Sickle cell anemia

An autosomal recessive hemoglobinopathy caused by a point mutation (Glu→Val) in the β-globin gene, leading to abnormal hemoglobin S (HbS) that polymerizes when deoxygenated. This results in RBC sickling, chronic hemolytic anemia, and recurrent vaso-occlusive crises.

• One of the most common inherited blood disorders worldwide, particularly affecting people of African and Mediterranean descent. SCD causes significant morbidity (painful crises, organ damage) and reduced lifespan. It's a classic example of a single-gene mutation with systemic effects (and heterozygote advantage against malaria), making it a high-yield topic on exams.

• Infants are usually asymptomatic until ~5–6 months old (due to protective HbF levels). The first sign can be dactylitis – painful swelling of hands and feet in a baby as fetal hemoglobin wanes. By early childhood, patients develop hemolytic anemia (fatigue, pallor, jaundice, gallstones) and high infection risk due to functional asplenia.
• Recurrent vaso-occlusive crises cause severe pain episodes ("pain crises"), often in bones (long bones, joints), chest, or abdomen. Triggers include dehydration, cold exposure, hypoxia, or infection. Episodes can cause fever and mimic other acute conditions (e.g., bone infection or acute abdomen).
• Major acute complications include acute chest syndrome (fever, chest pain, hypoxia, pulmonary infiltrates – often triggered by infection or fat emboli; a leading cause of death), stroke (especially in children), acute splenic sequestration (in children, marked fall in Hgb with enlarged spleen), and priapism (painful prolonged erection in males).
• Adults with SCD often show chronic organ damage: avascular necrosis of the femoral head (hip pain), leg ulcers, renal papillary necrosis (leading to hematuria and inability to concentrate urine), proliferative retinopathy, and cardiomyopathy from chronic anemia. By adolescence or adulthood, the spleen is typically auto-infarcted (small and fibrotic), leading to Howell-Jolly bodies on smear and ongoing infection susceptibility.

1. Confirm diagnosis with hemoglobin electrophoresis (newborn screening in many countries picks up SCD early). Electrophoresis in sickle cell anemia shows no HbA (adult hemoglobin), predominantly HbS and some HbF. In sickle cell trait, HbA > HbS is seen, and there are no sickle crises.
2. Recognize functional asplenia: any fever in an SCD patient warrants prompt evaluation and empiric broad-spectrum antibiotics (covering encapsulated organisms like Streptococcus pneumoniae). Ensure patients receive recommended vaccinations (pneumococcal, Hib, meningococcal, influenza). Young children should be on prophylactic penicillin to prevent pneumococcal sepsis.
3. During a vaso-occlusive pain crisis: provide aggressive hydration, oxygen, and adequate analgesia (often opioids) early to relieve pain. Evaluate for triggers or complications (e.g., chest X-ray to rule out acute chest syndrome if respiratory symptoms, or bone imaging if osteomyelitis is suspected).
4. Manage life-threatening complications swiftly: acute chest syndrome or stroke require urgent exchange transfusion (to reduce HbS%). Acute splenic sequestration or aplastic crisis (e.g., due to Parvovirus B19) needs prompt blood transfusions. For priapism >2 hours, urgent intervention (e.g., aspiration, intracavernosal injection) is needed to prevent impotence.

1. Acute crisis management: IV fluids, oxygen, and prompt analgesia (often opioids) for pain crises; treat inciting factors (e.g., antibiotics for infection). For severe anemia or acute chest syndrome, give blood transfusions; for stroke or recurrent acute chest, perform exchange transfusion.
2. Chronic management: Hydroxyurea (increases HbF production) is the cornerstone therapy – it reduces frequency of vaso-occlusive crises and acute chest syndrome. Folic acid supplementation is recommended (to support RBC production). In children with high stroke risk (abnormal transcranial Doppler), chronic transfusion programs are used to prevent stroke.
3. Preventive care: ensure all routine vaccinations are up to date (especially pneumococcal, Hib, meningococcal, annual influenza) and continue penicillin prophylaxis daily until at least 5 years old in HbSS children. Regular ophthalmology exams (screen for retinopathy) and kidney function monitoring are advised for early detection of chronic damage.
4. Curative approaches: Hematopoietic stem cell transplantation (bone marrow transplant) can cure SCD if a suitable donor is available (most successful in children). Emerging gene therapies (including CRISPR-based gene editing) have shown promise and were recently approved, offering potential cures without a donor.

• Mnemonic: HbS = Glu→Val (think "Val for Vaso-occlusion"). The β-globin mutation substitutes valine for glutamic acid, causing HbS to polymerize when deoxygenated.
• Infants <6 months old are protected by high HbF (fetal hemoglobin), so SCD symptoms typically begin around 5–6 months of age.
• Salmonella osteomyelitis is classically associated with SCD (due to asplenia), whereas Staphylococcus is the usual cause in others.
• Heterozygous sickle cell trait provides resistance to falciparum malaria – an evolutionary advantage (explaining the high gene frequency in malaria-endemic regions).

• Fever in an SCD patient → medical emergency (assume sepsis until proven otherwise due to asplenia). Requires prompt IV antibiotics covering encapsulated bacteria.
• Acute chest syndrome (new pulmonary infiltrate, hypoxia, chest pain) → life-threatening complication. Treat aggressively with oxygen, broad-spectrum antibiotics, and transfusion support (exchange transfusion often needed).
• Sudden drop in hemoglobin with low reticulocyte count → consider aplastic crisis (often due to Parvovirus B19); treat with urgent transfusions. (If accompanied by splenomegaly in a young child, think splenic sequestration crisis.)

1. Patient of at-risk ethnicity (e.g., African ancestry) with hemolytic anemia and pain crises → suspect SCD.
2. Confirm diagnosis with newborn screening or hemoglobin electrophoresis (shows predominantly HbS, no HbA in HbSS).
3. If diagnosed SCD: implement preventive measures early – start penicillin prophylaxis in infancy, ensure all immunizations, and screen annually with transcranial Doppler from age 2 to 16 for stroke risk.
4. Manage acute crises supportively: hydrate, oxygen, control pain; look for complications (acute chest, stroke) and treat immediately (e.g., exchange transfusion).
5. Long-term: start hydroxyurea in patients with frequent crises or significant symptoms to reduce vaso-occlusion. Refer for hematology consult regarding chronic transfusion protocols or bone marrow transplant evaluation in severe cases.

• 9-month-old infant (African descent) with swollen, painful hands and feet (dactylitis) and anemia → suspect sickle cell anemia (first presentation in infancy).
• Teenager with SCD, acute fever, chest pain, and new lung infiltrate on CXR → acute chest syndrome, an SCD emergency.
• Young adult with SCD and sudden one-sided weakness or facial droop → ischemic stroke from sickle cell vaso-occlusion (requires exchange transfusion).