Sickle Cell Anemia PDF

# Anemia drepanocítica ## Hemoglobinopatías * A group of hereditary disorders where mutations cause structural abnormalities in hemoglobin * **Sickle cell anemia** is the prototypical hemoglobinopathy * Caused by a mutation in the B-globin that leads to sickle hemoglobin (HbS) * There are many oth...

# Anemia drepanocítica ## Hemoglobinopatías * A group of hereditary disorders where mutations cause structural abnormalities in hemoglobin * **Sickle cell anemia** is the prototypical hemoglobinopathy * Caused by a mutation in the B-globin that leads to sickle hemoglobin (HbS) * There are many other hemoglobinopathies, but they are less common ## Sickle Cell Anemia * Most common inherited hemolytic anemia * HbS protects against malaria * HbS allele is prevalent in areas where malaria was endemic, including: * Equatorial Africa * Parts of India * Southern Europe * Middle East * 8% of people of African descent in the U.S. are heterozygous carriers of the HbS allele * 1 in 600 people of African descent in the U.S. have sickle cell anemia ## Pathogenesis * Sickle cell anemia is caused by the substitution of a single amino acid in the B-globin * This substitution causes a tendency for deoxygenated HbS to self-associate into polymers * Normal hemoglobins are tetramers composed of two pairs of similar chains * Adult erythrocytes contain 96% HbA, 3% HbA2, and 1% fetal hemoglobin (HbF) * HbS replaces HbA entirely in sickle cell anemia patients * HbS replaces approximately half of HbA in heterozygous carriers * HbS differs from HbA by having a valine residue instead of a glutamate residue at the sixth amino acid position of the B-globin * In deoxygenation, HbS molecules undergo a structural change that allows them to form polymers through intermolecular contacts involving the abnormal valine residue * These polymers distort the erythrocyte, making it sickle shaped (Fig. 10.3) ## Sickle Cell Crisis * Initially, erythrocyte deformation is reversible with reoxygenation * However, membrane distortion from each sickle cell episode leads to: * Influx of calcium * Potassium and water loss * Damage to the membrane skeleton * This cumulative damage leads to irreversibly sickle-shaped cells prone to hemolysis ## Factors Affecting Sickle Cell Polymerization * Intracellular concentrations of hemoglobins other than HbS * Intracellular concentration of HbS * The time it takes for erythrocytes to travel through the microvasculature ### Concentrations of hemoglobins other than HbS * Heterozygotes have approximately 40% HbS and 60% HbA * HbA interacts weakly with deoxygenated HbS * Erythrocytes in HbS heterozygotes have a much lower tendency to sickle * This is why HbS heterozygotes are said to have sickle cell trait * Fetal hemoglobin (HbF) interacts weakly with HbS * Newborn sickle cell anemia patients don't manifest the disease until HbF decreases to adult levels at 5-6 months * Hemoglobin C interacts weakly with HbS * HbC is also protective against *Plasmodium falciparum* malaria * 2.3% of African Americans are heterozygous carriers for HbC * 1 in 1250 are compound heterozygotes for HbC/HbS ### Intracellular concentration of HbS * Dehydration increases Hb concentration, making it easier for sickle cells to form * Alpha-thalassemia decreases Hb concentration and reduces sickling ### Time of transit through the microvasculature * Normal transit time through the capillary beds is too short for significant HbS polymerization * The spleen and bone marrow are the most sensitive tissues to sickle cell obstruction because of slow blood flow * Sickling can also occur in other microvascular beds where there are factors that slow erythrocyte transit, such as: * Inflammation ## Consequences of Sickling * Chronic hemolytic anemia, caused by erythrocyte membrane damage * Vaso-occlusion, causing ischemic tissue damage and pain crisis (Fig. 10.4) ## The Lifespan of Sickle Cells * Average lifespan of sickle cells is just 20 days, 1/6th of the normal lifespan * The severity of hemolysis correlates with the fraction of irreversibly sickled cells in the blood ## Vaso-occlusive Crisis * Not related to the number of irreversibly sickled cells * Caused by superimposed factors, such as: * Infection * Inflammation * Dehydration * Acidosis These factors increase the tendency for sickled cells to stop and become irreversibly sickled within the microvasculature ## Morphology * Sickle cell anemia is characterized by: * Chronic hemolytic anemia * Increased heme degradation to bilirubin * Microvascular obstructions that cause tissue ischemia and