Medicine chapters
Sickle cell disease
The cause of sickle cell disease, what triggers sickling, the types of crisis and long-term complications, parvovirus B19 aplastic crisis, and treatment including hydroxyurea and transfusion.
- Sickle cell anaemia is autosomal recessive: valine replaces glutamic acid at position 6 of the beta chain; deoxygenated HbS polymerises, cells sickle, block small vessels and haemolyse.
- Sickling is triggered by hypoxia, dehydration, cold, acidosis and infection; crises are vaso-occlusive (painful), acute chest, sequestration, aplastic (parvovirus B19) and haemolytic.
- Treat pain with fluids, oxygen if hypoxic, and opioids (morphine); prevent with penicillin, vaccines, folic acid and hydroxyurea, which raises HbF.
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Overview
Sickle cell disease is a group of inherited disorders with HbS. In sickle cell anaemia (HbSS) both beta genes carry the sickle mutation. Deoxygenated HbS forms rigid polymers, red cells become sickle-shaped, block small vessels and are destroyed early. The result is lifelong haemolytic anaemia, recurrent painful crises and damage to almost every organ.
The gene is common in Africa, the Middle East and India, and is found in parts of Pakistan (especially in communities of African descent in Sindh and Balochistan). Its spread follows falciparum malaria, against which carriers are partly protected.
Aetiology
- Point (missense) mutation in the beta-globin gene on chromosome 11: adenine to thymine.
- At position 6 of the beta chain, glutamic acid is replaced by valine (hydrophilic to hydrophobic).
- Autosomal recessive.
| Genotype | Name | Picture |
|---|---|---|
| HbSS | Sickle cell anaemia | Most severe |
| HbS/β0 thalassaemia | Sickle beta thalassaemia | As severe as HbSS |
| HbSC | HbSC disease | Intermediate; more retinopathy and thrombosis |
| HbAS | Sickle cell trait | No symptoms normally |
- HbF protects against sickling, so babies are well until HbF falls at about 6 months.
- If both parents have the trait, each child has a 25% risk of sickle cell anaemia.
Mechanism of sickling
- Deoxygenated HbS molecules stick together into long polymers (fibres).
- The cell distorts into a sickle; at first this reverses when oxygenated.
- Repeated sickling damages the membrane; potassium and water leave the cell (via the Gardos channel), so cells become dense, dehydrated and irreversibly sickled.
- Consequences: haemolysis (mainly extravascular, some intravascular) and vaso-occlusion (rigid cells, adhesion to endothelium) causing infarction.
- Unbound haemoglobin from intravascular haemolysis mops up nitric oxide, adding to vasoconstriction and pulmonary hypertension.
HbS gives up oxygen easily (right-shifted curve), so patients tolerate a low Hb fairly well.
Precipitating factors
- Hypoxia (high altitude, unpressurised flight, anaesthesia, pneumonia).
- Dehydration (diarrhoea, vomiting, hot weather, poor intake).
- Infection and fever.
- Cold exposure.
- Acidosis.
- Stress, exertion, pregnancy, alcohol.
- Often no cause is found.
Sickling is driven by "the 4 Ds and an I": De-oxygenation, Dehydration, a Drop in temperature, Drop in pH (acidosis), and Infection.
Sickle cell crises
| Crisis | What happens | Key findings | Management |
|---|---|---|---|
| Vaso-occlusive (painful) | Infarction in bone marrow, commonest crisis | Severe bone pain (back, chest, limbs); fever; Hb at baseline | Fluids, warmth, opioid analgesia, oxygen if hypoxic, treat trigger |
| Dactylitis (hand–foot syndrome) | Infarcts of small bones of hands and feet | Painful swollen fingers and feet; first presentation in infants | Analgesia, fluids |
| Acute chest syndrome | Infection, fat embolism from infarcted marrow, or lung infarction | Chest pain, fever, breathlessness, hypoxia, new infiltrate on CXR | Oxygen, antibiotics, analgesia, incentive spirometry, transfusion or exchange transfusion, ventilation |
| Splenic sequestration | Sickled cells pool in the spleen (young children, before autosplenectomy) | Rapid fall in Hb, suddenly enlarging painful spleen, high reticulocytes, shock | Urgent fluids and transfusion; splenectomy after recurrence |
| Aplastic | Parvovirus B19 stops red cell production | Rapid fall in Hb with very low or absent reticulocytes | Transfusion until the marrow recovers (1–2 weeks) |
| Haemolytic | Extra haemolysis (infection, drugs, G6PD deficiency) | Fall in Hb, more jaundice, high reticulocytes | Treat cause, transfuse if needed |
Aplastic crisis = reticulocytes low. Sequestration and haemolytic crises = reticulocytes high. Splenic sequestration also has a big spleen.
