Sickle Cell Disease

Autosomal recessive hemoglobinopathy caused by a point mutation in the β-globin gene (glutamic acid → valine at position 6), producing abnormal hemoglobin S (HbS).

Under hypoxic/acidotic/dehydrated conditions, HbS polymerizes, distorting red cells into a rigid sickle shape, causing hemolysis and vaso-occlusion.

Most common severe genotype: HbSS (sickle cell anemia); other clinically significant genotypes include HbSC disease and HbS-beta thalassemia (generally milder than HbSS but still clinically significant).

Sickle cell trait (HbAS, heterozygous carrier): generally asymptomatic, protective against severe malaria, but can rarely cause complications under extreme hypoxia (high altitude, extreme exertion) : important to distinguish from disease.

• Vaso-occlusive crisis (VOC) most common acute presentation: severe pain, typically in bones (long bones, spine, ribs), triggered by cold, dehydration, infection, stress, hypoxia; can affect any organ

• Dactylitis (hand-foot syndrome): often the earliest presentation in infants, painful swelling of hands/feet

• Acute chest syndrome (ACS): new pulmonary infiltrate on imaging + fever and/or respiratory symptoms; leading cause of mortality in SCD, requires urgent recognition and management, can be triggered by infection, fat embolism (from bone marrow infarction), or atelectasis from VOC

• Splenic sequestration crisis (mainly infants/young children before autosplenectomy occurs): sudden splenic enlargement, pooling of blood, rapid Hb drop, hypovolemic shock ; life-threatening emergency

• Aplastic crisis: parvovirus B19-triggered, sudden cessation of erythropoiesis, severe anemia with low reticulocyte count

• Chronic hemolysis: jaundice, pallor, gallstones (pigment stones from chronic hemolysis), leg ulcers

• Priapism: painful, prolonged erection; urological emergency, risk of permanent erectile dysfunction if untreated

• Stroke: significant risk especially in children ; ischemic (children) or hemorrhagic (adults) ; requires urgent recognition; silent cerebral infarcts also occur, screened via transcranial Doppler in children

• Chronic complications: avascular necrosis (femoral/humeral head), retinopathy (proliferative, especially HbSC), chronic kidney disease (papillary necrosis, glomerulopathy), pulmonary hypertension, functional asplenia (increased risk of encapsulated organism infection ; pneumococcus, H. influenzae, meningococcus), growth delay in children, leg ulcers

• Increased infection susceptibility: functional asplenia by early childhood in HbSS ; high risk of overwhelming sepsis from encapsulated organisms, any fever in SCD child/adult requires urgent evaluation

• Newborn screening (in many countries, universal): hemoglobin electrophoresis or isoelectric focusing/HPLC identifies HbS

• Hemoglobin electrophoresis / HPLC: definitive diagnosis, identifies HbS and quantifies percentage, distinguishes SS, SC, S-beta thalassemia, and trait

• FBC: chronic anemia (Hb typically 6-9g/dL in HbSS at baseline), reticulocytosis (compensatory, reflects chronic hemolysis)

• Blood film: sickle cells, target cells (especially HbSC), Howell-Jolly bodies (functional asplenia marker)

• Genetic testing: confirms specific mutations, useful for prenatal diagnosis/genetic counseling

• During acute crisis: FBC (compare to baseline ; significant drop suggests sequestration/aplastic crisis), reticulocyte count, LDH/bilirubin (hemolysis markers), blood cultures if febrile, CXR if respiratory symptoms (ACS evaluation), oxygen saturation

Differentials for VOC: osteomyelitis (can coexist/mimic ; Salmonella classically associated with SCD, distinguishing clinically challenging, consider if focal bone pain with fever not responding to standard analgesia), septic arthritis, other causes of acute abdomen if abdominal crisis.

Chronic/preventive management:

• Hydroxyurea: disease-modifying, first-line for most patients with HbSS/HbS-beta0 ; increases fetal hemoglobin (HbF), reduces sickling, reduces VOC frequency, ACS episodes, transfusion need, and mortality; starting dose ~15mg/kg/day, titrated to max tolerated dose (monitor FBC for myelosuppression)

• Newer disease-modifying agents: voxelotor (HbS polymerization inhibitor, increases Hb affinity for oxygen), crizanlizumab (P-selectin inhibitor, reduces VOC frequency) ; add-on options

• Folic acid supplementation (5mg od) ; supports increased erythropoietic demand

• Penicillin prophylaxis (children, until at least age 5, sometimes lifelong): penicillin V 125mg bd (<3y) or 250mg bd (≥3y) ; critical given functional asplenia risk of pneumococcal sepsis

• Vaccination: full pneumococcal coverage (conjugate + polysaccharide), meningococcal, Hib, annual influenza ; enhanced coverage given asplenia

• Transcranial Doppler screening (children, annually from age 2-16): identifies stroke risk, guides prophylactic transfusion decisions

• Regular ophthalmology screening (retinopathy, especially HbSC), renal function monitoring, echocardiography for pulmonary hypertension screening

Acute vaso-occlusive crisis:

• Analgesia : aggressive, per WHO pain ladder escalated rapidly: start with NSAIDs/paracetamol for mild pain; opioids (morphine, typically IV/PCA) for moderate-severe pain ; individualized dosing, do not undertreat (historically a major issue in SCD pain management), reassess frequently

• IV fluids: hydration (isotonic, avoid over-hydration ; ACS/pulmonary edema risk)

• Oxygen if hypoxic (not routinely if normoxic)

• Warmth, avoid known triggers

• Treat/identify precipitant (infection screen if febrile)

• Incentive spirometry: reduces atelectasis/ACS risk during hospitalization for pain crisis

Acute chest syndrome: oxygen, IV fluids (cautious), analgesia (balance adequate pain control against respiratory depression risk), empirical antibiotics (cover atypicals ; macrolide + cephalosporin, given difficulty distinguishing infectious from non-infectious triggers), incentive spirometry, bronchodilators if wheeze, blood transfusion (simple or exchange transfusion for severe/rapidly progressive cases) ; low threshold for escalation to ICU/exchange transfusion given mortality risk.

Splenic sequestration: urgent fluid resuscitation, blood transfusion, splenectomy consideration for recurrent episodes.

Stroke: urgent imaging, exchange transfusion (reduces HbS percentage rapidly), chronic transfusion program for secondary prevention.

Priapism: analgesia, hydration, urology involvement ; aspiration/irrigation if prolonged (>4 hours), consider alpha-agonist (etilefrine) intracavernosal, surgical shunt if refractory.

Blood transfusion: simple transfusion for symptomatic anemia/aplastic crisis; exchange transfusion for ACS, stroke, severe sequestration, pre-operative optimization ; reduces HbS% while avoiding excessive viscosity from simple transfusion alone; iron overload monitoring with chronic transfusion programs (chelation therapy as needed).

Curative option: allogeneic hematopoietic stem cell transplant (matched sibling donor, curative) ; considered in severe disease, particularly children with significant complications; gene therapy (increasingly available in some settings) ; emerging curative option.

Patient education: avoid triggers (dehydration, extreme temperature, high altitude/hypoxia, overexertion), prompt fever management (seek care immediately, sepsis risk), genetic counseling for family planning.