Week 4 - RBC Disorders Flashcards
Define anaemia.
• Decreased red cell mass affecting tissue oxygenation.
• Diagnosed using haematocrit or Hb levels (characterised by low Hb* or low HCT).
*Hb may be high but not functioning properly → clinical features of anaemia except pallor e.g. smokers (due to CO poisoning - Hb irreversibly bound to CO).
What are the 4 main causes of anaemia?
- Failure of erythrocyte production.
- Loss of erythrocytes.
- Abnormality of erythrocytes.
- Destruction of erythrocytes.
Outline the classification of anaemia.
Decreased production - deficiency anaemia
• Nutrient deficiency:
- Iron deficiency (IDA)/Megaloblastic (MBA).
• Haemopoietic cell defect:
- Anaemia of chronic disorders (ACD).
- Aplastic anaemia (AA).
- Dysplastic anaemia. Myelodysplastic Syndromes.
Increased loss/destruction - haemolytic anaemia
• Blood loss anaemia - acute/chronic - bleeding.
• Haemolytic anaemia - congenital/acquired.
▫ Acquired/external injury:
- Immune AIHA (warm/cold), mechanical, drugs, infections (e.g. clostridia, septicaemia) and parasites (e.g. malaria).
▫ Congenital/internal RBC defect:
- Defective membrane (spherocytic anaemia).
- Defective haemoglobin (qualitative - abnormal function: sickle cell anaemia. Quantitative - abnormal amount: Thalassemia α,β,δ).
- Defective enzyme (G6PD deficiency).
Outline haemopoiesis.
- Formation of blood cells.
- Starts from a common precursor cell.
- In foetus, occurs in yolk sack, liver & spleen.
- In children, occurs in distal long bones & axial skeleton.
- In adults, this occurs in the axial skeleton.
- In disease, can revert to use of early organs.
Describe RBC development.
- Stem cell → Committed cell → Developmental pathway (ribosome synthesis, Hb accumulation, ejection of nucleus).
- Blast early → Intermediate → Late → Reticulocyte → RBC.
- RBCs produced through maturation of erythroblasts gradually losing the nucleus and dividing multiple times finally giving rise to RBC.
- Cells dividing at each step, nucleus gradually becoming smaller.
- Gradual accumulation of Hb replacing all the other constituents of the cell.
- When there is no further division → nucleus ejected from cell.
- Mature RBC - Hb and enzymes, no cellular organelles.
What are 2 important constituents for RBC formation?
- Hb - iron required for Hb production in cytoplasm. Deficiency of iron → IDA.
- DNA - B12 and folate required for DNA synthesis. Without DNA, cells cannot fully mature and divide → MBA.
Outline the normal values for RBC indices.
- Hb - amount of Hb per RBC - 15 +/- 2.5 (grams/dl).
- RBC count - total no. of RBCs - 4.8 +/- 1 x 10^12/L.
- HCT/PCV - packed cell volume - proportion of blood occupied by RBCs - 0.47 +/- 0.07 (lit/lit (%)).
- MCV - average volume of RBCs - 80-100fL.
- MCH - average mass of Hb per RBC - 30 +/- 2.5 (picograms/L).
- MCHC - average concentration of Hb per RBC - 31.6-34.9 (grams/100mL).
- RDW - variation in RBC size/volume - 11.5-14.5%.
Outline the aetiology of iron deficiency anaemia.
- Is the most common cause of anaemia.
- Bleeding - commonest e.g. blood loss from GIT (bowel cancer, PUD, gastritis, NSAID/aspirin use, hookworm, IBD, diverticulitis, polyps), menstrual loss, gynaecological, multiple pregnancies, parasites.
- Nutrition - dietary deficiency. Good sources of iron are meat, fish, cabbage, broccoli, peas, beans, iron-enriched cereals and bread.
- Increased need - stores may be inadequate during periods of increased growth e.g. teenage years, pregnancy (growing foetus)/infancy.
- Malabsorption - iron may be ingested but inadequately absorbed from GIT.
- In developing countries, mainly due to blood loss from parasitic worm infestation + malnutrition.
- In developed countries, mainly due to blood loss from malignancy.
Describe the pathogenesis of iron deficiency anaemia.
Decreased iron → decreased Hb and excess cell division (normal DNA) leading to small RBCs (decreased MCV).
- Decreased iron stores.
- Decreased Hb synthesis (∴ only affect RBC).
- Delayed maturation of erythroblasts therefore remains in bone marrow for longer time (cytoplasmic).
