Haematology: Haemoglobinopathies and Transfusion

• Sickle cell disease: Haemoglobin and Its Disorders | Sickle Cell Disease | Acute Sickle Cell Complications | Managing a Sickle Cell Pain Crisis | Long-term Care in Sickle Cell Disease | Sickle Cell Trait
• Thalassaemia: Thalassaemia | Transfusion Iron Overload | Screening for Haemoglobin Disorders
• Transfusion: When to Transfuse | Blood Components | Special Requirements | Safe Transfusion Practice | Transfusion Reactions | Refusal of Blood and Alternatives
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Haemoglobin disorders and transfusion go together: sickle cell disease is the UK's fastest-growing genetic condition, and people with thalassaemia major depend on regular transfusion. Every doctor prescribes blood, so safe transfusion is everyone's responsibility. Major haemorrhage is covered in the Haematological Emergencies chapter.
Your four questions for every patient: Is this a sickle cell emergency that needs action within 30 minutes? Is a transfusion really needed - or is there an alternative? Does the patient have special blood requirements? Are the bedside checks right, and is the patient watched for reactions?

Haemoglobin and Its Disorders

• Normal adult haemoglobin:
  • HbA (2 alpha and 2 beta chains) - about 97%.
  • HbA2 (2 alpha, 2 delta) - about 2–3%.
  • HbF (fetal; 2 alpha, 2 gamma) - under 1% in adults.
• Two kinds of inherited disorder (both autosomal recessive):
  • Structural variants - an abnormal globin chain: HbS (sickle), HbC, HbE, HbD.
  • Thalassaemias - too little of a normal chain (alpha or beta).
• Inheritance: If both parents are carriers, each pregnancy has a 1 in 4 chance of an affected child, 1 in 2 of a carrier, and 1 in 4 of neither.
• Who: Commonest in people with family origins in Africa, the Caribbean, the Mediterranean, the Middle East, South and South-East Asia - areas where carriers were protected against malaria.
• Diagnosis: FBC (MCV, MCH), blood film, and haemoglobin analysis (HPLC or electrophoresis); DNA testing for alpha thalassaemia.

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Sickle Cell Disease

What it is: A group of inherited conditions in which red cells contain HbS. When oxygen is low, HbS polymerises and the cells become rigid and sickle-shaped. They block small vessels (vaso-occlusion), break down early (haemolysis), and damage blood vessel linings.

Types:

• HbSS (sickle cell anaemia) - the commonest and most severe.
• HbSC - milder anaemia, but more retinopathy and avascular necrosis.
• HbS/beta thalassaemia - severity depends on the beta mutation.

The basics in the UK:

• About 17,000 people have sickle cell disease.
• Found through newborn screening.
• Life expectancy is reduced (median about 60s in the UK, but often less in HbSS).

Triggers for crises:

• Infection; fever.
• Dehydration.
• Cold; sudden temperature change; swimming in cold water.
• Stress; overexertion.
• Low oxygen - altitude, unpressurised flights, anaesthesia.
• Alcohol; menstruation; pregnancy.

Blood tests:

• Chronic anaemia - Hb typically 60–90 g/L in HbSS (know the patient's baseline).
• Raised reticulocytes.
• Film: sickle cells and target cells.
• Howell–Jolly bodies (hyposplenism).

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Acute Sickle Cell Complications

⚠️ Safety Pearl: A patient with sickle cell disease who is breathless, hypoxic, or has chest pain has acute chest syndrome until proven otherwise. Get a chest X-ray and blood gas, and call haematology early.

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Managing a Sickle Cell Pain Crisis

NICE CG143 and the NCEPOD report "A Sickle Crisis?" (2024) stress speed, trust and listening to the patient.

