Sickle Cell Disease

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy caused by the HbS mutation (glutamate to valine at position 6). Sickling of red cells under hypoxia causes vaso-occlusion leading to bone infarcts, painful crises, and avascular necrosis (10-50% prevalence, commonly bilateral femoral head). The critical exam point is that Salmonella is the most common osteomyelitis organism in SCD (unique to this condition), requiring dual antibiotic coverage. Perioperative management must avoid the "5 Hs" that trigger sickling: Hypoxia, Hypothermia, Hypovolemia (dehydration), Hydrogen ions (acidosis), and Hypotension. Preoperative exchange transfusion targets HbS under 30%.

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy with significant orthopaedic manifestations.

Genetics:

• Inheritance: Autosomal recessive
• Mutation: HBB gene - Glutamate to Valine substitution at position 6 (Glu6Val)
• Genotypes: HbSS (most severe), HbSC (milder), HbS-beta thalassemia

Epidemiology (global):

• Birth burden: Over 300,000 affected births annually worldwide; roughly 75-80% occur in sub-Saharan Africa, with India and the Middle East also high-burden
• Carrier protection: HbS trait confers resistance to falciparum malaria (balanced polymorphism), explaining its distribution across the historical malaria belt
• Migration: Prevalence rising in Europe, North America and Australasia through migration; diaspora populations now make SCD a global, not regional, orthopaedic problem
• Survival: Median survival 40-60+ years in high-resource settings with hydroxyurea, vaccination and transfusion programmes; remains markedly lower in limited-resource regions where childhood mortality is high

Molecular Basis:

• HbS Formation: Single nucleotide mutation in beta-globin gene (Glu6Val)
• Deoxygenation triggers polymerization: HbS molecules aggregate when deoxygenated
• Polymer formation: Long polymer fibres distort red cell membrane into sickle shape
• Membrane damage: Repeated sickling causes irreversible membrane damage

Vaso-occlusive Mechanism:

• Sickled cells are rigid and adhere to endothelium
• Obstruction of microvasculature (capillaries, sinusoids)
• Ischemia of downstream tissues
• Reperfusion injury with inflammatory response

Bone-Specific Pathophysiology:

• Marrow infarction: Leads to painful crises and bone necrosis
• End-artery occlusion: Particularly affects epiphyses (AVN) and endplates (H-vertebrae)
• Marrow hyperplasia: Compensatory expansion to combat chronic haemolysis
• Cortical thinning: Secondary to marrow expansion
• Increased infection risk: Functional asplenia + micro-infarcts create nidus

Precipitating Factors (CHAID):

• Cold exposure
• Hypoxia
• Acidosis
• Infection
• Dehydration

Differentiating Crisis vs Osteomyelitis:

Differential Diagnosis of the Painful Limb/Joint in SCD:

Orthopaedic Complications:

• Avascular necrosis: 10-50% develop AVN of femoral head, humeral head
• Pathological fractures: Weakened bone prone to fracture
• Chronic osteomyelitis: Recurrent or incompletely treated infections
• Growth disturbance: Limb length discrepancy, angular deformity
• Joint contractures: From repeated crises and immobilisation

Surgical Complications:

• Infection: 10-15% (vs 1-2% general population)
• Sickling crisis: Perioperative trigger by hypoxia/hypothermia
• Acute chest syndrome: Postoperative complication, potentially life-threatening
• Wound healing: Delayed healing common
• Implant failure: Earlier loosening and revision

Systemic Complications:

• Acute chest syndrome: Most common cause of death in SCD
• Stroke: Occurs in 10% of children with SCD
• Renal failure: Sickle nephropathy
• Pulmonary hypertension: From chronic haemolysis
• Iron overload: From chronic transfusions

AVN Surgery Outcomes:

• THA survivorship: 80-90% at 10 years (lower than general population)
• Infection rate: 10-15%
• Dislocation rate: Increased
• Revision rate: Higher due to loosening and infection

Prognostic Factors:

• HbSS genotype: Worse prognosis than HbSC
• Frequent crises: Associated with more complications
• Age: Earlier AVN associated with worse long-term outcomes
• Transfusion burden: Iron overload complications

Life Expectancy:

• Modern care: Median survival 40-60 years
• Hydroxyurea: Reduces crisis frequency, improves survival
• Stem cell transplant: Potentially curative in selected patients

Comparison: SCD vs General Population Arthroplasty:

• Transfusion strategy for major orthopaedic surgery: The PTSCD trial validated simple transfusion to Hb 10 g/dL for most surgery, but whether the highest-risk arthroplasties (long operative time, HbSS, prior acute chest syndrome) still benefit from exchange to HbS under 30% remains unsettled and is individualised with haematology.
• Tourniquet use: Traditionally avoided for fear of regional hypoxia/acidosis precipitating sickling, but several series report safe use with limited time and good oxygenation. There is no high-level evidence either way - practice varies.
• Core decompression and biologics: Outcomes of core decompression (with or without concentrated bone marrow / cell therapy) are less predictable than in non-SCD osteonecrosis; patient selection (pre-collapse, small lesions) is key and the evidence base is largely observational.
• Cemented vs cementless fixation: Abnormal sclerotic bone and obliterated medullary canals complicate both techniques. No consensus exists; choice is guided by bone quality, canal anatomy and surgeon experience rather than robust comparative data.
• Distinguishing infarct from osteomyelitis: Even MRI plus inflammatory markers can be equivocal; some advocate early aspiration/biopsy, others a trial of conservative management with close monitoring. Over-diagnosis leads to unnecessary surgery; under-diagnosis risks sepsis.
• Curative therapies: Allogeneic stem cell transplant and emerging gene therapies may alter the future orthopaedic disease burden, but their long-term effect on established bone disease is unknown.

Global epidemiology:

• Over 300,000 affected births per year worldwide; the great majority in sub-Saharan Africa, with India and the Middle East also high-burden.
• Diaspora migration has made SCD a routine consideration in orthopaedic units across Europe, North America and Australasia.
• Femoral head osteonecrosis affects roughly 10% (higher with age and HbSS + alpha-thalassaemia); osteomyelitis and septic arthritis are over-represented compared with the general population.

Side-by-side society guidance:

Registry note:

• No dedicated SCD arthroplasty registry exists; national joint registries (NJR, AOANJRR, AJRR, Swedish/Norwegian) capture osteonecrosis as an indication but rarely sub-stratify SCD, so most outcome data come from single-centre and pooled series (e.g. the Hernigou experience).

High- vs limited-resource practice variation:

• High-resource: newborn screening, hydroxyurea, vaccination, antigen-matched blood, MRI access, planned exchange transfusion and elective protocol-driven arthroplasty.
• Limited-resource: late presentation, restricted safe-blood and MRI availability, higher childhood mortality, and a greater burden of advanced osteonecrosis and chronic osteomyelitis presenting for salvage rather than elective reconstruction.
• Universal principles regardless of setting: haematology co-management, avoidance of the sickling triggers, infection coverage for Salmonella plus Staph, and informed counselling about elevated surgical risk.