Anaemia and haemolysis

Approach to anaemia

• Anaemia is Hb below about 130 g/L in men and 120 g/L in women. It causes anaemic hypoxia: PaO₂ and saturation are normal, but oxygen content is low because there is too little haemoglobin to carry it.
• Classify by MCV, then ask whether the marrow is responding (reticulocyte count).

• Transfusion: in a stable surgical patient without heart disease, transfuse below 70 g/L (about 80 g/L with cardiac disease or symptoms). One adult unit raises Hb by about 10 g/L.

Iron deficiency

• Causes: chronic blood loss (menorrhagia; in men and postmenopausal women the gut until proven otherwise, so do upper and lower GI endoscopy for gastric and right-sided colon cancer), hookworm, poor intake, pregnancy, coeliac disease, partial gastrectomy (less acid, duodenal bypass), hereditary haemorrhagic telangiectasia (nosebleeds, blanching spots on lips and tongue, normal clotting).
• Features: koilonychia, angular stomatitis, glossitis, pica, Plummer–Vinson web.
• Labs: low ferritin (the single best test), low serum iron, high TIBC, low transferrin saturation; film microcytic hypochromic with pencil cells; platelets often raised.
• Iron deficiency versus thalassaemia trait: ferritin low in iron deficiency but normal in trait; trait has a raised HbA₂ (over 3.5%), a high red cell count and very low MCV for the Hb.
• Iron deficiency in inflammation: ferritin is an acute-phase protein, so with a high CRP a ferritin below about 100 µg/L may still hide iron deficiency. The soluble transferrin receptor rises in true iron deficiency but stays normal in anaemia of chronic disease.
• Treatment: oral iron (Hb should rise about 10 g/L per week; continue 3 months after normal). No response at 3 months: most often continued bleeding or poor adherence; also tea or calcium with the dose, malabsorption, wrong diagnosis.
• Before surgery: detect and treat anaemia weeks ahead. With under about 6 weeks before major surgery, IV iron works faster than oral (check phosphate after some preparations).

Anaemia of chronic disease and CKD

• Inflammation (IL-6) raises hepcidin, which blocks ferroportin and traps iron in macrophages: normal or high ferritin, low TIBC, normocytic or mildly microcytic.
• CKD anaemia is normocytic normochromic, mainly from reduced erythropoietin made by peritubular fibroblasts. Before starting an ESA, replete iron (usually IV); aim for Hb about 100–120 g/L, since normal targets increase strokes and cardiovascular events.

Sideroblastic anaemia

• Faulty haem synthesis leaves iron trapped in mitochondria around the nucleus: ring sideroblasts on Perls (Prussian blue) stain; microcytic with high ferritin and transferrin saturation.
• Causes: isoniazid (it depletes pyridoxine, the cofactor for ALA synthase), alcohol, lead, myelodysplasia, inherited. Give pyridoxine; do not give iron.

Megaloblastic anaemia

• B12 and folate are needed for DNA synthesis; nuclei mature slowly while cytoplasm grows: large precursors, hypersegmented neutrophils, oval macrocytes, often pancytopenia.
• Ineffective erythropoiesis: many megaloblasts die inside the marrow, releasing LDH and bilirubin. So a severe B12 deficiency can show high LDH, raised unconjugated bilirubin and low haptoglobin with a low reticulocyte count and a negative DAT.
• Pernicious anaemia: autoimmune gastritis of the body and fundus (antrum spared) destroys parietal cells, so acid and intrinsic factor are lost; achlorhydria drives a very high gastrin (not a gastrinoma). Anti-intrinsic factor antibody is the most specific test; anti-parietal cell antibody is more sensitive but less specific.
• Other B12 causes: total gastrectomy, terminal ileal resection or Crohn disease (including small bowel resection in a child after intussusception), fish tapeworm (raw freshwater fish), vegan diet. Liver stores last 3–5 years, so anaemia after gastrectomy appears years later; replacement must start at surgery and be lifelong IM.
• Folate (the commonest cause of megaloblastic anaemia overall): poor diet, pregnancy, haemolysis, methotrexate, phenytoin, trimethoprim.
• Homocysteine is raised in both deficiencies; methylmalonic acid only in B12 deficiency.
• Never give folate alone in B12 deficiency: the blood count improves, but subacute combined degeneration (numb feet, ataxia, dorsal columns) progresses.
• Alcohol causes round macrocytes without hypersegmented neutrophils, from a direct toxic effect on the marrow and membranes.

