Sickle Cell Disease

Definition & Epidemiology

Autosomal codominant genetic disorder.
Homozygous state (HbSS) produces Sickle Cell Anemia.
Gene frequency in India: 4.3%; high prevalence in tribal populations of Orissa, Maharashtra, Madhya Pradesh, Jharkhand, and Gujarat.
United States prevalence: 1 in 365 African-American births.
Sickle cell trait (HbAS) provides selective survival advantage against Plasmodium falciparum malaria (balanced polymorphism).

Point mutation (adenine replaced by thymine) at 6th codon of $β$ -globin gene on chromosome 11.
Amino acid substitution: Valine replaces glutamic acid (or glutamine).
Hemoglobin S (HbS) tetramers undergo conformational change in deoxygenated (T) state.
Hydrophobic interactions between deoxygenated HbS molecules cause aggregation into large, rigid polymers.
Red blood cells (RBCs) distort into characteristic "sickled" shape.
Downstream effects: Hemolysis-associated nitric oxide depletion, chronic inflammation, oxidative stress, impaired fibrinolysis, platelet/leukocyte activation, and endothelial dysfunction.
Fetal Hemoglobin (HbF) inhibits HbS polymerization, ameliorating clinical severity.
Co-inheritance of $α$ -thalassemia trait (35% frequency in African-Americans) reduces baseline anemia and stroke risk, but does not alter vaso-occlusive pain frequency.

Chronic hemolytic anemia: Baseline hemoglobin 6-11 g/dL.
Reticulocytosis: 5-30% reflecting brisk erythropoiesis.
White blood cell count: Elevated baseline neutrophilia.
Platelet count: Thrombocytosis common.
Hemolysis markers: Elevated indirect bilirubin, elevated lactate dehydrogenase (LDH), decreased haptoglobin.
Functional asplenia develops early; completely absent splenic function by 5 years of age.
Peripheral blood smear: Sickled RBCs, target cells, nucleated RBCs, polychromasia, and Howell-Jolly bodies (indicating hyposplenism).

Mandatory state screening utilizes isoelectric focusing (IEF) or high-performance liquid chromatography (HPLC) from dried blood spots.
Hemoglobins reported in order of quantitative predominance.

Newborn Screen Pattern	Probable Diagnosis	Confirmatory Requirement
FS	HbSS, HbS- $β 0$ -thalassemia, HbS-HPFH	Repeat hemoglobin analysis >6 months; parental $β$ -globin gene testing.
FSC	HbSC disease	Confirmatory testing at initial clinic visit.
FSA	HbS- $β +$ -thalassemia	Confirm >50% HbS, elevated HbA2 (>3.5%) post-newborn period.
FAS	Sickle cell trait (HbAS)	Exclude prior RBC transfusion.
AFS	Invalid (Transfused)	Infant received RBC transfusion prior to sampling. Diagnosis indeterminate.

Hemoglobin Electrophoresis/HPLC: HbSS profile shows 80-90% HbS, 2-20% HbF, absent HbA.
DNA-based mutation analysis confirms specific genotype.
Solubility test (sodium metabisulfite) induces in vitro sickling; positive in all sickle syndromes.

Genotype	Clinical Severity	Steady-State Hb (g/dL)	MCV (fL)	Reticulocytes (%)	Hb Electrophoresis
HbSS	Severe	6-11	Normal (>80)	5-30	80-90% S; 2-20% F
HbSC	Mild/Moderate	10-15	Normal/Low	2-6	50-55% S; 45-50% C
HbS- $β 0$ -Thal	Moderate/Severe	6-10	Low (<70)	3-20	50-85% S; >3.5% A2
HbS- $β +$ -Thal	Mild/Moderate	9-12	Low (<75)	2-6	50-80% S; 10-30% A
HbS-HPFH	Asymptomatic	12-14	Normal (>80)	1-3	60-80% S; 15-35% F
HbAS (Trait)	Asymptomatic	Normal	Normal	Normal	55-60% A; 35-45% S

