13.1 Anaemias & Blood Transfusion Medicine

Anaemias & Blood Transfusion Medicine

Anaemia is defined as a reduction in circulating haemoglobin (Hb) below normal physiological thresholds (typically <130 g/L in adult males, <120 g/L in non-pregnant adult females, and <110 g/L in pregnant females). Clinical evaluation begins with red blood cell indices, primarily the Mean Corpuscular Volume (MCV).

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1. Classification & Diagnostic Workup of Anaemias

Microcytic Anaemias (MCV <80 fL)

Microcytic hypochromic anaemias result from impaired haemoglobin synthesis, involving either deficient haem/iron synthesis or defective globin chain production.

• Iron Deficiency Anaemia (IDA): The commonest cause of anaemia worldwide.

  • Biochemical Profile: Low serum ferritin (<30 mcg/L; the most specific single test), elevated Total Iron Binding Capacity (TIBC / transferrin), low transferrin saturation (<15%–20%), and low serum iron.
  • Investigation of Underlying Cause: In adult men and postmenopausal women without overt blood loss, IDA must be presumed secondary to occult gastrointestinal malignancy until proven otherwise. British Society of Gastroenterology (2021) guidance recommends bidirectional endoscopy (gastroscopy and colonoscopy, or CT colonography if unfit) in men and postmenopausal women, with coeliac serology; under NICE NG12 (2023) a FIT result is used to triage colorectal investigation, and referral is on the suspected cancer pathway when criteria are met. In premenopausal women, menorrhagia is the commonest cause, but coeliac disease serology (anti-tissue transglutaminase [anti-tTG] IgA) must always be screened.
  • Treatment: Oral ferrous sulfate 200 mg once daily or on alternate days (alternate-day dosing enhances absorption by reducing hepcidin spikes and improves gastrointestinal tolerance). Continue treatment for 3 months after normalization of haemoglobin to replenish depleted bone marrow iron stores. Intravenous iron (e.g. ferric derisomaltose) is reserved for severe intolerance, malabsorption (e.g. Crohn's disease, coeliac disease), or advanced chronic kidney disease.

• Thalassaemia Trait (Alpha or Beta): Inherited disorders of globin chain synthesis.

  • Key Differentiating Clues: Disproportionately marked microcytosis (MCV frequently 60–70 fL) with only mild anaemia and a characteristically elevated Red Blood Cell (RBC) count.
  • The Mentzer Index: Calculated as $\text{MCV} / \text{RBC count}$. A ratio <13 strongly favors thalassaemia trait, whereas a ratio >13 strongly points toward iron deficiency anaemia.
  • Confirmation: Haemoglobin electrophoresis (elevated $\text{HbA}_2 >3.5\%$ in beta-thalassaemia trait; normal in alpha-thalassaemia trait, which requires genetic DNA testing). Ferritin is normal or elevated; iron supplementation is strictly contraindicated to prevent iatrogenic haemosiderosis.

• Anaemia of Chronic Disease (ACD): Driven by chronic systemic inflammation (infection, malignancy, autoimmune rheumatological disease). Hepcidin is upregulated by interleukin-6 (IL-6), blocking ferroportin channels on enterocytes and macrophages, sequestering iron in storage. Serum ferritin is normal or elevated (acute phase reactant), serum iron is low, and TIBC is low or normal.

• Sideroblastic Anaemia: Defective protoporphyrin synthesis trapping iron within erythroblast mitochondria. May be congenital (X-linked ALAS2 mutation) or acquired (myelodysplasia, lead poisoning, chronic alcohol excess, isoniazid therapy). Bone marrow aspirate reveals pathognomonic ring sideroblasts with Prussian blue staining.

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Normocytic Anaemias (MCV 80–100 fL)

Normocytic anaemias arise from acute blood loss, systemic disease, impaired erythropoietin secretion, or early nutritional deficiency.

• Acute Blood Loss: Haemorrhage depletes blood volume rapidly before compensatory microcytosis can develop; reticulocytosis ensues within 3–5 days.
• Anaemia of Chronic Kidney Disease (CKD): Impaired renal parenchymal production of erythropoietin (EPO); treated with recombinant human erythropoietin (e.g. epoetin alfa, darbepoetin) once iron stores are optimized (target ferritin >100 mcg/L, transferrin saturation >20%).
• Bone Marrow Failure / Aplastic Anaemia: Idiopathic autoimmune T-cell mediated destruction or toxic suppression (chloramphenicol, gold, carbimazole, parvovirus B19) causing pancytopenia without hepatosplenomegaly or lymphadenopathy. Bone marrow trephine shows profound hypocellularity with fatty infiltration.
• Haemolysis: Normocytic picture with marked reticulocytosis.

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Macrocytic Anaemias (MCV >100 fL)

Macrocytic anaemias are categorized based on bone marrow and peripheral blood film morphology into megaloblastic and non-megaloblastic types.