- Decreased cytoplasm maturation → more divisions ∴ smaller cells (microcytes).
- Decreased Hb content (hypochromia).
- Anaemia.
Identify the clinical features of iron deficiency anaemia.
- Tiredness
- Weakness
- Lethargy
- Pallor
- Glossitis
- Chelitis
- Stomatitis
- Koilonychia
- Dysphagia
- Dyspnoea (on exertion)
- Palpitations, chest pain → heart failure → pedal oedema
Describe the morphology of iron deficiency anaemia.
- Microcytic, hypochromic RBCs - excess cell division, low Hb.
- Anisopoikilocytosis - varying supply, abnormal haemopoiesis.
- Pencil cells - idiopathic.
Outline the investigations for iron deficiency anaemia.
FBC:
• Hb and MCV decreased - microcytic anaemia.
• MCH and MCHC decreased - hypochromic RBCs.
• RDW increased - anisocytosis (variation in size).
• Poikilocytosis - pencil and cigar poikilocytes characteristically seen (abnormally shaped RBC).
• Platelets increased - a thrombocytosis may be present.
• WCC normal - normal leucocytes.
Iron studies: • Serum iron decreased. • Transferrin increased. • Total iron binding capacity increased. • Transferrin saturation decreased. • Serum ferritin decreased - best test to confirm IDA.
Describe the management of iron deficiency anaemia.
- Oral iron supplementation.
- If the patient has angina, heart failure or evidence of cerebral hypoxia - should have transfusion.
- Investigate cause (i.e. bleeding due to hookworm) and treat appropriately.
Outline megaloblastic anaemia.
• Second most common type of anaemia.
• Due to vitamin B12 (cobalamin) and/or folate deficiency.
- Vitamin B12 is synthesised only by microorganisms or come from animal food (i.e. meat, fish, dairy products).
- Folate is only found in uncooked plant food (yeast, spinach, other greens, mushrooms, nuts).
• The common feature of MBA is a defect in DNA synthesis that affects the rapidly dividing cells in the bone marrow.
• Affects all rapidly dividing cells (eg. epithelium).
• Can have pure folate or pure vitamin B12 deficiency but a combination is most common.
Outline the aetiology of megaloblastic anaemia.
- Malnutrition - vegans/elderly due to impaired digestion and extraction of vitamin B12 from ingested food.
- Autoimmune - pernicious anaemia - intrinsic factor antibodies causing atrophy of the gastric cells → failure of absorption of vitamin B12.
- Gastrectomy (partial/total), ileal resection.
- GI disorders - gastritis, chronic gastroenteritis, IBD.
- Malabsorption syndromes - tropical sprue, blind loop syndrome.
- Cancer/cancer therapy - cancers growing utilise all the available B12 and folate, patients may suffer deficiency. Many of the anti-cancer drugs are also inhibitors of folate (folate is necessary for cell division).
Describe the pathogenesis of megaloblastic anaemia.
Both B12 and folate necessary for DNA synthesis. B12 and/or folate deficiency → decreased DNA → decreased cell division → decreased cells - all cells.
- Decreased vitamin B12 and/or folate.
- Decreased DNA synthesis.
- Delayed maturation of erythroblasts (nucleus).
- Increased cell size (macrocyte).
- Normal Hb content (normochromia), ↓ RBC number, ↓ WBC number (pancytopenia).
- Anaemia & Pancytopenia.
- As it is due to a defect in DNA, it affects all cell lines.
Identify the clinical features of megaloblastic anaemia.
• May be asymptomatic (detected by increased MCV on routine blood count).
• Symptoms of anaemia.
• GIT symptoms - anorexia, weight loss, diarrhoea or constipation, glossitis, chelitis, mild jaundice (unconjugated - due to haemolysis).
• Skin pigmentation (pallor/jaundice).
• Bruising/mucosal haemorrhage and susceptibility to infections (particularly of the respiratory and urinary tract) - thrombocytopenia and leukopenia may occur.
• Lesions of nervous system due to vitamin B12 deficiency.
- Brain: lesions in the white matter → dementia.
- Peripheral nerves: degeneration of myelin sheaths.
- Spinal cord: lesions of corticospinal tracts and posterior columns.
• Mild fever in severely anaemic patients.
• Infertility in both men and women.
Describe the morphology of megaloblastic anaemia.
- Oval macrocytic RBCs, pancytopenia - decreased cell division.
