Sickle Cell Disease Prevalence and Pathophysiology



Biree Andemariam, MD: Hello, and welcome to this HCPLive® Peer Exchange titled “Emerging Therapies in the Management of Sickle Cell Disease.” I am Dr Biree Andemariam from the University of Connecticut Health in Farmington, Connecticut.

Joining me today in this discussion are my esteemed colleagues Dr Michael DeBaun from Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease in Nashville, Tennessee; Dr Julie Kanter from the University of Alabama at Birmingham; Dr Wally Smith from Virginia Commonwealth University School of Medicine in Richmond, Virginia; and Dr Elliott Vichinsky from the University of California San Francisco [School of Medicine].

Our discussion will focus on providing an overview of sickle cell disease along with the available standard of care used in the management of the disease. We will also take a deep dive into the emerging therapies for the treatment of this common blood disorder. Welcome, everyone. Let’s get started.

First, let’s focus a little on the overview of sickle cell disease for some of those individuals in the audience who might not know a whole lot about it. Wally, what is sickle cell disease? What are its clinical manifestations?

Wally Smith, MD: Sickle cell disease is the most common hemoglobinopathy with worldwide prevalence. In the United States, it affects approximately 100,000 people. In Africa and India, it is far more prevalent. Because of migration, the prevalence is increasing the continents of Europe, South America, and even Australia. The disease is autosomal recessive. The prevalence is somewhat decreasing in areas where there’s genetic counseling but going up in other areas like continental Africa and India.

Biree Andemariam, MD: Interesting. What are some common clinical manifestations that are seen?

Wally Smith, MD: Clearly, early death was the first 1 that everybody noticed. Anemia is certainly another. Pain is 1 of the most common reasons for presentation. People are dying as children from infection, poor immunity, and strokes.

If you live to adulthood, it’s organ failure—particularly the lungs, the kidneys, and the brain. It is morbid and mortal. People have sudden death at home. People die from chronic disease if you make it to adulthood. People die from infection if you’re a child or from a stroke.

Biree Andemariam, MD: Let’s talk a little about that and try to understand the pathophysiology of sickle cell disease—maybe some of the genetic and epigenetic factors that lead to red blood cell sickling. Elliott, can you take that question on?

Elliott Vichinsky, MD: Yes, thank you. The pathophysiology of sickle cell disease is complex and multifactorial. But if you look at the damage and what’s activated, and you go early to the way the mutation occurs, you get a better understanding.

In mutation, the sickle mutation is the primary problem. In utero, the fetus doesn’t really have problems like that because sickle cells aren’t being made at the time. They’re making fetal blood. After birth or around then when the healthy hemoglobin A is supposed to be made, the fetus instead starts making sickle blood, hemoglobin S. This regulation is important because the switch to making hemoglobin S rather than hemoglobin F is affected by other genes so that the person always has the ability to turn on more of the F.

Once the sickle level of the hemoglobin increases in the cell, there are rather dramatic affects that happen. The red cell is deformable like a balloon. It can go through blood vessels that are smaller than itself and bounce back, and it effectively delivers oxygen. However, when the sickle level accumulates in the red cells, it is particularly sensitive to deoxygenation. When the red cell internally lowers the oxygen content or gets damaged—let’s say from membrane damage—the sickle molecules start lining up. Rather than floating around, they line up into these rigid rods together and cause a dramatic change in the cell. This cycle occurs on and off every day, 1500 to 2000 times a day. The net effect is when these rigid rods form, the cells are no longer deformable. They’re like eggshells. They’re fragile, and they have much more difficulty migrating through smaller blood vessels.

As this damage occurs because of this, the inside of the red cell is transferred to the outside and exposes the outside proteins and phospholipids that act as very high stimulators for an inflammatory response. With the sickle cell changing because of the sickle molecule forming these rods and the membrane changing so that things like PS, or phosphatidylserine, or integrons are on the outside, there’s an explosion of activity to activate thrombosis, inflammation of white cells, and macrophages. It’s a cascade of inflammatory multiarea reaction.

There are therapies that can aim for each 1 of these, but as the body starts adapting to this, its control of this is further aggravated by the vessels being damaged. There is a large phenotypic variability in these patients because this sickle molecule can be affected by the ability to regulate fetal hemoglobin and the type of sickle mutation that it’s combined with, whether it’s sickle with C or a sickle with a beta-thalassemia or sickle E. Those are all very important in a phenotypic expression.

Similarly, how anemic they are is important. The more anemic patients who have a very low hemoglobin count have a lot of problems with organ failure because of hypoxia and less with pain. People with very high hemoglobin tend to have fewer problems from the hypoxia but more from the vaso-occlusive events. The problem is if you treat any of these downstream effects, you may improve a part of it, but unless you get at the primary mutation, there’s going to be ongoing activation of these other pathways. With age, the sickle adult loses some of the ability to modify this. The vessels become rigid, and their need for oxygen increases, so there’s a gradual deterioration on top of these events as it combines with age.

Transcript Edited for Clarity

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