Hematology · Hemoglobinopathies
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Sickle cell disease is caused by a point mutation in the beta-globin gene resulting in the substitution of valine for glutamic acid at the sixth position of the beta-globin chain.
Hydroxyurea is the first-line disease-modifying therapy used to increase fetal hemoglobin (HbF) levels and reduce the frequency of vaso-occlusive crises.
Patients with sickle cell disease are functionally asplenic due to autosplenectomy from repeated microvascular infarctions, necessitating prophylactic penicillin until age five and encapsulated organism vaccinations.
Acute chest syndrome is the leading cause of death in adults with sickle cell disease, characterized by new pulmonary infiltrates on chest X-ray, fever, and respiratory distress.
Osteomyelitis in sickle cell patients is most commonly caused by Salmonella species, whereas Staphylococcus aureus remains the most common cause in the general population.
Aplastic crisis is a transient arrest of erythropoiesis typically triggered by Parvovirus B19 infection, presenting with a profound drop in hemoglobin and an absent reticulocyte count.
Transcranial Doppler (TCD) ultrasonography is the gold standard screening tool in children aged 2–16 with HbSS or HbSβ0 thalassemia to assess the risk of ischemic stroke by measuring cerebral blood flow velocity.
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A 24-year-old male with a history of sickle cell disease presents to the emergency department with a 2-day history of fever, cough, and shortness of breath. Physical examination reveals tachypnea and oxygen saturation of 88% on room air. Chest X-ray demonstrates a new consolidation in the right lower lobe. The patient is currently on daily hydroxyurea and folic acid.
What is the most appropriate next step in management?
Empiric antibiotics (ceftriaxone and azithromycin), supportive care (oxygen, fluids, pain control, incentive spirometry), and red blood cell transfusion for the hypoxemia
The patient presents with classic signs of acute chest syndrome, which is a medical emergency requiring immediate supportive care, incentive spirometry, and antibiotics covering typical and atypical pathogens (cephalosporin plus macrolide); with an SpO2 of 88% on room air this qualifies as severe ACS, for which ASH recommends red cell transfusion (exchange transfusion if rapidly progressive).
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Etiology / Epidemiology
Autosomal recessive mutation in beta-globin gene (HbS). High prevalence in African descent due to malaria protection.
Clinical Manifestations
Vaso-occlusive crisis causing dactylitis (infants) and acute chest syndrome. Splenic sequestration is a life-threatening emergency.
Diagnosis
Hemoglobin electrophoresis is the gold standard. Peripheral smear shows sickle cells and Howell-Jolly bodies.
Treatment
Hydroxyurea is first-line for prevention. Avoid dehydration and hypoxia to prevent sickling.
Prognosis
High risk of functional asplenia by age 5. Prophylactic penicillin required until age 5.
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Epidemiology & Etiology
Autosomal recessive inheritance of the HbS mutation (glutamic acid to valine substitution). Most common in individuals of African, Mediterranean, and Middle Eastern descent. Heterozygotes (trait) are generally asymptomatic but provide a survival advantage against Plasmodium falciparum.
Pertinent Anatomy
The spleen undergoes progressive infarction and fibrosis, leading to functional asplenia. Microvascular occlusion affects the bones, lungs, and brain, causing end-organ damage.
Pathophysiology
Deoxygenated HbS polymerizes into rigid fibers, distorting RBCs into a sickle shape. These cells cause microvascular occlusion and hemolysis. Chronic hemolysis leads to pigment gallstones and hyperbilirubinemia.
Clinical Manifestations
Patients present with dactylitis (painful swelling of hands/feet) in early childhood. Acute chest syndrome is defined by new pulmonary infiltrates and respiratory distress. Splenic sequestration presents with rapid splenic enlargement and profound anemia.
Diagnosis
Hemoglobin electrophoresis confirms the diagnosis. Peripheral smear reveals sickle cells and Howell-Jolly bodies (indicating asplenia). Newborn screening is universal in the US.
Treatment
Hydroxyurea is the first-line agent to increase HbF levels. Other FDA-approved options include L-glutamine and crizanlizumab, plus the curative-intent gene therapies exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) (approved December 2023). Voxelotor (Oxbryta) was voluntarily withdrawn worldwide in September 2024 for safety and should no longer be prescribed. Avoid dehydration, hypoxia, and cold exposure to prevent crises. Management of acute pain requires aggressive hydration and opioid analgesics.
Prognosis
Patients require prophylactic penicillin until age 5 to prevent Streptococcus pneumoniae sepsis. Stroke is a major complication; monitor with transcranial Doppler in children.
Differential Diagnosis
HbSC disease: milder anemia but higher risk of retinopathy
Thalassemia: microcytic anemia with target cells
Hereditary spherocytosis: positive osmotic fragility test
G6PD deficiency: episodic hemolysis triggered by fava beans or drugs
Aplastic anemia: pancytopenia without splenomegaly