Functional asplenia imparts 300-600 fold increased risk of overwhelming sepsis (S. pneumoniae, H. influenzae type b, N. meningitidis, Salmonella spp.).
Penicillin Prophylaxis: Initiate oral penicillin VK by 3-4 months of age.
- Dose: 125 mg twice daily (<3 years); 250 mg twice daily ( $\geq$ 3 years).
- Duration: Continue until at least 5 years of age.
- Alternative: Erythromycin ethylsuccinate for penicillin allergy.
Immunizations:
- Routine childhood schedules.
- Conjugate 13-valent pneumococcal vaccine (PCV-13).
- 23-valent pneumococcal polysaccharide vaccine (PPV-23) administered at age 2, booster 5 years later.
- Meningococcal vaccine.
- Annual influenza vaccine.

Assessment	Starting Age	Frequency/Indications
Complete Blood Count & Reticulocytes	Diagnosis	Every 1-3 months. Monthly if on Hydroxyurea.
Transcranial Doppler (TCD)	2 years	Annually until 16 years. Detects stroke risk (Time-Averaged Mean Maximum velocity $\geq$ 200 cm/s indicates high risk).
Ophthalmology Exam	8-10 years	Annually. Screens for proliferative retinopathy ("sea fans").
Renal Function / Urinalysis	1-10 years	Annually. Screens for microalbuminuria/proteinuria and concentrating defects (hyposthenuria).
Echocardiography	10 years	Every 3 years. Evaluates pulmonary hypertension (elevated tricuspid regurgitant velocity).
Pulmonary Function	5 years	Every 3 years. Screens for lower airway disease/asthma.
Brain MRI/MRA	5-6 years	Baseline screening for silent cerebral infarcts. Indicated for cognitive difficulties or conditional TCD.

Mechanism: Chemotherapeutic agent. Primary HbF modulatory therapy; inhibits polymerization. Additional benefits: increases red cell hydration, decreases adhesion molecule expression, lowers WBC/platelet/reticulocyte counts, increases nitric oxide production.
Efficacy: Reduces frequency of vaso-occlusive pain, acute chest syndrome (ACS), dactylitis, and hospitalizations.
Indications: Recommended for all children with sickle cell anemia starting at 9 months of age, regardless of clinical symptoms.
Dosing: Start 10-20 mg/kg/day. Escalate by 5 mg/kg/day increments up to maximum 35 mg/kg/day.
Monitoring: Strict CBC monitoring required every 4-8 weeks to assess for transient myelosuppression.

L-Glutamine: Oral amino acid therapy. Reduces oxidative stress. Indicated for ages $\geq$ 5 years; reduces hospitalizations and pain crises.
Voxelotor: Small molecule oral inhibitor of HbS polymerization. Increases hemoglobin affinity for oxygen. Indicated for ages $\geq$ 4 years. Demonstrates reduced hemolysis and mean hemoglobin increase of 1.1 g/dL.
Crizanlizumab: Humanized monoclonal anti-P-selectin antibody. Administered intravenously every 4 weeks. Indicated for ages $\geq$ 16 years. Reduces annual vaso-occlusive event rates by 50%.

Indications: Primary and secondary stroke prevention, recurrent ACS, pulmonary hypertension.
Methods: Automated erythrocytapheresis (preferred to limit iron burden), manual exchange, or simple transfusion.
Alloimmunization Prevention: Perform extended RBC phenotyping/genotyping at diagnosis. All transfused units must be leukoreduced and prophylactically matched for C, E, and K antigens.
Iron Overload Management: Monitor serum ferritin and liver/cardiac T2* MRI. Initiate oral chelation (deferasirox, deferiprone) or subcutaneous deferoxamine for chronic iron toxicity.

Hematopoietic Stem Cell Transplant (HSCT): Only established cure. Highest success utilizes HLA-matched sibling donors. Prevents end-organ damage and eliminates disease phenotype.
Gene Therapy: Lyfgenia (lovotibeglogene autotemcel). Utilizes lentiviral vector carrying modified beta-A-T87Q globin gene to increase non-sickling hemoglobin levels. Evaluated for severe disease phenotypes.