• Megaloblastic Anaemia (Impaired DNA Synthesis): Characterised by asynchronous nuclear-cytoplasmic maturation, giant erythroblasts, and hypersegmented neutrophils (≥5 lobes) on blood film.
  • Vitamin B12 (Cobalamin) Deficiency: Causes include pernicious anaemia (autoimmune destruction of gastric parietal cells leading to loss of intrinsic factor; positive anti-intrinsic factor antibodies [highly specific] or anti-parietal cell antibodies), terminal ileum disease/resection (Crohn's disease), strict veganism, or gastrectomy. Features include glossitis, peripheral neuropathy, and Subacute Combined Degeneration of the Spinal Cord (dorsal column vibration/proprioception loss, lateral corticospinal tract spastic paraparesis). Treatment: intramuscular hydroxocobalamin 1 mg on alternate days for 2 weeks (or until neurological symptoms improve), followed by maintenance 1 mg every 2–3 months for life.
  • Folate Deficiency: Causes include poor dietary intake (green vegetables), excessive alcohol intake, pregnancy, malabsorption (coeliac disease), and antifolate medications (methotrexate, trimethoprim, phenytoin). Serum red cell folate or serum folate is low.

• Non-Megaloblastic Macrocytosis: Normal DNA synthesis without hypersegmented neutrophils. Round macrocytes. Common causes include chronic alcohol misuse (most common), non-alcoholic chronic liver disease, reticulocytosis (reticulocytes are larger than mature erythrocytes), hypothyroidism, and myelodysplastic syndromes (MDS).

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2. Haemolytic Anaemias

Haemolytic anaemias involve premature destruction of red blood cells (erythrocyte lifespan <120 days). Destruction can be extravascular (in the splenic and hepatic reticuloendothelial system) or intravascular (within the circulation).

Universal Biochemical Hallmarks of Haemolysis

• Elevated Serum Total & Unconjugated Bilirubin: Jaundice with normal pale/dark stool patterns.
• Elevated Serum Lactate Dehydrogenase (LDH): Released from lysed erythrocytes.
• Low or Undetectable Serum Haptoglobin: Haptoglobin binds free circulating haemoglobin; the complex is rapidly cleared by hepatic reticuloendothelial cells.
• Reticulocytosis (>2% or absolute count >100 x 10^9/L): Compensatory marrow erythropoiesis producing polychromasia on blood film.
• Urinary Haemosiderin & Free Haemoglobin: Seen predominantly in intravascular haemolysis.

Clinical Entities

• Autoimmune Haemolytic Anaemia (AIHA): Identified by a positive Direct Antiglobulin Test (DAT / Coombs test).
  • Warm AIHA (~80%): Mediated by IgG autoantibodies binding erythrocyte surface antigens optimally at 37°C. Extravascular haemolysis in the spleen; blood film shows microspherocytes. Triggers include idiopathic, SLE, CLL, lymphoma, or drugs (methyldopa). First-line treatment: high-dose oral prednisolone (1 mg/kg/day); second-line includes rituximab or splenectomy.
  • Cold AIHA (Cold Agglutinin Disease, ~20%): Mediated by IgM autoantibodies binding red cells at low temperatures (<32°C–37°C) and fixing complement (C3d), precipitating intravascular lysis and acrocyanosis (painful bluish discoloration of fingers, nose, ears upon cold exposure). Triggers: Mycoplasma pneumoniae infection, Epstein-Barr virus (EBV/infectious mononucleosis), or low-grade B-cell lymphoma. Treatment: keep the patient warm; rituximab is effective; corticosteroids and splenectomy are ineffective.
• Hereditary Spherocytosis: Autosomal dominant defect in erythrocyte cytoskeleton structural proteins (ankyrin, band 3, spectrin), producing rigid, spherical cells vulnerable to splenic sequestration. Features: jaundice, splenomegaly, pigmented bilirubin gallstones. Blood film demonstrates microspherocytes; DAT is negative; diagnosis confirmed by eosin-5-maleimide (EMA) binding flow cytometry. Management: folic acid maintenance; curative splenectomy for severe cases (post-splenectomy vaccination against encapsulated organisms mandatory).
• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: X-linked recessive enzymopathy impairing NADPH production, rendering glutathione reductase unable to regenerate reduced glutathione to protect red cells from oxidative injury. Triggers of acute intravascular haemolysis include fava beans, infections, and oxidative drugs (ciprofloxacin, dapsone, primaquine, nitrofurantoin, sulfonamides). Blood film shows Heinz bodies (denatured globin inclusions seen on supravital stain) and "bite cells" / "blister cells" from splenic macrophage culling. Note: G6PD enzyme levels may be falsely normal during an acute crisis because old, enzyme-deficient cells have lysed and newly released reticulocytes contain normal enzyme levels; re-test 8–12 weeks after the acute episode.
• Sickle Cell Disease (HbSS): Point mutation in beta-globin gene (glutamic acid substituted by valine at position 6), generating abnormal HbS that polymerizes into rigid sickle shapes under hypoxic or acidotic conditions.
  • Vaso-occlusive Painful Crisis: Microvascular occlusion of bone marrow. Immediate management: rapid analgesia with strong opioids (e.g. subcutaneous or IV morphine) within 30 minutes of arrival, generous oral/IV hydration, supplemental oxygen only if SpO2 <95%, empirical broad-spectrum antibiotics if febrile, and keeping the patient warm.
  • Acute Chest Syndrome (ACS): Leading cause of mortality; defined as new pulmonary infiltrates on chest X-ray plus fever, chest pain, tachypnoea, or hypoxaemia. Emergency management: urgent exchange blood transfusion, respiratory support/CPAP, analgesia, empirical IV antibiotics (covering atypical pathogens like Mycoplasma and Chlamydia), and incentive spirometry.
  • Splenic Sequestration Crisis: Acute pooling of erythrocytes in the spleen occurring in infants and young children before autosplenectomy. Causes rapid abdominal distension, enlarging tender splenomegaly, profound anaemia, and hypovolaemic shock. Emergency treatment: urgent judicious blood transfusion.

