, ↓ in ACD), hepcidin (↓ in IDA, ↑ in ACD) → Therapeutic trial of iron may be given in difficult situations

Answer 30

Genetics: HBA1/2 code for same α-globin chain in α-gene cluster (ch16) One person has four genes → α0 (0 α genes) to α4 (4 α genes) presents with a spectrum of varying disease severity Majority are deletions (90%) Pathogenesis: mutated HBA1/2 resulting in ↓α-globin synthesis α-globin required for production of both fetal (α2γ2) and adult (α2β2) Hb → affects both fetus and adults Effects: → Fetus: excess γ chains form Hb Bart’s (γ4) → Adults: excess β chains form Hb H (β4) → Result: abnormal HbH tetramer unstable → ↑haemolysis

Answer 31

A-thal. minima (silent carrier) - 1 gene deletion, i.e. αα/α-; no effect on MCV and Hb analysis A-thal minor (Thal. trait) - 2 gene deletions, i.e. αα/-- (SE Asians), α-/α- (Blacks); may have hypochromia/microcytosis with mild anaemia A-thal intermedia (HbH disease) - 3 gene deletions, i.e. α-/-- → excessive HbH (β4); Transfusion-dependent, moderate McHc anaemia A-thal major (Hb Bart's hydrops fetalis) - 4 gene deletions, i.e. --/-- → Hb Bart’s (γ4) in fetal blood; Severe fetal anaemia culminating in hydrops fetalis (fetal high-output HF)

Answer 32

Genetics: **single HBB gene** code for β-globin chain in β-gene cluster (ch11) Majority due to **point mutations** instead of deletions **Majority compound heterozygotes** → clinical severity depends on combination and nature of mutation in each of the two HBB gene Pathogenesis: → α-globin only required for production of adult HbA, HbA2 → only becomes manifest at ≥6y/o → α4 tetramer is unstable, precipitate into inclusion bodies → damage RBC membrane and ineffective erythropoiesis → Free α-chains in peripheral RBCs → aggregate and precipitate → ↑haemolysis Other sources of variability in clinical severity: - Genetic determinant of HbF level: HbF can compensate partly for function of HbA - Configuration of α cluster: excessive α alleles → ↑imbalance → ↑clinical severity

Answer 33

β-thal minor (thal trait) *β/β+ or β/β0; asymptomatic mild anaemia with marked microcytosis β-thal intermedia *β+/β+, β+/β0 (majority) *transfusion-independent anaemia (β-thal minor with exacerbating genetic variant (eg. triplicated/quadriplicated α genes, HbE) or β-thal major with alleviating genetic variant are also classed as intermedia) β-thal major (Cooley’s anaemia) *β0/β0, β0/β+ or β+/β+ with very low β-chain production (rare) *lifelong transfusion-dependent anaemia with onset at 6-12mo *Hemolytic symptoms, progress to high-output HF, FTT, Infection, iron overload…etc

Answer 34

**Splenomegaly** due to extramedullary haematopoiesis and haemolysis * Common in thal major, some thal intermedia * Hypersplenism may exacerbate situation **Hepatomegaly** due to extramedullary haematopoiesis and iron overload * Early-life symptom, cirrhosis with long iron overload **Nephromegaly** **Jaundice, dark urine, pigment gallstones**

Answer 35

Childhood onset in those with chronic transfusion w/o chelation, adult onset in those with intermedia or transfusion w/ chelation **Chronic liver disease**: hepatomegaly, cirrhosis, HCC **Endocrine and metabolic abnormalities** due to iron deposits in endocrine glands  **Hypogonadism**: delayed puberty, oligo/amenorrhoea, ↓libido, ↓2o sexual features  **Hypothyroidism**  **Insulin resistance** during 2nd decade of life and DM (bronze diabetes) **Leaden-grey skin pigmentation** **Infection by sideroophilic organisms**, eg. L. monocytogenes, Yersinia enterolitica, Salmonella enterica, Klebsiella pneumoniae and E. coli

