Sickle Cell Disease

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Pathophysiology

Summary

Sickle cell anemia is an autosomal recessive disorder that results from sickle-shaped RBCs caused by a variant of hemoglobin, hemoglobin S (HbS). This arises from a missense mutation in the beta globin gene on chromosome 11, where glutamic acid is replaced by valine due to a GAG to GTG mutation. In sickle cells, replacing the negatively charged glutamic acid with nonpolar valine enhances hydrophobic interactions in hemoglobin. This triggers the polymerization of deoxy-HbS into fibers that distort the RBC shape. Factors like hypoxia, cellular dehydration, and acidosis facilitate this polymerization and sickling.

The cycle of polymerization and depolymerization damages sickle cells, leading to potassium leakage and further cellular dehydration, which exacerbate sickling. These sickle cells become rigid, making them especially vulnerable to extravascular hemolysis within the spleen. They are also susceptible to intravascular hemolysis, though to a lesser degree.

Carriers with one mutated beta globin allele display sickle cell trait and usually lack anemia symptoms due to the presence of normal beta subunits that offset low deoxy-HbS levels, inhibiting polymerization. Nevertheless, extreme circumstances such as severe hypoxia or acidosis can trigger sickling.

Having two HbS mutations leads to full-blown sickle cell disease, marked by anemia and vasoocclusive complications from increased adhesion molecules on sickle cells. Initially, patients experience the abnormally shaped RBC collect in the spleen, causing splenomegaly. Over time, the spleen becomes fibrotic and dysfunctional, leading to the presence of Howell-Jolly bodies in blood smears that signify compromised splenic function. Most patients with SCD eventually undergo autosplenectomy, increasing vulnerability to encapsulated bacterial infections and necessitating vaccinations and penicillin prophylaxis.

For children with SCD, preventive care includes vaccination for encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae to mitigate serious infection risks. A common pediatric complication is splenic sequestration, where rapid blood accumulation in the spleen leads to drops in hemoglobin, hematocrit, and triggers hypotension from reduced intravascular volume.

SCD can trigger an aplastic crisis, often induced by Parvovirus B19, leading to a rapid decrease in both hemoglobin and hematocrit levels. Reticulocyte count is decreased in aplastic crisis due to inhibition of bone marrow RBC production. Another hallmark of SCD is vasoocclusion, where sickle cells block small capillaries and result in multi-organ pain and damage. Clinical features include dactylitis, or hand-foot syndrome, along with severe complications such as avascular necrosis of the femoral head and acute chest syndrome.

In acute chest syndrome, CXR commonly show pulmonary infiltrates, mimicking pneumonia. Extramedullary hematopoiesis gives the skull a ‘crew cut’ appearance on X-ray. SCD can lead to neurological and genitourinary issues like ischemic stroke, priapism, hematuria, and eventually chronic kidney disease due to renal micro-infarcts. Another SCD adaptation is extramedullary hematopoiesis, where hematopoiesis extends from medullary to cortical bone in response to ongoing hemolysis.

Sickle cell trait provides a protective effect against Plasmodium falciparum, and hemoglobin electrophoresis in sickle cell trait shows primarily HbA1, the normal adult hemoglobin, with a smaller HbS band. Conversely, sickle cell disease is characterized by a predominance of HbS on electrophoresis, along with prolonged production of fetal hemoglobin (HbF) into adulthood. Hydroxyurea serves as an essential treatment for sickle cell disease by promoting HbF production. When sickle cell trait coexists with another beta globin defect, such as beta thalassemia trait, the phenotype resembles sickle cell disease.

Hemoglobin C results from a missense mutation in the beta globin gene and causes mild hemolytic anemia when homozygous. Hemoglobin SC disease, resulting from one HbS and one HbC mutation, results in a condition that is similar to but milder than sickle cell disease.

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FAQs

What is the underlying genetic cause of sickle cell disease and how does it affect red blood cells?

Sickle cell disease is caused by a missense mutation in the beta globin gene located on chromosome 11. This mutation changes a single nucleotide, leading to the substitution of glutamic acid with valine in the hemoglobin molecule, forming hemoglobin S (HbS). The presence of valine increases hydrophobic interactions between hemoglobin molecules, causing them to polymerize. This polymerization leads to the formation of elongated, rope-like fibers within the red blood cells, distorting them into a sickle shape. These sickle-shaped cells are prone to clumping and are less flexible, leading to various complications.

What factors promote the sickling of red blood cells in sickle cell disease?

Several factors can exacerbate the sickling of red blood cells in sickle cell disease. Hypoxia promotes the polymerization of deoxygenated HbS, which increasing sickling. Cellular dehydration also contributes by increasing the intracellular concentration of HbS, thereby promoting polymerization. Acidic conditions shift the hemoglobin dissociation curve to the right, making it easier for hemoglobin to give up oxygen, which in turn increases the levels of deoxygenated HbS and promotes polymerization and sickling.

How does sickle cell disease affect the spleen?

In sickle cell disease, the spleen becomes congested and enlarged in early childhood due to the sequestration of sickled red blood cells, leading to splenomegaly. Over time, the spleen becomes dysfunctional due to occlusion of its microvasculature by sickled cells, resulting in ischemia and fibrosis, a condition known as ‘splenic fatigue.’ Autosplenectomy often occurs by adulthood, resulting spleen becomes severely dysfunctional and fibrotic. This leads to an increased risk of infections, making vaccinations and penicillin prophylaxis critical in early childhood.

What complications can arise in sickle cell disease?

Sickle cell disease can lead to a variety of complications due to vasoocclusion, where sickled cells get stuck in small capillaries. This can result in pain in various organs, dactylitis or ‘hand-foot syndrome,’ and even avascular necrosis of the femoral head. Acute chest syndrome, characterized by severe pain and respiratory distress, can also occur. Other complications include ischemic stroke, priapism, hematuria, and chronic kidney disease.

How is sickle cell trait different from sickle cell disease?

Sickle cell trait occurs when an individual has one mutated beta globin allele and one normal allele, leading to a mix of normal hemoglobin (HbA) and hemoglobin S (HbS). In most cases, the low concentration of HbS is insufficient to cause sickling and anemia under normal conditions. However, under extreme circumstances such as severe hypoxia, dehydration, or acidosis, significant sickling can occur. Unlike sickle cell disease, which is a chronic condition, sickle cell trait generally does not cause anemia or the range of complications seen in the disease.