• Give pain relief within 30 minutes of arrival. Use the patient's individual care plan if they have one.
• Believe the patient's pain - there is no test for a pain crisis. Delays and suspicion cause harm.
• Analgesia:
  • Strong opioid for severe pain - e.g. morphine or diamorphine (IV, SC or intranasal), or oral oxycodone. Avoid pethidine.
  • Add regular paracetamol and an NSAID (if kidney function allows).
  • Reassess every 30 minutes until pain is controlled, then at least every 4 hours (pain, sedation, breathing rate, oxygen saturation).
  • Patient-controlled analgesia for ongoing severe pain.
• Give with opioids: Laxatives, antiemetics, and antihistamines for itch.
• Supportive care:
  • Fluids - oral or IV (avoid overload).
  • Oxygen if saturations are low.
  • Keep warm.
  • Incentive spirometry (reduces acute chest syndrome).
  • VTE prophylaxis.
• Look for complications and triggers:
  • FBC and reticulocytes (compare with baseline).
  • U&E, LFTs.
  • Group and save.
  • Cultures if febrile.
  • Chest X-ray if there are chest symptoms.
• Involve the specialist haemoglobinopathy team within 24 hours.
• Transfusion is not needed for an uncomplicated pain crisis.

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Long-term Care in Sickle Cell Disease

Chronic complications:

• Hyposplenism (infections).
• Avascular necrosis of the hip and shoulder.
• Leg ulcers.
• Retinopathy (especially HbSC - yearly eye screening).
• Kidney disease - albuminuria, CKD, inability to concentrate urine (bedwetting).
• Pulmonary hypertension.
• Gallstones (pigment).
• Silent cerebral infarcts and cognitive problems.
• Delayed growth and puberty.
• Chronic pain.
• Depression.

Preventive care:

• Penicillin V prophylaxis (lifelong in many) and vaccines (pneumococcal, MenACWY and MenB, Hib, annual influenza, COVID-19, hepatitis B).
• Folic acid.
• Hydroxycarbamide - the key disease-modifying drug:
  • It raises HbF and reduces crises, acute chest syndrome, transfusions and deaths.
  • Offered to all children with HbSS from 9 months, and to adults with frequent complications.
  • Monitor FBC (marrow suppression).
  • Avoid in pregnancy; contraception for men and women.
• Transcranial Doppler screening (ages 2–16 years) - high velocities mean high stroke risk, so start regular transfusion.
• Regular transfusion or exchange programmes for stroke prevention and severe recurrent complications.
• Annual review: BP, urine ACR, eyes, echo if symptoms, iron status.
• Curative options:
  • Stem cell transplant - mainly children with a matched sibling.
  • Gene therapy - exagamglogene autotemcel ("exa-cel", Casgevy) is available on the NHS for selected people aged 12 and over with severe disease.
• Withdrawn drugs: Crizanlizumab and voxelotor were withdrawn in 2024 (lack of benefit, and safety concerns with voxelotor).
• Pregnancy:
  • High risk - joint care.
  • Stop hydroxycarbamide (ideally 3 months before conception).
  • Folic acid 5 mg.
  • Low-dose aspirin from 12 weeks.
  • LMWH in antenatal admissions and postpartum.
  • Partner testing.
• Surgery and anaesthesia:
  • Plan with haematology.
  • Pre-operative transfusion (Hb about 100 g/L) for medium and high-risk surgery.
  • Keep the patient warm, hydrated and oxygenated.
• Everyday advice: Drink plenty, keep warm, avoid extreme exertion; take malaria prophylaxis when travelling; seek help early with fever.

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Sickle Cell Trait

• What it is: Carrying one sickle gene (HbAS). About 1 in 4 people of West African descent are carriers.
• Usually no symptoms and a normal blood count.
• Rare problems:
  • Painless haematuria (renal papillary necrosis).
  • Inability to concentrate urine.
  • Exertional rhabdomyolysis and collapse with extreme exercise, heat and dehydration (military, athletes).
  • Renal medullary carcinoma (very rare, young people).
  • A slightly increased VTE risk.
  • Splenic infarction at high altitude.
• Practical points:
  • Partner testing before or early in pregnancy.
  • Tell the anaesthetist (generally safe).
  • Stay hydrated during intense exercise.

