Sickle Cell Disease (SCD)

Genetics and Epidemiology

• Approximately 250,000 children worldwide are born with homozygous SCD annually
• In the United States, about 8% of people of African descent are heterozygous carriers (sickle cell trait), and about 1 in 600 have sickle cell anemia
• The HbS allele is prevalent in areas where Plasmodium falciparum malaria was endemic (equatorial Africa, parts of India, southern Europe, Middle East) because heterozygosity confers protection against malaria
• Median age at death: 48-58.5 years in women, 42-53 years in men

Pathophysiology

1. Polymer formation - Deoxygenated HbS molecules change conformation and self-associate into long polymers via contacts involving the abnormal valine residue. These distort red cells into the characteristic sickle/crescent shape.
2. Reversible vs. irreversible sickling - Early sickling episodes are reversible on reoxygenation in the lungs. However, each cycle causes calcium influx, loss of K⁺ and water, and membrane skeleton damage. Repeated cycles create irreversibly sickled cells (ISCs) prone to hemolysis. Mean red cell lifespan is reduced to ~20 days (vs. 120 days normal).
3. Three major determinants of sickling severity:
   • Intracellular HbS concentration - Higher concentration worsens sickling. HbF inhibits polymerization (explains why neonates are protected until HbF falls at 5-6 months)
   • HbS percentage - HbA (in carriers) and HbF interpose and retard polymerization
   • Transit time through microvasculature - Tissues with sluggish flow (spleen, bone marrow) are most susceptible; inflammation prolongs transit times
4. Dual consequences:
   • Hemolytic anemia - Extravascular (macrophage phagocytosis of ISCs) and intravascular hemolysis; releases free hemoglobin, which scavenges nitric oxide (NO) and releases arginase (destroys arginine, the substrate for NO synthesis)
   • Vaso-occlusion - Sickled cells adhere to endothelium; triggered by infection, inflammation, dehydration, and acidosis. Produces ischemia-reperfusion injury, inflammatory, thrombotic, and oxidant stress
5. NO deficiency - A state of endothelial dysfunction results, skewing the vascular balance toward vasoconstriction, platelet activation, and upregulation of cell adhesion molecules. Heme released post-hemolysis also activates TLR4 and inflammasome signaling, amplifying inflammation.

Clinical Manifestations

Acute Complications

• The hallmark of SCD; most common cause of hospitalization
• Triggered by infection, dehydration, stress, cold, or unprovoked
• Infants: dactylitis (hand-foot syndrome - painful swelling of fingers/toes)
• Older patients: arms, legs, trunk, back pain
• Almost 30% of adults experience pain on >95% of days
• Diagnosis is clinical; no specific diagnostic test exists

• A lung injury syndrome analogous to ARDS
• Defined by: new pulmonary opacity on CXR (≥1 complete segment, consolidation not atelectasis) + chest pain, fever, tachypnea, or hypoxia
• Typically begins 24-72 hours after onset of a pain crisis
• Most common cause of mortality in adults (accounts for 28% of deaths in long-term studies)
• Causes: infection, fat embolism from infarcted bone marrow, in situ sickling

• Occurs in ~11% of children before age 20
• Most common in young children and older adults
• Transcranial Doppler (TCD) screening identifies children at high risk; elevated velocities prompt primary prevention with chronic transfusion

• Transient cessation of red cell production, usually triggered by Parvovirus B19 infection
• Dangerous given already short red cell lifespan

• Acute pooling of blood in the spleen (especially in children <5 years)
• Presents with rapid splenomegaly, falling hemoglobin, circulatory compromise

• Functional asplenia (autosplenectomy) by adulthood leads to high susceptibility to encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis
• Salmonella osteomyelitis is characteristic

Chronic Complications

Diagnosis

• Newborn screening (mandatory in the US): Hemoglobin electrophoresis or HPLC - pattern HbSS shows only HbS and HbF (no HbA)
• Peripheral blood smear: Elongated, crescent/spindle-shaped irreversibly sickled cells, target cells, Howell-Jolly bodies (asplenia)
• Sickling tests (sodium metabisulfite or solubility) - confirm HbS presence but do NOT differentiate HbAS from HbSS
• Hemoglobin electrophoresis or HPLC: Gold standard for genotype
• Tandem mass spectrometry: Identifies the specific amino acid change
• DNA sequencing: Identifies the specific globin gene mutation

Management

General Measures

• High fluid intake and good nutrition
• Folic acid supplementation (accelerated RBC turnover depletes folate)
• Education about triggers and "red flag" symptoms requiring emergency care
• Regular outpatient monitoring for chronic complications
• Vaccinations: pneumococcal, Haemophilus, meningococcal, influenza
• Penicillin prophylaxis in children (until age 5) against pneumococcal infection
• Psychological and social support

Red Flag Symptoms Requiring Hospital Admission

• Severe pain unresponsive to usual analgesia
• Fever >38°C
• Chest pain or hypoxia
• Neurological signs
• Acute splenic enlargement
• Priapism >4 hours