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3. Blood Transfusion Medicine & Reactions

Pre-Transfusion Testing & Transfusion Thresholds

• Type and Screen: Confirms ABO and RhD blood group status and screens recipient serum for atypical red cell antibodies.
• Crossmatch: Mixes donor erythrocytes with recipient serum (electronic or full serological match) to ensure compatibility.
• NICE Restrictive Transfusion Guidelines (NG24):
  • Standard Medical/Surgical Patients: Restrictive threshold of Hb <70 g/L, with a target post-transfusion Hb of 70–90 g/L.
  • Patients with Acute Coronary Syndrome (ACS): Threshold of Hb <80 g/L, with a target post-transfusion Hb of 80–100 g/L.
  • Transfuse a single red cell unit at a time in non-bleeding patients, followed by clinical and laboratory reassessment.

Acute Transfusion Reactions (Within 24 Hours of Infusion)

1. Acute Haemolytic Transfusion Reaction (AHTR):

   • Mechanism: ABO incompatibility caused by clerical error; recipient pre-formed anti-A or anti-B IgM antibodies trigger massive intravascular complement-mediated lysis.
   • Features: Fever, chills, severe flank/loin pain, tachycardia, profound hypotension, hemoglobinuria (dark red/brown urine), and oozing from venepuncture sites due to rapid consumption into Disseminated Intravascular Coagulation (DIC).
   • Emergency Action: STOP the transfusion immediately. Disconnect giving set but preserve IV access. Aggressively infuse IV 0.9% normal saline to maintain renal perfusion (target urine output >100 mL/h). Return the implicated blood pack and giving set to the transfusion laboratory with repeat crossmatch and DAT blood tubes. Initiate supportive management for shock and DIC.

2. Transfusion-Related Acute Lung Injury (TRALI):

   • Mechanism: Donor plasma contains anti-HLA or anti-human neutrophil antigen (HNA) antibodies that bind and activate recipient neutrophils sequestered within the pulmonary microvasculature, triggering acute non-cardiogenic capillary leak.
   • Features: Sudden onset acute dyspnoea, tachypnoea, severe hypoxaemia, fever, and hypotension developing within 6 hours of transfusion. Chest radiograph demonstrates bilateral diffuse non-cardiogenic pulmonary infiltrates.
   • Differentiating Clues: Jugular Venous Pressure (JVP) is normal or low, cardiac auscultation shows no gallop, and B-type natriuretic peptide (BNP) is normal.
   • Management: Stop transfusion; provide high-flow oxygen and mechanical ventilatory support in an intensive care setting. Diuretics are ineffective and potentially hazardous due to systemic hypotension.

3. Transfusion-Associated Circulatory Overload (TACO):

   • Mechanism: Hydrostatic pulmonary oedema secondary to excessive volume or overly rapid infusion, especially in elderly patients, those with underlying cardiac or renal impairment, or severe baseline anaemia.
   • Features: Acute dyspnoea, orthopnoea, cough with pink frothy sputum, tachypnoea, hypertension, elevated JVP, bilateral lung crackles, and peripheral oedema developing during or up to 6 hours after transfusion.
   • Differentiating Clues: Marked elevation of BNP / NT-proBNP, cardiomegaly and upper lobe diversion on CXR, positive fluid balance, and clinical response to diuretics.
   • Management: STOP transfusion immediately. Sit the patient fully upright. Administer high-flow oxygen and IV furosemide 20–40 mg. Consider nitrate infusions if hypertensive.

4. Anaphylaxis: Immediate hypersensitivity mediated by anti-IgA antibodies in an IgA-deficient recipient receiving IgA-containing donor blood. Characterised by bronchospasm, stridor, urticaria, angioedema, and cardiovascular collapse. Emergency treatment: immediate intramuscular adrenaline (0.5 mg 1:1000), stop the transfusion, airway support and IV fluids, then follow the anaphylaxis algorithm (antihistamines and corticosteroids are adjuncts only and must not delay adrenaline).