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Thalassaemia

Alpha thalassaemia - deletion of some of the 4 alpha globin genes:

• 1 gene missing - silent carrier.
• 2 genes missing (alpha thalassaemia trait) - mild microcytosis, no anaemia. Normal HbA2. Often South-East Asian, African or Mediterranean origin.
• 3 genes missing (HbH disease) - moderate haemolytic anaemia, splenomegaly; may need transfusions during illness.
• 4 genes missing (Hb Bart's hydrops fetalis) - fatal in the womb or soon after birth without intrauterine transfusion; serious risk to the mother (pre-eclampsia). Main risk is in couples of South-East Asian origin who both carry two-gene deletions on the same chromosome ("cis").

Beta thalassaemia - reduced or absent beta chains:

• Beta thalassaemia trait (minor):
  • Microcytosis (low MCV and MCH) with normal or mildly low Hb and a high red cell count.
  • Raised HbA2 (over 3.5%) is diagnostic.
  • Normal ferritin - don't give iron unless iron deficiency is proven.
• Beta thalassaemia intermedia (non-transfusion-dependent) - moderate anaemia; transfusions at times; iron overload from absorption.
• Beta thalassaemia major (transfusion-dependent):
  • Severe anaemia from 3–6 months of age (as HbF falls).
  • Without treatment: failure to thrive, bone marrow expansion (frontal bossing, "hair-on-end" skull X-ray), hepatosplenomegaly.

Treating transfusion-dependent thalassaemia:

• Regular transfusions every 2–4 weeks to keep the pre-transfusion Hb at about 95–105 g/L (this suppresses the marrow).
• Iron chelation (see below).
• Luspatercept reduces transfusion needs in some adults.
• Splenectomy if transfusion requirements are very high.
• Curative: Stem cell transplant (children with a matched donor); gene therapy (exa-cel) for selected patients.
• Monitoring:
  • Heart iron (cardiac T2* MRI).
  • Endocrine function - diabetes, hypogonadism, hypothyroidism, hypoparathyroidism, growth.
  • Bone density.
  • Liver (iron, hepatitis).
• Cardiac iron overload (heart failure, arrhythmias) is the leading cause of death.

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Transfusion Iron Overload

• Why it happens: Each unit of red cells contains about 200–250 mg of iron, and the body has no way to excrete it. After about 20 units, iron overload is likely.
• Effects:
  • Liver fibrosis and cirrhosis.
  • Cardiomyopathy and arrhythmias.
  • Diabetes; hypogonadism; growth failure.
  • Skin pigmentation.
• Monitoring:
  • Ferritin.
  • MRI liver iron and cardiac T2*.
• Chelation drugs:
  • Desferrioxamine - subcutaneous infusion over 8–12 hours, 5–7 nights a week. Side effects: hearing and vision problems, Yersinia infection.
  • Deferasirox - once-daily tablet. Side effects: kidney and liver toxicity, GI upset.
  • Deferiprone - tablets; good for cardiac iron. Causes agranulocytosis - weekly FBC and stop immediately with a fever or sore throat.
  • Combinations for severe cardiac overload.
• Also relevant in MDS, sickle cell disease on transfusion programmes, and other chronic transfusion needs.

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Screening for Haemoglobin Disorders

• NHS Sickle Cell and Thalassaemia Screening Programme (England):
  • Antenatal screening - offered to all pregnant women, ideally by 10 weeks. A family origin questionnaire is used in low-prevalence areas, with lab screening for all in high-prevalence areas.
  • If the mother is a carrier - test the baby's father promptly.
  • If both are carriers - counselling and the offer of prenatal diagnosis (CVS from 11 weeks), with informed choice about the pregnancy.
  • Newborn bloodspot screening at 5 days detects sickle cell disease (and carriers).
• Pre-conception testing for couples from high-risk backgrounds.
• Pre-implantation genetic diagnosis with IVF is available.
• Pre-operative sickle testing is recommended for people from at-risk groups whose status is unknown.