- Anisopoikilocytosis - haemolysis.
- Hypersegmented neutrophils - large cells/megaloblasts (in bone marrow).
Outline the investigations for megaloblastic anaemia.
FBC: • Hb decreased, MCV increased. • RBC count decreased. • MCH high, MCHC normal - total Hb per RBC is high but the percentage of space occupied by Hb is the same (concentration is the same). • WBCs, platelets decreased.
- S-vitamin B12 level.
- S-folate level, RBC folate.
- Iron studies as a mixed deficiency may be present.
Antibodies:
• Intrinsic factor antibody
- Type I - blocking - Ab prevents the combination of IF and vitamin B12.
- Type II - binding - Ab prevents the attachment of IF to ileal mucosa.
• Parietal cell antibody.
Evidence for haemolysis:
• Urine - increased urobilinogen, haemosiderinuria.
• Blood - increased unconjugated bilirubin, decreased haptoglobin level, increased lactate dehydrogenase (LDH).
Describe the management of megaloblastic anaemia.
Vitamin B12 deficiency:
• Vitamin B12 injections - 1000μg weekly for a month, then monthly thereafter.
• Intranasal vitamin B12.
• Oral vitamin B12 - 1000μg daily for nutritional deficiency.
Folate deficiency:
• Folic acid 1-2mg orally daily.
• When treatment is commenced for vitamin B12 deficiency, or a mixed vitamin B12 and folate deficiency, the patient should receive a loading dose of Vitamin B12 prior to commencement of folate therapy, to prevent precipitation of subacute combined degeneration of the cord.
Outline pernicious anaemia.
- Autoimmune atrophic gastritis in aged (vitamin B12 deficiency anaemia due to autoimmune atrophic gastritis).
- IF and parietal cell antibody (type I, II, III).
- Reduced tetra-hydrofolate (FH4).
- Decreased DNA synthesis.
- Severe lack of IF due to gastric atrophy. IF is required for absorption of vitamin B12 in the ileum.
- Autoimmune gastritis - antibodies against intrinsic factor and parietal cell antibody which block vitamin B12 absorption giving rise to decreased tetra-hydrofolate (folic acid derivative) → results in decreased DNA synthesis.
• Clinical - MBA plus neurological deficits (spinal dorsal tract). Loss of proprioception.
Outline the aetiology of anaemia of chronic disease.
- Impaired red blood cell production associated with chronic disease.
- Is one of the most common types of anaemia.
- Is frequently associated with other forms of anaemia.
• Aetiology: chronic infections, inflammatory conditions, malignancy and anaemia of renal disease* (anaemia seen in patients suffering from many other chronic disorders).
• Associated with a range of chronic inflammatory diseases:
- Chronic microbial infections (eg. osteomyelitis, bacterial endocarditis, lung abscess).
- Chronic immune disorders (eg. rheumatoid arthritis, regional enteritis).
- Neoplasms.
Describe the pathogenesis of anaemia of chronic disease.
- IFN, TNF, IL block iron transfer from macrophage store to RBC.
- Decreased erythropoietin*
- Any disorder → produces inflammation → inflammation produces inflammatory mediators → block iron transfer in the bone marrow from the macrophage to RBC.
- Also enhances RBC phagocytosis by the macrophages. • Also inhibits EPO production.
- All this together suppresses the production of RBCs and block the iron transfer. Functional iron deficiency.
• Occurs in inflammatory conditions, infection, tissue injury and malignancy, all of which have ↑levels of inflammatory cytokines and of the acute phase protein, hepcidin. The anaemia develops in part due to inadequate iron delivery to the marrow, in spite of normal or increased iron stores.
• Cytokines:
- Inhibit release of erythropoietin (EPO) from the kidney.
- Suppress the response of the marrow to EPO.
- Promote haemolysis of senescent red cells.
- Promote release of hepcidin from the liver (acute phase response).
∴ ↓ red cell production in marrow + ↓ red cell survival + ↑ hepcidin.
• Hepcidin:
- Inhibits iron absorption from the intestine and inhibits iron transfer from marrow particles to developing erythrocytes and release of iron from other storage sites. These effects cause a fall in serum iron and poor haemoglobinisation of red cells.
∴ ↓ iron absorption + ↓ release of iron from stores.
Describe the morphology of anaemia of chronic disease.
- Looks like iron deficiency but is mild.
- Mild microcytic, hypochromic RBCs (often cells are normocytic and normochromic).
- Decreased RBC and reticulocytes.
