Sickle Cell Disease Pathophysiology

Ify Osunkwo, MD, MPH: Patients with sickle cell disease often face unique challenges and have long suffered silently through vaso-occlusive crises. This can very painful and is a very frequent reason for emergency department visits and hospitalizations. For nearly 2 decades, hydroxyurea was the only FDA-approved therapy for sickle cell disease.

In today’s discussion our panel of experts will discuss the emerging therapies that have been developed to target specific pathophysiological mechanisms of sickle cell disease, either as preventive therapy or abortive approaches to vaso-occlusive crisis.

My name is Dr Ify Osunkwo. I’m a professor of medicine at Atrium Health in Charlotte, North Carolina. I’m also the director of the Sickle Cell Disease Enterprise at the Levine Cancer Institute and at Atrium Health.

I am joined by 4 amazing experts. First, I have by Dr Biree Andemariam, who’s an associate professor of medicine, and the director of the New England Sickle Cell Institute at the University of Connecticut Health Center in Farmington, Connecticut. Biree, welcome to the panel.

Biree Andemariam, MD: Thank you.

Ify Osunkwo, MD, MPH: I am also joined by Dr Matt Heeney, the associate director of the hematology program in the Division of Hematology and Oncology, the director of the sickle cell program, and an assistant professor at Harvard Medical School in Boston, Massachusetts. Welcome, Matt. Good to see you.

Matthew M. Heeney, MD: Thank you.

Ify Osunkwo, MD, MPH: Next, on my left is Dr Julie Kanter, a lifespan hematologist, director of the Adult Sickle Cell Program, and associate professor at the University of Alabama School of Medicine in Birmingham, Alabama. Welcome Dr Kanter.

Julie Kanter, MD: Thanks.

Ify Osunkwo, MD, MPH: Last but not the least, I have Dr Nirmish Shah. He’s an associate professor of medicine, pediatrics and nursing at Duke University School of Medicine, in Durham, North Carolina. Welcome.

Nirmish Shah, MD: Thanks.

Ify Osunkwo, MD, MPH: Thank you for joining us, and let’s begin this panel.

We’re going to begin our conversation, I’m going to ask each of the panelists some questions and they’re going to give us their perspective, and we’ll have a back and forth dialogue.

Starting with Dr Heeney, what is the pathophysiology of sickle cell disease? Tell us about the genetics of the disease and how people can get sickle cell disease.

Matthew M. Heeney, MD: Sickle cell disease is a classic autosomal recessive disorder, meaning that you must inherit the trait from each parent, and this is a disease of the red blood cell and particularly hemoglobin, the main protein within the red blood cell. The mutation in the blood cell, when the hemoglobin deoxygenates, it exposes a hydrophobic amino acid on the protein, and those hydrophobic amino acids can noncovalently polymerize, or join to each other. And when enough of those hemoglobin molecules polymerize, they can change the shape of the red blood cell from its normal biconcave disc into a pathognomonic sickle cell. That sickle cell it’s rheologically unfavorable, it’s stiff, it’s not as pliable, and can play a role in complications such as vaso-occlusion. It can contribute to the blockage of blood flow, particularly in capillary beds.

The other consequence is that change of cell shape over the lifespan of the red cell, it prematurely hemolyzes, it breaks down, and that’s the other main finding in sickle cell disease, the hemolytic anemia, the shortened red-cell lifespan.

Ify Osunkwo, MD, MPH: There are different types of the sickle cell disease. Could you touch on the different genotypes and what means in terms of clinical severity of the disease?

Matthew M. Heeney, MD: The classic sickle mutation is a beta-globin mutation, and that results when bound with alpha-globin in the heterotetramer, it’s hemoglobin S. The classic form is hemoglobin SS, where you inherit the S mutation from each parent.

However, there are other combinations, compound heterozygous forms of sickle disease, where you inherit the S mutation from 1 parent, and then either another beta-globin mutation such as hemoglobin C to give SC disease, or hemoglobin S plus a beta thalassemia allele, whether it be a blank that produces no beta-globin, or it produces a small amount of beta hemoglobin, being a beta-plus thalassemia mutation. There are a variety of other rarer compound heterozygous forms, such as SO and SD, that are also considered severe sickling disorders.

Transcript edited for clarity.