Sickle cell disease

Sickle cell disease

Updated: 7/11/2024

© Jun Wang, MD, PhD

 

General features

• All genotypes containing at least one sickle gene, in which HbS makes up at least half the hemoglobin
• Autosomal recessive
• Caused by a single point mutation in the β globin gene
• Characterized by the presence of hemoglobin S (HbS)
• Sickle shaped RBC resulted from HbS polymerization under deoxygenated conditions
• Homozygous HbS disease (HbSS) most common in North America
• More common in people of African and Mediterranean ancestry

Major forms

• HbSS disease or sickle cell anemia (SCA): most common, homozygote S globin, a severe or moderately severe phenotype and with the shortest survival
• HbS/β-0 thalassemia: heterozygote for both HbS and β-0 thalassemia, indistinguishable from SCA
• HbS/β+ thalassemia: Mild-to-moderate severity with variability in different ethnicities
• HbSC disease: heterozygote for both HbS and HbC, moderate clinical severity
• HbS/hereditary persistence of fetal Hb (S/HPHP): Very mild or asymptomatic phenotype
• HbS/HbE syndrome: Very rare, similar to HbS/β+ thalassemia
• Others: Rare, HbD Los Angeles, G-Philadelphia, HbO Arab, and others

Key pathogenesis

• Glutamate to Valine substitution at codon 6 of b chain
• Polymerization triggered by hypoxia results in sickling of RBCs and membrane damage

o   Calcium influx trigger cross-linking of membrane proteins

o   Activation of ion channels cause efflux of K and water

• Polymerization may be precipitated by infection, acidosis, dehydration, or deoxygenation produced by physiologic stress
• Abnormal RBC aggregates may cause vaso-occlusive crisis

Key clinical features

• Periodic crises and hemolytic anemia
• Ranging from mild to severe symptoms
• Anemia

o   Moderately severe hemolytic anemia: Hct of 18-30%

o   Usually mild anemia symptoms: HbS releases oxygen more easily to tissues

• Crises: Vaso-occlusive, sequestration, aplastic or hemolytic
• Complications: Acute chest syndrome, hand-foot syndrome, stroke, etc
  

Vaso-occlusive crisis

• Most common sites: bones, lungs, liver, brain, spleen, penis
• Associated with slow transit time in spleen, marrow and inflamed tissues
• Slower transit time in inflamed tissues due to

o   Adhesion of WBCs and RBCs to activated endothelial cells

o   Transudation of fluid

o   Higher levels of cell adhesion molecules of sickle cells

o   Binding to endothelial P-selectin on cells

o   Platelets P-selectin promotes RBC and WBC aggregates

• Precipitated by sickling in microvascular beds triggered by

o   Infection

o   Acidosis

o   Dehydration

o   Deoxygenation

• Results in hypoxic injury and infarction with severe pain
• Free hemoglobin depletes NO (nitric oxide), resulting in vasoconstriction and enhancing platelet aggregation

Sequestration crises

• Splenic sequestration
• Most common in children <5
• Massive entrapment of sickle red cells causing rapid spleen enlargement, hypovolemia and sometimes shock
• Can be life-threatening
• Recurrent attacks may require splenectomy

Aplastic crises

• Associated with parvovirus B19 infection
• Reduced blood production with reduced reticulocytes
• May be self-limited, marrow function may recover in 7-10 days

Hemolytic crisis

• Increased rate of hemolysis
• Decreased Hb
• Relative rise in reticulocytes
• Usually accompanied by a pain crisis

Acute chest syndrome

• New radiodensity on chest radiograph with fever and/or respiratory symptoms
• Medical emergency needing immediate treatment
• May lead to acute respiratory distress syndrome
• Commonly associated with infection, pulmonary, fat emboli
• UNKOWN CAUSE in over 40%
• Inflammation/hypoxemia triggered vaso-occlusion
• Vaso-occlusive crises involving ribs, spine and abdomen resulting in hypoventilation, atelectasis and hypoxia
• Fever, cough, chest pain, tachypnea, pulmonary infiltrates with decreased arterial PO₂

Other complications

• Hand-foot syndrome

o   Painful crises involving bones, esp. in hands and feet

o   Common in children

o   Need to differentiate from osteomyelitis, frequently caused by Salmonella species

o   Frequently multiple sites and symmetrical

• Stroke

o   Results of vascular occlusion

o   Many pts may have silent cerebral infarcts by 6 years old

• Pulmonary hypertension
  
• Proliferative retinopathy
• Pigmented gallstones
• Papillary necrosis of kidneys (can’t concentrate urine leading to propensity to dehydration which may worsen sickling)
• Infection: poor or absent spleen function
• Other presentations depending on organ/structure affected by occlusion

Key Laboratory and pathological findings

• Peripheral blood smear

o   Sickle cells

§  Dehydrated, dense and rigid sickle shaped RBC

§  May cause microvascular occlusion and infarction

§  Removed by spleen (extravascular hemolysis) or intravascular hemolysis due to mechanical fragility

o   Reticulocytosis

o   Target cells

o   Aniso- and poikilocytosis: Variation in size and shape

o   Howell-Jolly bodies: Remnant of nuclei

• Bone marrow: hyperplastic with erythroid hyperplasia
• Bone: resorption with expansion of marrow and secondary new bone formation
• Findings of complications: infarct

Diagnosis

• Mandatory screening for HbS at birth in the United States
• History of chronic hemolytic anemia and vaso-occlusive crisis
• Electrophoresis: presence of HbS and other hemoglobinopathies
• Workups for complications

Management

• Symptom control and management of disease complications
• Self-treatment with bed rest, oral analgesia, and hydration
• Prevention and treatment of infections, stroke
• Detection and treatment of Pulmonary hypertension
• Transfusion as prophylaxis: in patients with frequent crises, suppress HbS production
• Hydroxyurea

o   Increases HbF levels

o   Anti-inflammatory effect by inhibiting WBC production

• Stem cell transplantation

Sickle cell trait

• Heterozygotes with one HbS allele and one normal adult hemoglobin (HbA) allele
• Around 40% HbS
• Resistance to Plasmodium falciparum malaria
• Less severe clinical course in individuals with one copy of HbS and one copy of a gene that codes for another abnormal variant of hemoglobin, such as HbC or Hb b-thalassemia
• May have hematuria, with inability to concentrate urine, but no anemia
• Tissue hypoxia may cause sickling
• Similar complications to SCD if hypoxia or physiologic stress

 

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