Answer 36

Due to marrow expansion from ineffective erythropoiesis * ‘Chipmunk’ facies * Change in body habitus: Convex ribs and limb bones, Shortened limbs * Osteopenia/ Osteoporosis * Growth impairment/ delay * Bony masses (expanding marrow break bone cortex

Answer 37

Cardiovascular: * Major cause of death in thalassaemia * Heart failure * Bradyarrhythmia * Thromboembolism due to hypercoagulation Pulmonary: * Pulmonary hypertension * Asymptomatic pulmonary dysfunction: e.g. restrictive ariway/ obstructive defects, decrease VO₂ max…etc

Answer 38

CBC: * McHc anaemia with marked ↓MCV, N/↑ reticulocyte13 and ↑RBC * Mentzer index (MCV/RBC count): \>13 = IDA, \<13 = thalassaemia trait PBS: * profoundly hypochromic microcytic red cells with bizarre RBC morphology (target, pencil cells) Markers of haemolysis: ↑LDH, ↑unconj bilirubin, ↓haptoglobin, ↑methaemalbumin, DAT –ve Iron studies: ↑serum iron, ↑Tf sat, ↑ferritin due to iron overload Haemoglobin studies: Hb electrophoresis for beta Supravital stain for alpha (HbH) DNA-based genotyping

Answer 39

Folate supplementation Low iron diet, eg. avoid red meat, spinach Regular transfusion: mainstay of treatment * hypertransfusion to maintain stable Hb level and suppress ineffective erythropoiesis * use leukodepleted packed cells to ↓FNHTR and TRALI Iron chelation: for B-thal major Splenectomy Allogeneic HSCT

Answer 40

* *Abnormal DNA metabolism** * *- Vitamin B12 deficiency** * *- Folate deficiency** - Copper deficiency - Drugs, including antiretroviral, cytotoxic agent, immunosuppressant, TKI **Primary marrow disorder** * **Myelodysplastic syndrome (esp in elderly)** * Congenital dyserythropoietic anaemia * Sideroblastic anaemia (some) * LGL leukaemia **Reticulocytosis:** * **Haemolytic anaemia** * **Stress-induced erythrocytosis** **Lipid abnormalities** * Liver disease * Hypothyroidism Others: * *Alcohol abuse** * *Multiple myeloma** and other plasma cell dyscrasia

Answer 41

CBC: * *Severe macrocytosis (MCV \>110-115) → almost exclusively megaloblastic anaemia** * *≥1 additional cytopenias → Primary BM problem, eg. megaloblastic anaemia, MDS** PBS: → Megaloblastic anaemia: macro-ovalocytes, hypersegmented neutrophils (\>5 lobes) → Liver disease: target cells → Myelodysplastic syndrome: hypolobulated or hypogranular, dysplastic neutrophils □ Ix for cause: → Reticulocyte count: ↑ in haemolysis, ↓ in BM disorders → Serum B12 and folate (± copper if gastric bypass) for megaloblastic anaemia → TFT for hypothyroidism → LFT for liver disease □ BM examination: only when uncertain diagnosis or pancytopenia

Answer 42

Consider factitious cause, eg. RBC clumping, osmotic swelling with hyperGly or prolonged storage, EDTA tube

Answer 43

Megaloblastic anaemia: due to **delay in maturation of nucleus relative to cytoplasm** □ Result from **defective DNA synthesis** → delayed M phase entry → continuous ↑cytoplasmic size without mitosis (**nuclear-cytoplasmic dyssynchrony**) □ D**eficiency in vitamin B12 (vast majority) or folate**

Answer 44

Found in leafy vegetables (spinach, broccoli, lettuce), fruits (banana, melon) and animal protein (liver, kidney) Seldom deficient with any normal diet in developed countries (\>50μg/d) Absorbed folate converted to methyl tetrahydrofolate (THF) by small intestines then transported inside plasma Total body stores small → deficiency occur in weeks