Acute Pain Management

• Mild: NSAIDs, acetaminophen, oral fluids, rest at home
• Severe: Hospital admission; parenteral opioids (patient-controlled analgesia reduces total opiate intake); monitor for respiratory depression
• Incentive spirometry to reduce ACS risk
• Taper opiates as pain resolves

Acute Chest Syndrome Treatment

• Oxygen, bronchodilators
• Empirical antibiotics (cover atypical organisms)
• Simple or exchange transfusion
• Incentive spirometry

Transfusion

• Acute indications: Aplastic crisis, acute chest syndrome, stroke, multiorgan failure, symptomatic severe anemia - NOT indicated for simple pain crises
• Chronic indications: Primary/secondary stroke prevention, recurrent pain or ACS not responding to hydroxyurea
• Exchange transfusion: Preferred for stroke and high-risk surgery (cardiac, neurosurgery); target HbS <30%
• Simple transfusion: For low-to-moderate risk surgery, target Hb >9 g/dL
• Goal: Reduce HbS% to <40%, maintain Hb ~10 g/dL
• Risks: Alloimmunization, iron overload, transfusion reactions

Disease-Modifying Therapies

• Mechanism: Increases HbF levels (inhibits HbS polymerization); reduces cellular adhesion, hemolysis, and neutrophil count
• Dose: Up to 30 mg/kg/day (dose-escalation protocols superior to fixed 20 mg/kg/day)
• Benefits: Reduces pain crises, ACS, hospitalizations, stroke risk (when TCD elevated)
• Recommended for ALL infants, children, and adolescents with SCD regardless of severity; adults with recurrent pain, severe/recurrent ACS, or symptomatic anemia
• Side effects: Myelosuppression (requires regular CBC monitoring); avoid in pregnancy (potential teratogenicity and effects on spermatogenesis)

• Reduces oxidative stress in sickle red cells
• FDA-approved; reduces acute complications

• Anti-P-selectin monoclonal antibody; blocks sickle cell adhesion to endothelium
• Reduces frequency of vaso-occlusive crises

• Increases Hb-O₂ affinity; stabilizes oxygenated HbS, reducing polymerization
• Raises hemoglobin level and reduces hemolysis markers

• The only established curative therapy
• Allogeneic HSCT from HLA-matched sibling donor; best outcomes in young patients with severe disease before organ damage accumulates
• 5-year event-free survival >90% with matched sibling donor in children
• Limited by donor availability and transplant-related morbidity

• Betibeglogene autotemcel (Zynteglo) and lovotibeglogene autotemcel (Lyfgenia) - FDA-approved lentiviral gene addition therapies (2023)
• Exa-cel (Casgevy) - CRISPR-Cas9 gene editing (reactivates HbF by disrupting BCL11A); FDA-approved December 2023 - the first approved CRISPR therapy
• These approaches offer curative potential without donor dependency

Special Situations

Pregnancy

• 6-fold increased risk of maternal death vs. controls
• Complications: more frequent pain crises, ACS, VTE (1.7-10x more frequent), preeclampsia, preterm birth, fetal growth restriction
• Hydroxyurea is contraindicated (teratogenic); NSAIDs avoided after 30 weeks
• Regional anesthesia preferred for cesarean section
• Prophylactic transfusion may reduce complications; therapeutic transfusion goal: HbS <40%, Hb ~10 g/dL
• Low-dose aspirin (81 mg/day) for preeclampsia prevention

Surgery and Anesthesia

• General anesthesia increases risk of pain crises and ACS
• Preoperative hydration and oxygenation are essential
• Low-to-moderate risk surgery: simple transfusion to Hb >9 g/dL
• High-risk surgery (cardiac/neuro): preoperative exchange transfusion

Stroke Prevention

• Annual TCD screening in children aged 2-16 years
• If TCD velocity elevated (>200 cm/s): chronic transfusion program reduces stroke risk by ~90%
• Hydroxyurea is an alternative when transfusion is not available

Morphological Summary (Pathology)

• Peripheral smear: sickled cells, target cells, polychromasia, nucleated RBCs
• Bones: "crewcut" skull (marrow expansion), H-shaped vertebrae, avascular necrosis
• Spleen: autosplenectomy in adults (fibrous remnant); splenomegaly in young children
• Gallbladder: pigment gallstones (bilirubin)
• Heart/liver/kidney: fatty changes from hypoxia
• Bone marrow: erythroid hyperplasia; extramedullary hematopoiesis in liver/spleen

• Goldman-Cecil Medicine, Ch. 149 (Sickle Cell Disease)
• Robbins & Kumar Basic Pathology, Ch. 10 (Sickle Cell Anemia)
• Murray & Nadel's Textbook of Respiratory Medicine (Acute Chest Syndrome)
• Rosen's Emergency Medicine (SCD in Pregnancy)