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When to Transfuse

Principles of patient blood management (NICE NG24):

• Treat the cause - e.g. iron deficiency (oral or IV iron), B12 deficiency - rather than transfusing.
• Restrictive thresholds for stable patients without major bleeding:
  • Hb under 70 g/L - transfuse to a target of 70–90 g/L.
  • Acute coronary syndrome - Hb under 80 g/L, target 80–100 g/L.
  • Individual thresholds for chronic transfusion (e.g. MDS, thalassaemia, symptoms).
• Single-unit transfusions in non-bleeding adults, then reassess (check Hb and symptoms) before giving more.
• One unit raises Hb by about 10 g/L in a 70 kg adult - use a smaller volume in low body weight (dose by weight).
• Before surgery:
  • Check Hb weeks ahead and correct anaemia (IV iron if needed).
  • Tranexamic acid for surgery with expected blood loss over 500 mL.
  • Cell salvage where appropriate.
• Consent: Explain the reason, risks, benefits and alternatives. Document it, and give written information.

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Blood Components

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Special Requirements

• All UK blood is leucodepleted (white cells removed) - this greatly reduces CMV transmission and febrile reactions.
• Irradiated blood - prevents transfusion-associated graft-versus-host disease (TA-GvHD), which is almost always fatal. Needed for:
  • Hodgkin lymphoma (lifelong).
  • Treatment with purine analogues (fludarabine, cladribine), bendamustine, alemtuzumab, ATG.
  • Stem cell transplant recipients and donors; CAR-T therapy.
  • Congenital T-cell immunodeficiency (e.g. DiGeorge syndrome).
  • Intrauterine and neonatal exchange transfusions.
  • Blood from relatives (directed donations); HLA-matched platelets.
• CMV-negative components - for intrauterine transfusions, neonates, and pregnancy (elective transfusions). Leucodepleted blood is otherwise acceptable.
• Phenotyped (antigen-matched) blood - sickle cell disease and thalassaemia (Rh and Kell matched, plus others) to prevent antibodies.
• Washed red cells - severe recurrent allergic reactions; IgA deficiency with anti-IgA antibodies (or use IgA-deficient donors).
• HLA-matched platelets - "platelet refractoriness" due to HLA antibodies.
• Anti-D - for RhD-negative women of childbearing potential exposed to RhD-positive blood or during pregnancy sensitising events.
• Document special requirements clearly and tell the patient (alert cards) - omissions are a common transfusion error.

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Safe Transfusion Practice

Most serious transfusion harm comes from human error, not the blood itself (SHOT haemovigilance reports).

• Sampling:
  • Positive patient identification at the bedside (ask name and date of birth; check the wristband).
  • Label the sample at the bedside - never pre-label.
  • Many hospitals require two separate samples to confirm the blood group before non-urgent red cells are issued.
• Before giving:
  • Check the prescription, the patient's ID, the component and its compatibility label, expiry, and special requirements - at the bedside.
  • Record baseline observations.
• During and after:
  • Observations at 15 minutes and at the end (and more often if unwell).
  • Watch unconscious or sedated patients especially closely.
  • Most severe reactions happen in the first 15 minutes.
• TACO risk assessment - older age, heart failure, kidney disease, low albumin, fluid overload, low body weight. Consider single units, slower rates, and diuretics.
• Timing: Avoid transfusing at night unless clinically necessary.
• Report all adverse events and errors to SHOT and SABRE (MHRA).

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Transfusion Reactions

💡 Clinical Pearl: TACO vs TRALI - TACO has high BP, a raised JVP and responds to diuretics. TRALI often has low BP, no fluid overload, and diuretics make it worse.

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Refusal of Blood and Alternatives

• Adults with capacity may refuse blood for any reason, even if they may die. Many Jehovah's Witnesses refuse whole blood and its main components (red cells, platelets, plasma, white cells); some accept fractions (albumin, clotting factors, immunoglobulins) or cell salvage - ask about each one.
• Document clearly:
  • An advance decision (many carry one).
  • Discuss in private, without family pressure.
  • Record exactly what is and isn't acceptable.
• Blood conservation options:
  • Treat anaemia early (IV iron, B12, folate, erythropoietin).
  • Minimise blood tests (paediatric tubes).
  • Stop antithrombotics where safe.
  • Tranexamic acid.
  • Careful surgery; cell salvage.
  • Early intervention for bleeding (endoscopy, embolisation).
• Children: Parents can't refuse life-saving treatment for a child. In an emergency, doctors may act in the child's best interests; otherwise seek a court order. Involve senior clinicians and legal advice.
• Hospital liaison committees for Jehovah's Witnesses can help.