Answer 45

Found in meat, fish, eggs, milk Seldom deficient (\>1μg/d) unless vegan diet Bound to intrinsic factor (IF) produced by gastric parietal cells → IF-B12 complex absorbed in terminal ileum → transported in plasma while binding with transcobalamin II Liver has 3-year stores of B12 and recycles B12 via enterohepatic cycling → takes years before deficiency manifest

Answer 46

1. **Methyl B12** serves as co-factor in **methylation of homocysteine into methionine** with demethylation of **methyl THF into THF** 2. **THF converts to 5,10-methylene THF**, serves as coenzyme for **conversion of dUMP into dTMP for DNA synthesis** 3. **Deoxyadenosyl B12** also serves as co-enzyme in conversion of **methylmalonyl CoA into succinyl CoA**

Answer 47

**Dietary insufficiency:** usually only in poor, elderly, alcoholics **Malabsorption** **High demand** due to pregnancy, haemolytic anaemia, myeloproliferative diseases **Antifolate agents**, eg. trimethoprim, OCP, pyrimethamine, phenytoin, methotrexate

Answer 48

Dietary insufficiency in long-term vegans **Gastric causes:** Pernicious anaemia Status post-gastrectomy: 10-20% by 5y **Bowel causes:** SBIO with bacteria consuming B12 due to motility disorder, ↓γ-globulin, stagnant loop Terminal ileal pathology, eg. Crohn’s disease Fish tapeworm

Answer 49

# Define: Autoimmune disorder with **atrophic gastric mucosa and loss of parietal cells** Pathogenesis: **anti-IF or anti-parietal cell Ab** (a/w chronic atrophic gastritis) **attack parietal cells → ↓intrinsic factor production** Risk factors: Autoimmune diseases Complications: Chronic atrophic gastritis, Gastric Cancer (achlorhydria) Diagnosis: presence of auto-antibodies - **Anti-Intrinsic Factor Ab and Anti-parietal cell antibody**

Answer 50

* Anaemia S/S * Jaundice * **Oral: atrophic glossitis, oral ulcers, angular stomatitis** * **Skin: greying of hair, skin hyperpigmentation** Neuropsychiatric: * **Subacute combined degeneration of cord:** affects dorsal (DC-ML) and lateral columns (CST) * Peripheral neuropathy: classically ↑knee jerk (from SCD) + ↓ankle jerk (from PN) * depression, irritability, cognitive slowing, dementia, psychosis

Answer 51

1. CBC: macrocytic anaemia (typically \>115fL) with mild leukopenia/thrombocytopenia + ↓RET 2. PBS: macro-ovalocytes + hypersegmented neutrophils 3. Markers of haemolysis 4. **Serum B12 level: deficient \<200pg/mL** 5. **RBC folate: \<150ng/mL** 6. **Anti-IF, anti-parietal cell Ab for pernicious anemia** 7. **Metabolite testing (MMA, homocysteine)** 8. **Upper endoscopy for atrophic gastritis and CA stomach**

Answer 52

Management: by replacement of B12 and/or folate Urgent Folate with B12 supplement for severe anaemia/ symptomatic- Parental or oral Oral B12 supplement: vegan diet require lifelong replacement Oral folate supplement: indicated for folate deficiency and other conditions e.g. haemolytic anaemia with poor RBC survival

Answer 53

**S/S anaemia**: SOB on exertion, Pallor, Tiredness, Dizziness , Palpitation **Pica**: desire for or compulsion to eat substances not fit as food, eg. dirt (geophagia), ice (pagophagia) **Restless leg syndrome (RLS)** **Nail changes: brittle nails, koilonychias** (spoon-shaped nails) **Epithelial/mucosal changes:** → **Atrophic glossitis** with loss of tongue papillae ± tongue pain, dry mouth → Cheilosis (**angular cheilitis**) → **Oesophageal webs** (rare) → termed Plummer-Vinson syndrome when a/w dysphagia

Haematology - Anaemia: IDA, Thalassemia, Megaloblastic anemia, Polycythemia Flashcards

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