What is sickle cell disease and how is it managed in patients of African, Mediterranean, or Middle Eastern descent with a history of anemia, infections, and organ damage?

Sickle Cell Disease: Comprehensive Overview

Pathophysiology

Sickle cell disease is a serious inherited genetic blood disorder caused by a specific mutation (C to A substitution at codon 6 of the beta globin gene) that replaces glutamic acid with valine, creating abnormal hemoglobin S (HbS) that polymerizes when deoxygenated, causing red blood cells to deform into sickle shapes, leading to chronic hemolytic anemia, painful vaso-occlusive crises, and progressive multi-organ damage. 1

Molecular Mechanism

• When HbS molecules become deoxygenated, they form polymers that cause red blood cells to deform into the characteristic sickle shape 1
• This sickling process is reversible with oxygenation, creating a continuous cycle of sickling and un-sickling as red cells travel through the circulation 2
• If red cells are delayed in returning to the lungs, polymerization becomes more extensive, causing permanent damage to the red cell membrane and cytoskeleton 2
• Irreversibly sickled cells undergo hemolysis and are removed by the reticuloendothelial system 2
• Damaged red cell membranes increase adherence to vascular endothelium, leading to vaso-occlusion, ischemia-reperfusion injury, and end-organ damage 2
• Intravascular hemolysis depletes nitric oxide and releases free heme, worsening vascular endothelial damage 2, 1

Genetic Patterns and Prevalence

• SCD affects approximately 300,000 infants born annually worldwide, with most living in sub-Saharan Africa, India, the Mediterranean, and Middle East 3
• In the United States, approximately 100,000 individuals have SCD 3
• In England, SCD is diagnosed in more than 1:2000 live births annually 1
• The disease predominantly affects people of African or Caribbean background (98% in UK registry) 1

Genotypes

• Severe forms include HbSS (sickle cell anemia) and HbSβ0-thalassemia, typically presenting with early onset of painful crises, severe anemia, and more frequent complications 1
• Compound heterozygous states include HbSC and HbS-β-thalassemia 1
• Sickle cell trait (HbAS) is the heterozygous carrier state, which is generally benign with HbA levels of 55-65% and HbS levels of 30-40% 2, 4
• Higher fetal hemoglobin (HbF) levels (>8%) are associated with milder disease phenotype 1

Important Distinction: Sickle Beta-Thalassemia

• Sickle beta-thalassemia compound heterozygotes are not benign carriers but have actual sickle cell disease requiring disease-specific management 4
• In HbS-β+ thalassemia: HbA levels are 10-25%, HbS levels are 70-80%, and HbA2 is elevated above 3-5% 4
• In HbS-β0 thalassemia: no HbA is present, HbS levels are 80-90%, HbF is 5-15%, creating a severe phenotype resembling HbSS disease 4

Clinical Manifestations

Acute Complications

• Painful vaso-occlusive crises are severe acute pain episodes caused by vaso-occlusion and ischemia 1, 3
• Acute chest syndrome presents with chest pain, fever, and pulmonary infiltrates 3
• Stroke is a life-threatening complication presenting with hemiparesis, aphasia, seizures, severe headache, or altered consciousness 1
• Splenic sequestration involves rapid spleen enlargement with trapped blood 1
• Transient aplastic crisis is an exacerbation of anemia with decreased reticulocyte count, often triggered by parvovirus B19 1
• Priapism occurs in two forms: stuttering episodes lasting <4 hours and severe acute ischemic episodes lasting ≥4 hours 1

Chronic Complications

• Chronic hemolytic anemia results from repeated cycles of sickling and red cell destruction 2, 1
• Progressive multi-organ damage affects multiple systems 1:
  • Eyes: retinopathy 1
  • Lungs: pulmonary hypertension 1
  • Kidneys: nephropathy 3
  • Bones: avascular necrosis 3
  • Skin: leg ulcers 3
• Increased susceptibility to infections, particularly pneumococcal infections 1
• Neuropsychological impairment affecting school and job performance 1
• Chronic pain from repeated ischemic injury 3

Diagnosis and Screening

Newborn Screening

• NHS sickle cell and thalassemia screening programme was established in 2001 as part of newborn blood spot screening, fully established in England by 2006, Scotland by 2010, Northern Ireland by 2012, and Wales by 2013 2
• Children born in the UK after program introduction in their area will have been screened, with parents informed if they have SCD and the child referred to specialist care 2

Pre-operative Screening

• All patients at risk of hemoglobinopathy should be screened before surgery, unless they are ethnically of solely northern or eastern European, Jewish, or South-East Asian heritage, or have been screened previously 2

