What is the diagnostic workup and management, including splenectomy and prophylaxis, for hereditary spherocytosis?

Hereditary Spherocytosis: Diagnostic Workup and Management

Diagnostic Workup

The diagnosis of hereditary spherocytosis (HS) is established by demonstrating spherocytes on peripheral blood smear in a patient presenting with anemia, jaundice, and splenomegaly, confirmed by a positive osmotic fragility test. 1, 2

Initial Laboratory Evaluation

• Complete blood count with peripheral blood smear is the cornerstone of diagnosis, looking specifically for spherical-shaped erythrocytes, elevated mean corpuscular hemoglobin concentration (MCHC), and reticulocytosis indicating hemolysis 1, 3
• Osmotic fragility test (OFT) should be performed to demonstrate increased fragility of spherocytes, which is supportive of the diagnosis 2
• Bilirubin levels (both direct and indirect) to assess degree of hemolysis and jaundice 1, 4
• Reticulocyte count will be elevated, reflecting compensatory bone marrow response to hemolysis 1
• Lactate dehydrogenase (LDH) and haptoglobin to confirm hemolysis 2

Genetic Testing

• Next-generation sequencing (NGS) or whole-exome sequencing should be performed when classical features are not clearly demonstrated on blood film or OFT, particularly in resource-limited settings or atypical presentations 2, 3
• Target genes include ANK1, SPTB, SPTA1, SLC4A1, and EPB42, with ANK1 and SPTB being the most frequently mutated genes in Chinese populations (and likely other populations) 3
• Genetic testing is especially valuable for confirming diagnosis before splenectomy, identifying family members at risk, and providing prognostic information 2, 3

Assessment for Complications

• Abdominal ultrasound to evaluate for splenomegaly (universally present) and cholelithiasis, which increases with age and is uncommon before 10 years 1, 4
• Iron studies (ferritin, transferrin saturation) to assess for secondary hemochromatosis in chronically transfused patients 2
• Red blood cell antibody screening in patients requiring transfusions, as alloantibodies can develop 2

Management

Splenectomy Indications and Timing

Splenectomy is indicated in virtually every patient with hereditary spherocytosis, as it removes the primary site of red cell destruction and achieves clinical cure of anemia in most patients. 1

Specific Indications for Splenectomy:

• Moderate to severe HS with symptomatic anemia requiring transfusions 1, 5
• Growth retardation or failure to thrive in children 5
• Recurrent hemolytic crises 1
• Development of complications such as gallstones (perform concurrent cholecystectomy) 1, 4
• Significant splenomegaly with risk of traumatic rupture 1

Optimal Timing:

• Delay splenectomy until after age 5-6 years when possible to minimize the risk of overwhelming post-splenectomy infection (OPSI), as children under 5 years have the highest risk 6, 1
• In mild cases, splenectomy may be deferred or avoided entirely, though this remains controversial 5
• Emergency splenectomy may be required for splenic rupture or severe acute sequestration 1

Preoperative Preparation for Splenectomy

All children undergoing splenectomy must receive preoperative immunization against encapsulated bacteria at least 2 weeks before surgery, followed by lifelong antibiotic prophylaxis with phenoxymethylpenicillin. 6

Vaccination Protocol:

• 23-valent polysaccharide pneumococcal vaccine (>90% effective in healthy children) 6
• Meningococcal vaccine (essential for preventing meningococcal sepsis) 6
• Haemophilus influenzae type B vaccine 6
• Annual influenza vaccine to reduce risk of secondary bacterial infection 6
• Vaccines must be completed at least 2 weeks before elective splenectomy to ensure optimal antibody response 6

Preoperative Assessment:

• Complete blood counts, reticulocyte count, renal and liver function tests, and bilirubin to verify optimal baseline 6
• Blood typing and antibody screening for potential transfusions 6
• Cardiovascular and respiratory assessment, review of recent infections, and transfusion history 6
• Active infection or acute hemolytic crisis are absolute contraindications to elective splenectomy 6

Surgical Considerations:

• Identify and remove any accessory spleens at the time of splenectomy to prevent recurrence of hemolysis 1
• Perform concurrent cholecystectomy if gallstones are present 1, 4

Post-Splenectomy Management

Immediate Postoperative Care:

• If vaccines were not given preoperatively, vaccinate as soon as the patient is stable postoperatively, ideally within 14 days of surgery 6
• Maintain aggressive hydration, oxygenation (SpO2 >95%), normothermia, and multimodal analgesia 6
• Continue intravenous hydration until oral intake is fully re-established 6
• Encourage early mobilization and incentive spirometry to prevent pulmonary complications 6

Lifelong Infection Prophylaxis:

• Lifelong prophylactic phenoxymethylpenicillin (oral penicillin V) should be offered in all cases, with particular emphasis on the first two years post-splenectomy when risk is highest 6
• Erythromycin for patients allergic to penicillin 6
• Patients should keep amoxicillin at home to use immediately if symptoms of infection develop 6
• Reimmunization every 5-10 years for long-term protection 6

Patient Education:

• The risk of overwhelming post-splenectomy infection (OPSI) is lifelong, with 0.5-2% incidence and 30-70% mortality, with most deaths occurring within 24 hours of symptom onset 6
• Cases of fulminant infection have been reported more than 20 years after splenectomy 6
• Animal bites require immediate antibiotic coverage (5-day course of co-amoxiclav or erythromycin) due to susceptibility to Capnocytophaga canimorsus 6
• Provide information leaflet and patient card about splenectomy for emergency situations 6
• Notify general practitioner of splenectomy and vaccinations given 6

Expected Outcomes

• Spherocytosis persists following splenectomy, but hemolysis is alleviated and clinical cure of anemia is achieved for most patients 1
• Patients with recessively inherited spherocytosis are exceptions—although significantly benefited by splenectomy, their anemia is not completely corrected 1
• Splenectomy reduces hemolysis and thereby decreases the risk for development of pigment gallstones 1
• Hemoglobin levels normalize, reticulocyte counts decrease to nearly normal, and hyperbilirubinemia resolves 1

Management Without Splenectomy

• Mild HS cases may be managed conservatively with observation, folic acid supplementation (to support increased erythropoiesis), and monitoring for complications 5
• Avoid splenectomy in very mild cases where anemia is minimal and quality of life is not impaired 5
• Regular monitoring for gallstone development and hemolytic crises is essential 4

Common Pitfalls and Caveats

• Do not perform splenectomy in children under 5-6 years unless absolutely necessary due to life-threatening complications, as OPSI risk is highest in this age group 6, 1
• Never proceed with elective splenectomy during active infection or hemolytic crisis 6
• Failure to identify and remove accessory spleens can result in persistent hemolysis 1
• Inadequate preoperative vaccination (given <2 weeks before surgery) results in suboptimal antibody response 6
• Genetic diagnosis may be missed when relying solely on blood smear and OFT in atypical presentations—maintain high index of suspicion and proceed to NGS when diagnosis is uncertain 2, 3
• Overtransfusion must be avoided in patients with acute splenic sequestration, as sequestered red cells may be acutely released from the spleen 7