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Drug Reference Table

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Spot the Diagnosis

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Exam-style Scenarios

1. A 24-year-old with HbSS arrives with severe back and leg pain typical of his crises.
Answer: Acute sickle pain crisis.

• Strong opioid within 30 minutes (follow his care plan), plus regular paracetamol and an NSAID if kidney function allows.
• Reassess every 30 minutes; laxative, antiemetic.
• Fluids, warmth, incentive spirometry, VTE prophylaxis.
• FBC and reticulocytes vs baseline; watch for acute chest syndrome; inform the haemoglobinopathy team.

2. A 30-year-old woman with Hb 115 g/L and MCV 66 fL has been given iron repeatedly without effect. Ferritin is 120 µg/L.
Answer: Probable thalassaemia trait - stop the iron.

• Haemoglobin analysis (HbA2); DNA testing for alpha thalassaemia if HbA2 is normal.
• Partner testing if planning pregnancy.

3. A 79-year-old with heart failure has Hb 74 g/L from chronic GI blood loss and is not bleeding now.
Answer: Restrictive approach.

• One unit of red cells over 2–3 hours, with TACO precautions (consider furosemide); then recheck Hb and symptoms.
• IV iron; investigate the cause.

4. Fifteen minutes into a transfusion, a patient develops a temperature of 39 °C, back pain and a BP of 80/40.
Answer: Possible acute haemolytic reaction or bacterial contamination.

• Stop the transfusion; keep the line open; resuscitate (fluids, oxygen).
• Recheck patient and component ID; inform the lab and return the bag.
• DAT, haemolysis screen, clotting, U&E; blood cultures from the patient and the bag; broad-spectrum antibiotics.
• Report to SHOT and SABRE.

5. A man with Hodgkin lymphoma is listed for a red cell transfusion.
Answer: He needs irradiated blood components (lifelong) to prevent TA-GvHD.

• Inform the lab and record it on the patient's record; give him an alert card.

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Key Points

• Haemoglobin disorders are autosomal recessive - two carrier parents give a 1 in 4 risk with each pregnancy.
• Sickle crises are triggered by infection, dehydration, cold and low oxygen.
• Pain crisis: strong analgesia within 30 minutes, reassess every 30 minutes, believe the pain.
• Chest symptoms or hypoxia in sickle cell disease means acute chest syndrome until proven otherwise - antibiotics, oxygen, transfusion.
• Stroke in sickle cell disease needs urgent exchange transfusion; transcranial Doppler screening in children prevents stroke.
• Hydroxycarbamide is the key disease-modifying drug; penicillin and vaccines for hyposplenism. Crizanlizumab and voxelotor were withdrawn in 2024.
• Beta thalassaemia trait: microcytosis, normal ferritin, raised HbA2 - don't give iron.
• Thalassaemia major: regular transfusion plus chelation; cardiac iron is the main cause of death.
• Restrictive transfusion: Hb under 70 (under 80 in ACS); single units in non-bleeding patients, then reassess.
• Platelets under 10 for prophylaxis in marrow failure; avoid in TTP and HIT.
• Warfarin reversal in major bleeding: PCC plus IV vitamin K - not FFP.
• Irradiated blood for Hodgkin lymphoma, purine analogues and stem cell transplant.
• Wrong-blood errors cause acute haemolysis - careful bedside identification prevents them.
• TACO: high BP, overload, diuretics help. TRALI: no overload, diuretics harm.

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Guidelines and Further Reading

• NICE CG143: Sickle cell disease - managing acute painful episodes in hospital
• NCEPOD: A Sickle Crisis? (2024); APPG report "No One's Listening" (2021)
• Sickle Cell Society: Standards for the clinical care of adults with sickle cell disease in the UK
• UK Thalassaemia Society: Standards for the clinical care of children and adults with thalassaemia
• NHS Sickle Cell and Thalassaemia Screening Programme
• NICE NG24: Blood transfusion
• BSH guidelines: administration of blood components; platelet transfusion; irradiated components; investigation of acute transfusion reactions
• SHOT (Serious Hazards of Transfusion) annual reports
• BNF - for current doses

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