Parvovirus B19 in sickle cell anaemia
- Parvovirus B19 (erythrovirus) infects and kills red cell precursors via the P antigen, stopping red cell production for a short period (around a week).
- In healthy people this goes unnoticed (red cells live 120 days). In sickle cell anaemia red cells live only a few days to weeks, so the Hb falls dramatically.
- Clues: recent fever or "slapped cheek" contact; pallor and fatigue without extra jaundice; reticulocytes near zero; marrow shows giant pronormoblasts.
- Treatment: red cell transfusion; it is self-limiting and gives lasting immunity. Siblings with sickle cell disease should be watched.
- The same crisis occurs in other chronic haemolytic states (spherocytosis, thalassaemia).
Complications
Infection and the spleen
- Repeated splenic infarcts lead to a small, fibrotic, non-functioning spleen (autosplenectomy), usually by early childhood.
- Functional hyposplenism: high risk of encapsulated organisms: Streptococcus pneumoniae (leading cause of death in young children), Haemophilus influenzae type b, meningococcus.
- Film shows Howell–Jolly bodies and target cells.
- Osteomyelitis: characteristically Salmonella; Staph aureus and S. pneumoniae also occur.
Bones
- Avascular necrosis of the femoral head (child with a limp may be mistaken for Perthes disease) and humeral head.
- Vertebral collapse ("fish-mouth" or H-shaped vertebrae), bone infarcts.
Lungs and heart
- Acute chest syndrome: up to 30% of patients; with pulmonary hypertension and chronic lung disease, the main cause of death in adults.
- Pulmonary hypertension (about 10%): an independent predictor of death.
- Cardiomegaly, heart failure, iron overload cardiomyopathy.
Nervous system
- Stroke: about 11% of patients under 20 years without screening; mainly in children from stenosis of the distal internal carotid and proximal middle cerebral arteries.
- Transcranial Doppler screening in children identifies high stroke risk; regular transfusion in high-risk children prevents most strokes.
- Silent infarcts with learning problems; seizures.
Kidneys and genitourinary
- Renal papillary necrosis (haematuria) and inability to concentrate urine (isosthenuria, nocturia, enuresis).
- Chronic kidney disease, proteinuria.
- Priapism: urgent treatment with fluids, analgesia, aspiration and an alpha-agonist; risk of impotence.
Others
- Pigment gallstones and cholecystitis.
- Leg ulcers over the malleoli.
- Proliferative retinopathy (especially HbSC), vitreous haemorrhage.
- Growth and pubertal delay.
- Pregnancy: miscarriage, growth restriction, pre-eclampsia, more crises.
- Folate deficiency (megaloblastic crisis).
- Iron overload from repeated transfusion.
Sickle cell trait (HbAS)
- About 60% HbA and 40% HbS (HbA is made a little more efficiently).
- No anaemia; normal blood count and film.
- Sickling only under extreme hypoxia (unpressurised flight, severe exercise at altitude, anaesthesia).
- The renal medulla (low oxygen, high osmolality) can sickle: painless haematuria, papillary necrosis, poor urine concentration.
- Protection against falciparum malaria (balanced polymorphism), but still needs antimalarial prophylaxis.
- Diagnosed by a positive sickle solubility test and electrophoresis.
Investigations
- FBC: Hb usually 60–80 g/L; reticulocytes high (10–20%); raised platelets and white cells from hyposplenism.
- Film: sickle cells, target cells, polychromasia, Howell–Jolly bodies (hyposplenism), nucleated red cells.
- Sickle solubility test (sodium dithionite; e.g. Sickledex) or sodium metabisulphite sickling test: turbid or sickling; positive in both disease and trait; used for screening (e.g. before anaesthesia).
- Haemoglobin electrophoresis or HPLC (confirms and separates disease from trait):
| Condition | HbA | HbS | HbF |
|---|---|---|---|
| Sickle cell anaemia (SS) | None | 80–95% | 2–20% |
| Sickle cell trait (AS) | About 60% | About 40% | Normal |
- Haemolysis markers: raised bilirubin and LDH.
- Parents show sickle cell trait; prenatal diagnosis by chorionic villus sampling or amniocentesis; newborn screening.
Screening tests (solubility, metabisulphite) cannot tell trait from disease. Electrophoresis/HPLC is needed: no HbA means sickle cell anaemia.
Treatment
Acute painful crisis
- Rapid assessment and prompt analgesia on arrival.
- Opioids: morphine is the drug of choice for severe pain (e.g. 0.1 mg/kg IV or subcutaneously, repeated until pain is controlled, or PCA), with paracetamol and NSAIDs (care in kidney disease). Avoid pethidine.