Laboratory Testing

• Hospital laboratories use high performance liquid chromatography, capillary electrophoresis, mass spectrometry, or gel electrophoresis for hemoglobinopathy screening 2
• These methods are highly sensitive, reliable, and reproducible, detecting homozygous, heterozygous, or compound heterozygous states 2
• A positive sickle solubility test should not be used in isolation as it does not differentiate between heterozygous, compound heterozygous, or homozygous states 2

Management Approaches

First-Line Disease-Modifying Therapy

Hydroxyurea remains first-line therapy for most individuals with SCD, as it increases fetal hemoglobin and reduces red blood cell sickling. 3

• Hydroxyurea increases production of fetal hemoglobin, reducing the frequency and severity of pain crises 5
• It has been the standard of care for decades and remains the foundation of SCD management 3

FDA-Approved Adjunctive Therapies

L-Glutamine (FDA-approved 2017)

L-glutamine is indicated to reduce acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. 6

Dosing:

• Administer orally twice daily based on body weight 6:
  • <30 kg (<66 lbs): 5 grams per dose (10 grams/day) 6
  • 30-65 kg (66-143 lbs): 10 grams per dose (20 grams/day) 6

  • 65 kg (>143 lbs): 15 grams per dose (30 grams/day) 6

• Mix immediately before ingestion with 8 oz. of cold or room temperature beverage or 4-6 oz. of food 6

Efficacy:

• In clinical trials, L-glutamine reduced median number of sickle cell crises from 4 to 3 through 48 weeks 6
• Reduced median hospitalizations from 3 to 2 6
• Reduced median cumulative days hospitalized from 11 to 6.5 days 6
• Reduced incidence of acute chest syndrome from 23.1% to 8.6% 6
• Increased median time to first crisis from 54 to 84 days 6
• Reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo 3

Safety:

• Most common adverse reactions (>10%): constipation (21%), nausea (19%), headache (18%), abdominal pain (17%), cough (16%), pain in extremity (13%), back pain (12%), chest pain (12%) 6
• Treatment discontinuation due to adverse reactions occurred in only 2.7% of patients 6

Crizanlizumab (FDA-approved 2019)

• Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo 3

Voxelotor (FDA-approved 2019)

• Voxelotor increased hemoglobin by at least 1 g/dL in 51% of patients compared to 7% with placebo 3

Gene Therapies (FDA-approved 2023)

• Exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) were approved in 2023 7

Curative Therapy

Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. 3

• Barriers to transplant include lack of suitable donors, immunologic rejection, long-term adverse effects, prognostic uncertainty, and poor end-organ function, especially in older patients 8
• Gene therapy to correct the βs point mutation is under investigation as another curative modality 8

Transfusion Management

When transfusion is necessary, the target hemoglobin should be 100 g/L (10 g/dL) and blood products must be HbS-negative, Rh and Kell antigen matched, with extended phenotype matching to prevent alloimmunization. 4

• Hemoglobin should not be increased by more than 40 g/L in a single transfusion episode to avoid hyperviscosity 4
• Regular blood transfusions may be needed for certain complications, particularly stroke prevention 1

Preventive Measures

• Patients should avoid precipitating factors such as nitrates, dapsone, local anesthetics (benzocaine, prilocaine), and sulfonamides 4
• Aggressive preventive measures are needed perioperatively 4
• Iron supplementation should not be given unless iron deficiency is biochemically proven, due to risk of iron overload from repeated transfusions 1
• Regular screening and preventive care are essential to reduce complications 1

Pain Management

• Pain management includes analgesics, hydration, and blood transfusions to improve oxygen delivery 5
• Patients with SCD are not more likely to develop addiction to pain medications than the general population 3

Family Counseling

• First-degree relatives of patients with sickle beta-thalassemia should be tested and the entire family should receive genetic counseling, as this is a disease of high health impact with autosomal recessive inheritance 4

Prognosis

• In the US, nearly all children with SCD survive to adulthood 3
• Average life expectancy remains 20 years less than the general population 3
• Higher mortality occurs as individuals transition from pediatric to adult-focused health care systems 3
• With optimal multidisciplinary care, survival into the 7th decade can be expected 1
• Death in childhood is now uncommon in the UK (1-2%) 1

Critical Clinical Considerations

Perioperative Risk

• Patients with SCD are at increased risk of complications during surgery and anesthesia 1
• End-organ dysfunction and increased susceptibility to infection contribute to increased surgical risk, particularly in older patients 2

Disease Variability

• Clinical severity varies by genotype and within genotypes 1
• The clinical picture varies with age and is very variable between patients 2
• Clinical features relate to acute painful crises, anemia and infection, or acute or chronic end-organ damage 2