What is the pathophysiology and management of sickle cell anemia in a patient of African, Mediterranean, Middle Eastern, or South Asian descent with a known family history of the disease?

Sickle Cell Anemia: Comprehensive Overview

Pathophysiology

Sickle cell anemia results from a single nucleotide 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 sickle and leading to vaso-occlusion, hemolysis, and progressive multiorgan damage. 1

Molecular Mechanism

• The genetic mutation produces HbS (α2βS2) instead of normal adult hemoglobin (HbA, α2β2), which has markedly reduced solubility when deoxygenated 1, 2
• HbS molecules form polymers during deoxygenation as red cells traverse capillary beds, causing cells to deform into the characteristic sickle shape 1, 2
• This polymerization is reversible with reoxygenation, creating a continuous cycle of sickling and unsickling, but extensive polymerization damages the red cell membrane and cytoskeleton, forming irreversibly sickled cells 1
• Damaged red cells demonstrate increased adherence to vascular endothelium, leading to vaso-occlusion, ischemia-reperfusion injury, and end-organ damage 1
• Intravascular hemolysis depletes nitric oxide and releases free heme, worsening vascular endothelial damage 1

Disease Genotypes and Severity

• HbSS (sickle cell anemia), HbSβ0-thalassemia, and HbSD represent severe phenotypes with hemoglobin levels of 60-90 g/L, early onset painful crises, 80-95% HbS with no HbA present, and highest complication rates 1, 3
• HbSC disease typically presents with higher baseline hemoglobin (around 100-110 g/L), 50-55% HbS and 40-45% HbC, generally fewer symptoms but still requires careful management 1
• HbSβ+ thalassemia shows 10-25% HbA, 70-80% HbS, elevated HbA2 (>3-5%), and represents a mild phenotype 1, 4
• Fetal hemoglobin (HbF) levels above 8% reduce HbS polymerization and confer protection, resulting in milder phenotypes with fewer symptoms 1

Epidemiology and At-Risk Populations

• Sickle cell disease affects approximately 300,000 infants born annually worldwide, with most living in sub-Saharan Africa, India, the Mediterranean, and Middle East 5
• In the UK, approximately 14,000 patients have sickle cell disease (240,000 healthy carriers with sickle cell trait), with 98% of African or Caribbean background 1
• The disease also occurs in families from the Middle East, India, and the southern and eastern Mediterranean regions 1, 6
• Approximately 100,000 individuals with sickle cell disease live in the United States 5

Clinical Manifestations

Baseline Hematologic Status

• Patients with severe sickle cell disease maintain chronically low baseline hemoglobin of 60-90 g/L, which represents their steady state, not a crisis 7
• This chronic anemia results from ongoing hemolysis and is the patient's normal condition, so absolute hemoglobin value alone does not indicate crisis 7
• Patients experience chronic hemolytic anemia with damaged red cells removed by the reticuloendothelial system 1

Acute Complications

• Painful vaso-occlusive crises do NOT cause significant drops in hemoglobin and are diagnosed clinically based on pain and fever, not hemoglobin monitoring 7
• Acute chest syndrome presents with new pulmonary infiltrates, fever, chest pain, and respiratory symptoms, representing a medical emergency 1
• Aplastic crisis, hyperhemolytic crisis, and sequestration crisis are the specific subtypes that DO cause hemoglobin drops 7
• Stroke occurs due to vascular endothelial damage and requires urgent evaluation 1
• Priapism results from vascular endothelial damage and vaso-occlusion 1

Chronic Complications

• Progressive end-organ damage includes nephropathy, retinopathy, pulmonary hypertension, avascular necrosis, and leg ulcers 1, 5
• Chronic pain syndromes develop from repeated ischemia-reperfusion injury 1
• Increased susceptibility to infection, particularly encapsulated organisms, due to functional asplenia 1
• Cholecystitis from chronic hemolysis requiring cholecystectomy 1

Diagnostic Approach

Screening Recommendations

• All patients at risk should be screened for hemoglobinopathies before surgery, unless they are ethnically of solely northern or eastern European, Jewish, or South-East Asian heritage, or have been previously screened 1
• NHS newborn blood spot screening programs established between 2001-2013 screen all infants in the UK 1
• Diagnosis is confirmed through hemoglobin electrophoresis showing specific patterns based on genotype 4