infarction * Peripheral blood smears show irreversibly sickled erythrocytes (Fig. 10.3) * Hypoxia causes fatty changes in the heart, liver, and renal tubules * Compensatory hyperplasia of erythroid progenitors in the bone marrow * Increased proliferation leads to: * Bone marrow reabsorption * Formation of new bone * Prominent cheekbones * A "crew-cut" appearance in skull radiographs * Extramedullary hematopoiesis in the liver and spleen * In children, there is moderate splenomegaly due to congestion of the red pulp from trapped sickled cells * Chronic splenic stasis leads to: * Hypoxic damage * Infarction * Reduction of the spleen to a non-functional nodule of fibrous tissue * This process is known as **autosplenectomy** and usually completes in adulthood * Vascular congestion, thrombosis, and infarction can affect any organ, including: * Bones * Liver * Kidneys * Retina * Brain * Lungs * Skin * The bone marrow is particularly prone to ischemia due to: * Slow blood flow * High metabolic rate * **Priapism** is another common issue and can cause penile fibrosis and erectile dysfunction * Pigment stones are common in patients with sickle cell anemia, just like those in other hemolytic anemias ## Clinical Features * Sickle cell anemia is characterized by a chronic hemolytic anemia and superimposed vaso-occlusive crises * Usually asymptomatic until 6 months of age when HbF changes to HbS * Anemia is moderate to severe, with hematocrits typically between 18% and 30% (Normal range 38-48%) * Chronic hemolysis is associated with: * Hyperbilirubinemia * Compensatory reticulocytosis ### Vaso-occlusive Crises * More severe than the underlying anemia * Characterized by pain and can cause tissue damage and significant morbidity and mortality * The most common and severe types of vaso-occlusive crises are: * **Hand-foot syndrome** * Infarction of the bones of the hands and feet * The most common presenting symptom in young children * **Acute chest syndrome**: * Inflammation of the lung * Decreased blood flow * Sickled cells trapped in the hypoxic pulmonary beds * Worsens pulmonary and systemic hypoxemia * Can trigger a vicious cycle of worsening hypoxemia, worsening pulmonary function, and increased sickling * Can be caused by fat emboli from infarcted bone * **Stroke** * Can occur in the context of acute chest syndrome * Leading causes of death in sickle cell anemia * **Proliferative retinopathy** * Vaso-occlusive events in the eye * Can cause vision loss and blindness ### Aplatic Crisis * Sudden decrease in red blood cell production * Commonly caused by parvovirus B19 infection of erythroblasts * Severe, but self-limiting ### Infections * Patients of all ages with sickle cell anemia are prone to infection * Both adults and children with sickle cell anemia are functionally asplenic * This makes then susceptible to infections caused by encapsulated bacteria, like *Streptococcus pneumoniae* * This is due to the auto-infarction of the spleen * In early childhood, even patients with enlarged spleens are susceptible to fatal bacterial infections * Sickle cell anemia patients are also prone to bacterial osteomyelitis which can occur from bacterial seeding into infarcted bone * The most common causative organisms are encapsulated bacteria and gram-negative organisms, such as: * *Escherichia coli* * *Salmonella* ## Diagnosis * Homozygous sickle cell anemia is obvious on routine peripheral blood smear and shows irreversible sickling * Sickle cell trait can be diagnosed by inducing sickling in vitro by exposing cells to hypoxia * Neonatal screening for sickle cell disease is mandatory in the United States * HbS and other hemoglobins can be detected by techniques such as gel electrophoresis * Prenatal diagnosis of sickle cell anemia can be diagnosed by: * Analyzing fetal DNA obtained from amniocentesis * Analyzing fetal DNA obtained from chorionic villus sampling ## Prognosis * Variable and highly variable * With improved supportive care, approximately 50% of patients live beyond the age of 50 * Treatment focuses on: * **Prevention of infection** * Vaccination, especially in children under 5 years old * Prophylactic penicillin * **Hydroxyurea**: * "Soft" inhibitor of DNA synthesis * Reduces crises and anemia by: * Increasing HbF levels * Exerting anti-inflammatory effects * Increasing erythrocyte size, which lowers intracellular Hb concentration * Metabolizing to NO, which is a potent vasodilator and platelet aggregation inhibitor * **Bone marrow transplantation**: * Potentially curative * **Gene transfer therapy**: * Potentially curative