Impact of Anemia & Hemolysis in Sickle Cell Disease - Episode 1
Sophie M. Lanzkron, MD, MHS, defines sickle cell disease (SCD) and discusses its pathophysiology.
Sophie Lanzkron, MD, MHS: Sickle cell disease (SCD) is an autosomal recessive genetic disorder that’s found mostly in people of African descent but can be found in people from the Mediterranean as well as East Asia. It is characterized by this genetic mutation that leads to abnormal hemoglobin, which has lots of downstream effects. The most prominent, worrisome, and concerning are acute episodes of excruciating pain.
The pathophysiology behind sickle cell disease is related to that abnormal hemoglobin that occurs due to a point mutation. You have abnormal hemoglobin that, under the right clinical conditions, begins to form polymers within the red [blood] cells. When these polymers continue to grow, the red cell changes its shape, and eventually it breaks apart and causes intravascular hemolysis as well as extravascular hemolysis. Although it’s complicated, a main component is these stiff red cells that can’t get through the microvasculature. Because the red cells are stiff and they break apart, there’s increase expression of adhesion molecules in the vascular space, and you have a very sticky environment that contributes to poor flow and venous occlusion. Patients then have vaso-occlusive events, most again, characterized by pain. There are several different types of sickle cell disease based on genotype. The most common are people who are homozygous for the sickle mutation, those who have SS disease. We also see variant disease in which patients have compound heterozygotes for hemoglobin S, and most commonly with hemoglobin C. They can also be compound heterozygous for hemoglobin S and the beta thalassemias, and there are also a few very rare genotypes that exist.
The genetic, underlying factor related to sickling is the sickle hemoglobin and the point mutation, which is the placement availing for glutamine at the sixth amino acid position of the beta globin chain. We know that single point mutations don’t happen in isolation, and there are lots of other factors that help us characterize the disease and change the disease phenotype. Those things include baseline white [blood cell] count. We know that individuals who have higher white counts at baseline will potentially have a more severe disease. We know that people who have hereditary persistence of fetal hemoglobin will have a more mild form of the disease. There are other things like coinheritance of alpha thalassemia that can also affect the disease phenotype. But there are things that are undoubtedly genetic that we don’t know, or don’t understand well enough, that change the phenotype. There is this broad spectrum of people who have hemoglobin SS who can have mild disease to very severe disease. The same is true for people who have the variants like hemoglobin SC disease. We don’t necessarily understand all of the factors that are related to the expression of the disorder and the severity of the disease.
For the prevalence of sickle cell disease, in the United States it is considered rare, with only about 100,000 people who have the disease. But that’s not true worldwide. We know there are millions of people who have sickle cell disease, mostly in Africa. We know that about 50,000 children in Africa die per year before their fifth birthday due to sickle cell disease. While the burden in this country is not overwhelming, it is certainly very impactful in other parts of the world.
Transcript edited for clarity.