Understanding Red Blood Cell Health and the Management of Sickle Cell Disease - Episode 9

Impact of Biochemical, Epigenetic, and Genetic Factors in RBC Health

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Matthew M. Heeney, MD, and Elna Saah, MD, highlight the role of 2,3-disphosphoglycerate as well as epigenetic and genetic factors in RBC form and function.

Biree Andemariam, MD: That’s the perfect segue into a question I want to ask Matt. How does an increase in the levels of 2,3-DPG [diphosphoglycerate] impact red blood cell function?

Matthew M. Heeney, MD: An increase in 2,3-DPG shifts the sigmoid-shaped oxygen dissociation curve to the right. That increases the p50 measure we use in the lab, which is the partial pressure of oxygen at which 50% of the hemoglobin is saturated at that time. By increasing 2,3-DPG, you decrease hemoglobin affinity for oxygen. Imagine if you went for a run. You’d increase acid in the muscle, and you’d increase temperature in the muscle. You could also increase 2,3-DPG to allow more oxygen delivery to that muscle. It’s working and needs more oxygen and more energy delivery. That’s 1 way the body can alter how it responds physiologically to certain situations.

Pharmacologically, the other way to manipulate this curve would be to try and find a way to decrease 2,3-DPG. That’s why there’s a great deal of interest in pyruvate kinase activators—allosteric activators that increase the activity of 1 of the final steps of the glycolytic pathway—to increase flux through that pathway and to produce more ATP [adenosine triphosphate] energy, which may make the cell healthier but also decreases some of the shunt product of 2,3-DPG. By doing that, by using up or not allowing that 2,3-DPG to accumulate, you can increase oxygen affinity and therefore have potentially beneficial effects in some red blood cell disease states. It’s an interesting molecule, and it’s 1 way we’ve developed over time to modulate the oxygen delivery to our tissues when they’re needed. We can potentially manipulate that pharmacologically.

Biree Andemariam, MD: It’s super exciting to talk about pharmacological manipulation of these important biochemical pathways. I want to pivot a little. I’m going to go back to you, Elna. Talk about some of the genetic and epigenetic factors that play a role in the health and wellness of red blood cells. Where is there going to be some pathology that leads to an unhealthy red blood cell with respect to genetics and epigenetics?

Elna Saah, MD: That’s another 60-min discussion. In sickle cell [disease] and red blood cells, we’ve looked for end points and biomarkers over the past 2 to 3 decades to give us an indication of how severe an individual patient’s sickle cell disease might be. A few have been validated and are known. The first of them is fetal hemoglobin. With fetal hemoglobin of patients, if you retain after the switching from fetal to adult hemoglobin, it’s supposed to completely disappear by 6 months of age. Patients with hemoglobinopathies retain some of that fetal hemoglobin, and that depends on a lot of genetic inheritance patterns. Some people retain more, and some lose almost all of it—and have just 3%, 5%, 7%—and some retain slightly higher fetal hemoglobin. Fetal hemoglobin induces, and that’s how we figured out that inducing hemoglobin as a pharmacological modality—as a disease-modifying agent—is very valuable. We have 20 years for us to validate the proof of principle.

The other thing that’s genetically modulated is the concomitant inheritance of the alpha thalassemia trait. We’re talking about beta-hemoglobin disorders. If you have an inheritance of the alpha thalassemia trait and a little more microcytosis, it modulates the disease and intends to have slightly higher hemoglobin and slightly modulated pathophysiological events in an end-organ dysfunction. [There are] other things, such as epigenetics. In patients who have concomitant iron deficiency, it may make the red blood cell a little more stiff. Iron overload, on the other hand, is when patients have loaded from transfusion that we give.

The one that hasn’t been validated over time and … is the slightly higher white blood cell count. The Genome Center [at The University of Texas at Dallas] proved that that may not be as strong of an epigenetic or genetic biomarker as we thought. All red blood cell and white blood cell microantigens, like Duffy [antigens], also correlate with a slightly low white blood cell count. Those indirect things may modulate the severity of sickle cell disease. But by and large, very few have been validated as potential biomarkers of disease severity or how healthy the sickle cell behaves.

Biree Andemariam, MD: Thank you, Elna. Nirmish or Matt, would you like to talk more about some other epigenetic factors that are becoming more well-known?

Nirmish Shah, MD: I’ll start by emphasizing that even if you have hemoglobin SS or sickle cell disease SS, there’s a lot of variation. There are patients who have SS and have high hemoglobins…. We have patients with SS who historically have lots of problems. There are subphenotypes, and part of that is genetic. I don’t think we have a complete understanding. Some are well described, as Elna said, as having fetal hemoglobin or alpha-globin abnormalities. But there’s a lot that’s not understood. There’s an effort to do whole-genome sequencing. Look at these smaller mutations to try to find the subphenotypes. That’s critical because when you find these subphenotypes, it would be nice to be able to find—this is almost the holy grail—subphenotypes of patients who have, for example, type SS but would be most responsive to this type of therapy vs another type. Right now, we’re throwing everything at patients, and I’m so thankful that we have options. But we don’t have that subphenotyping yet. The genetics is part of the puzzle. I’m glad it’s being brought up because that’s where we need to go.

Transcript edited for clarity