Hemoglobin Electrophoresis Patterns

• Standard sickle cell trait (HbAS) shows HbA 55-65%, HbS 30-40%, HbF <1%, HbA2 <3-5%, with normal MCV—this is a benign carrier state 4
• HbSS disease shows 0% HbA, 80-95% HbS, 5-15% HbF, and HbA2 <3-5% 1, 4
• HbSC disease shows 0% HbA, 50-55% HbS, 40-45% HbC, and <3% HbF 1
• Sickle β+ thalassemia compound heterozygotes show 10-25% HbA, 70-80% HbS, elevated HbA2 >3-5%, representing actual sickle cell disease requiring disease-specific management, not just benign trait 4

Management Strategies

Disease-Modifying Therapy

• Hydroxyurea is now recommended as standard first-line therapy for most patients with sickle cell disease, as it raises HbF levels and reduces the frequency and severity of pain crises 1, 5
• Hydroxyurea acts as a ribonucleotide reductase inhibitor, increasing fetal hemoglobin production and reducing red blood cell sickling 8
• The medication reaches peak plasma concentrations in 1-4 hours and distributes throughout the body with approximately 40% urinary recovery 8
• Dose reduction is required when creatinine clearance is <60 mL/min or in ESRD following hemodialysis, as exposure increases 64% in renal impairment 8
• L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo in clinical trials 5
• Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo 5
• Voxelotor increased hemoglobin by at least 1 g/dL in 51% versus 7% with placebo 5

Acute Crisis Management

• Painful vaso-occlusive crises are treated with hydration and analgesia without blood transfusion 9
• Patients with sickle cell disease are not more likely to develop addiction to pain medications than the general population 5
• Aggressive pain management with analgesics is appropriate and necessary 10

Transfusion Therapy

• Blood transfusion should only be used for specific indications: acute hemolytic crisis, aplastic crisis, sequestration crisis, acute chest syndrome, stroke prevention, priapism, or perioperatively 9
• When transfusion is necessary, target hemoglobin should be 100 g/L (10 g/dL), blood products must be HbS-negative, Rh and Kell antigen matched, with extended phenotype matching to prevent alloimmunization 4, 9
• Hemoglobin should not be increased by more than 40 g/L in a single transfusion episode to avoid hyperviscosity 4
• Exchange transfusion is indicated for acute chest syndrome, severe priapism, or perioperatively in high-risk cases 9
• Patients with HbSC disease are more likely to require exchange transfusion when acutely unwell due to higher baseline hemoglobin 1

Preventive Measures

• Avoid precipitating factors including nitrates, dapsone, local anesthetics (benzocaine, prilocaine), and sulfonamides 4
• Maintain adequate hydration to prevent sickling 10
• Prophylactic antibiotics for infection prevention given functional asplenia 10
• ACE inhibitors may be used for nephropathy management 4

Perioperative Management

• Patients with sickle cell disease are at increased risk of perioperative complications (acute chest crisis, painful crisis, stroke, infection, thrombosis), requiring careful planning, assessment of comorbidities, and multidisciplinary team working 1
• HbSS patients require the most aggressive preventive measures perioperatively and have the highest complication rates 3
• Maintain normothermia, adequate oxygenation, and avoid dehydration throughout the perioperative period 1

Curative Therapy

• Hematopoietic stem cell transplant is the only curative therapy, with best results in children with a matched sibling donor, but limited by donor availability 5
• This is now standard care for severe disease with an appropriate donor 5

Prognosis and Life Expectancy

• In the UK, death in childhood is uncommon (1-2%) with optimal multidisciplinary care in specialist haematology clinics 1
• Survival up to the 7th decade can be expected with optimal care 1
• In the US, nearly all children survive to adulthood, but average life expectancy remains 20 years less than the general population 5
• Higher mortality occurs during transition from pediatric to adult-focused healthcare systems 5

Genetic Counseling

• First-degree relatives of patients with sickle cell disease 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
• Regional βS haplotypes (Benin 29%, Bantu 3%, Senegal 1%, Arab Indian 6.7%) show geographic variation and influence disease severity 6
• The Senegal haplotype is linked to higher HbF levels (average 14.6%) and milder symptoms 6