Haemolysis: the signs

• Raised reticulocytes, LDH, unconjugated bilirubin and urinary urobilinogen; low haptoglobin (free haemoglobin binds haptoglobin, and the complex is cleared). Pigment gallstones and splenomegaly with chronic haemolysis; marrow shows erythroid hyperplasia, and the film shows polychromatic (large bluish-grey) cells. Give folate, or the overworked marrow becomes megaloblastic.
• Intravascular haemolysis adds haemoglobinuria and haemosiderinuria; chronic urinary iron loss causes iron deficiency (PNH, mechanical valves).
• Parvovirus B19 stops erythropoiesis for a week or two, causing an aplastic crisis in any chronic haemolytic anaemia.
• A haemolysed blood sample (narrow needle, left overnight, pink serum) gives falsely high potassium; repeat it urgently.

• Splenectomy for hereditary spherocytosis (usually after age 6): vaccinate against pneumococcus, Hib and meningococcus at least 2 weeks before; remove the gallbladder at the same operation if it has stones.

Thalassaemia

• Beta-thalassaemia is a reduced or absent synthesis of beta-globin chains (mostly point mutations); carrier rate about 5–7% in Pakistan.
• Why major is so severe: unpaired excess alpha chains precipitate inside erythroblasts and kill them in the marrow (ineffective erythropoiesis), so the marrow is packed but output is poor; surviving cells are haemolysed in the spleen. Symptoms start at 3–6 months as HbF falls.
• Expanded marrow causes frontal bossing, maxillary overgrowth and a hair-on-end skull X-ray; hepatosplenomegaly, growth failure.
• Treatment: regular transfusion (keep pre-transfusion Hb above about 95 g/L) plus iron chelation (desferrioxamine, deferasirox, deferiprone). Iron overload causes cardiomyopathy (commonest cause of death), endocrine failure and cirrhosis. Splenectomy for hypersplenism; stem cell transplant is curative. Carrier screening, counselling and prenatal diagnosis prevent new cases.
• Trait: microcytosis, normal ferritin, HbA₂ over 3.5%; no treatment and no iron.
• Alpha-thalassaemia: HbH disease (three genes lost), Hb Barts hydrops (four genes).

Sickle cell disease

• Glutamate replaced by valine at position 6 of beta-globin (autosomal recessive). Deoxygenated HbS polymerises into rigid fibres, distorting cells into sickles, causing haemolysis and vaso-occlusion.
• Polymerisation is promoted by hypoxia, acidosis (shifts the curve right, more deoxy-HbS), dehydration (raises Hb concentration) and cold (vasoconstriction and stasis). That is why these four are avoided in surgery; tourniquets are relatively contraindicated because they create local stasis and hypoxia. Top-up transfusion to about 100 g/L before medium- or high-risk surgery.
• HbF does not join the polymer, so babies are protected for the first months; hydroxycarbamide (hydroxyurea) raises HbF and cuts painful crises and acute chest syndrome.
• Painful crisis: rapid strong analgesia (often IV opioid), fluids and warmth; believe the pain; oxygen only if hypoxic.
• Other crises: acute chest syndrome (commonest cause of adult death; exchange transfusion), splenic sequestration in children, aplastic crisis (parvovirus), stroke, priapism.
• Functional asplenia from repeated splenic infarction: Howell–Jolly bodies on the film, pneumococcal sepsis, *Salmonella* osteomyelitis; give penicillin prophylaxis and vaccines. Also avascular necrosis of the femoral head, dactylitis, gallstones, papillary necrosis.

Polycythaemia

• Polycythaemia vera causes both thrombosis and bleeding at surgery: venesect to haematocrit below 0.45 before elective operations.
• Aplastic anaemia: pancytopenia with a hypocellular marrow on trephine; drugs (chloramphenicol, carbamazepine), benzene, viral hepatitis, PNH; ATG with ciclosporin or stem cell transplant.

Remember Size, then reticulocytes: microcytic means haem or globin trouble, macrocytic means DNA trouble, high reticulocytes mean loss or destruction.

Exam trap Microcytosis with high ferritin is not iron deficiency: think anaemia of chronic disease, sideroblastic anaemia or thalassaemia trait.

Exam trap In beta-thalassaemia the toxic chain is alpha; in sickle cell, hypoxia, acidosis, dehydration and cold promote polymerisation.

How FCPS asks about this

• Thalassaemia trait versus iron deficiency: ferritin and HbA₂; beta-thalassaemia is reduced beta-chain synthesis with toxic excess alpha chains.
• Pernicious anaemia: parietal cells attacked; anti-intrinsic factor most specific; folate alone worsens neuropathy; B12 stores last years after gastrectomy.
• CKD anaemia: low erythropoietin, normocytic; replete iron before EPO.
• Haemolysis: free Hb binds haptoglobin; bite cells from removal of Heinz bodies; cold agglutinins are IgM with C3d.
• Sickle cell: functional asplenia with Howell–Jolly bodies; hydroxyurea raises HbF; strong analgesia for crises.
• Before surgery: transfuse below 70 g/L; IV iron if surgery is weeks away; vaccinate 2 weeks before splenectomy; venesect PV to haematocrit below 0.45.
• Polycythaemia after altitude or with a renal mass: secondary, high EPO.