- Hydration (oral or IV fluids).
- Oxygen if saturations are low.
- Keep warm; treat infection (blood cultures, antibiotics if febrile).
- Laxatives and antiemetics with opioids; incentive spirometry to prevent acute chest syndrome.
Acute chest syndrome
- High-flow oxygen, analgesia, broad-spectrum antibiotics covering atypicals (e.g. cefotaxime plus clarithromycin), fluids.
- Top-up or exchange transfusion to lower HbS (below about 30%, or lower in severe cases).
- CPAP or ventilation if worsening.
Transfusion
- Not for steady-state anaemia or an uncomplicated painful crisis.
- Simple transfusion: aplastic crisis, splenic sequestration, acute chest syndrome, before major surgery (raise Hb to about 100 g/L).
- Exchange transfusion: stroke, severe acute chest syndrome, multi-organ failure, priapism not settling.
- Regular transfusion: stroke prevention (abnormal transcranial Doppler or previous stroke), some pregnancies.
- Use blood matched for Rh and Kell to reduce alloimmunisation; chelate iron if on long-term transfusion.
Long-term care and prevention
- Penicillin prophylaxis daily from early infancy, at least through childhood.
- Vaccination: pneumococcal, Hib, meningococcal, hepatitis B, yearly influenza.
- Folic acid daily.
- Malaria prophylaxis in endemic areas.
- Avoid triggers; good hydration; warmth.
- Yearly eye checks, transcranial Doppler in children, kidney monitoring.
- Parent education to feel the spleen daily for early detection of sequestration.
Role of hydroxyurea (hydroxycarbamide)
- Mechanism: increases HbF production, which dilutes HbS and blocks polymer formation; also lowers white cells and adhesion, and improves red cell hydration.
- Benefits: fewer painful crises, fewer acute chest episodes, fewer transfusions and admissions, and better survival.
- Indications: now offered from about 12 months of age to almost all children and adults with HbSS or HbS/β0, especially those with frequent crises or acute chest syndrome.
- Side effects: myelosuppression (neutropenia), so monitor the blood count; it is teratogenic (stop in pregnancy; use contraception); raised MCV is expected.
- Taken daily by mouth; dose adjusted to blood counts.
Hydroxyurea raises fetal haemoglobin (HbF). This is the single most-tested fact about its use in sickle cell disease. Monitor for neutropenia.
Curative and new treatments
- Allogeneic stem cell transplant from an HLA-matched sibling: best in children under 16 with severe disease (stroke, recurrent chest syndrome).
- Gene therapies are emerging.
Expect: the exact amino acid change and its position; autosomal recessive inheritance and why symptoms begin after 6 months; triggers of sickling; the types of crisis and how reticulocytes and spleen size separate aplastic from sequestration crises; parvovirus B19 in sickle cell disease; acute chest syndrome as the leading cause of adult death; autosplenectomy, Howell–Jolly bodies and pneumococcal infection; Salmonella osteomyelitis and avascular necrosis of the hip; papillary necrosis in trait; electrophoresis findings in disease versus trait; morphine for painful crisis; and how hydroxyurea works and its side effects.
Quick revision
- Glu → Val at position 6 of beta chain; autosomal recessive; HbF protects until about 6 months.
- Triggers: hypoxia, dehydration, cold, acidosis, infection.
- Crises: painful, dactylitis, acute chest, sequestration (big spleen, high retics), aplastic (parvovirus, low retics), haemolytic.
- Autosplenectomy → pneumococcus, Hib; Howell–Jolly bodies; penicillin and vaccines.
- Osteomyelitis: Salmonella (also Staph aureus); avascular necrosis of femoral head.
- Trait: normal blood count; renal papillary necrosis, haematuria.
- Electrophoresis: SS has no HbA; AS about 40% HbS.
- Painful crisis: fluids, oxygen if hypoxic, morphine.
- Hydroxyurea raises HbF; watch neutropenia; teratogenic.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
Why do newborns with sickle cell anaemia have no symptoms?
They still make mostly fetal haemoglobin, which does not polymerise, so problems begin as HbF falls around 6 months.
How does parvovirus B19 cause a crisis?
It infects and halts red cell precursors for a short time, and because sickle cells survive so briefly the haemoglobin falls steeply with almost no reticulocytes.
Which organism classically causes osteomyelitis in sickle cell disease?
Salmonella species, although Staphylococcus aureus is also common.
How does hydroxyurea reduce crises?
It increases fetal haemoglobin, which dilutes HbS and slows polymerisation, so fewer cells sickle.
Does sickle cell trait cause anaemia?
No; the blood count and film are normal, though the renal medulla can sickle and cause haematuria.