Impact of biochemical, epigenetic and genetic factors on erythrocyte health

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

Matthew M. Heeney, MD: An increase in 2,3-DPG shifts the sigmoid-shaped oxygen dissociation curve to the right. This increases the measurement of p50 that we use in the laboratory, which is the partial pressure of oxygen at which 50% of hemoglobin is saturated at that time. By increasing 2,3-DPG, you decrease hemoglobin’s affinity for oxygen. Imagine if you were going for a run. You would increase the acid in the muscle, and you would increase the temperature in the muscle. You can also increase 2,3-DPG to allow more oxygen delivery to this muscle. It works and needs more oxygen and more energy. It is a way in which the body can modify the way it reacts physiologically to certain situations.

Pharmacologically, the other way to manipulate this curve would be to try to find a way to decrease 2,3-DPG. This is why there is a lot of interest in pyruvate kinase activators – allosteric activators that increase the activity of one of the last steps of the glycolytic pathway – to increase the flow through this pathway and produce more d ‘ATP. [adenosine triphosphate] energy, which can make the cell healthier but also decreases some of the by-product of 2,3-DPG. By doing this, using or not allowing this 2,3-DPG to build up, you can increase oxygen affinity and therefore have potentially beneficial effects in certain red blood cell disease states. It’s an interesting molecule, and it’s a way we’ve developed over time to modulate the delivery of oxygen to our tissues when they need it. We can potentially manipulate this pharmacologically.

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

Elna Saah, MD: This is another 60 minute discussion. In sickle cell disease [disease] and red blood cells, we have researched parameters and biomarkers over the past 2-3 decades to give us an indication of how severe a patient’s sickle cell disease is. A few have been validated and are known. The first of these is fetal hemoglobin. With patients’ fetal hemoglobin, if you keep after the transition from fetal hemoglobin to adult hemoglobin, it is supposed to disappear completely at the age of 6 months. Patients with hemoglobinopathies retain some of this fetal hemoglobin, and this depends on many patterns of genetic inheritance. Some people retain more, and some lose almost all of it – and only have 3%, 5%, 7% – and some retain slightly higher fetal hemoglobin. Fetal hemoglobin induces, and that’s how we realized that hemoglobin induction as a pharmacological modality – as a disease modifying agent – is very useful. We have 20 years to ourselves to validate the proof of principle.

The other genetically modulated thing is the concurrent inheritance of the alpha-thalassemia trait. We are talking about beta-hemoglobin disorders. If you have alpha thalassemia trait inheritance and slightly more microcytosis, it modulates the disease and intends to have slightly higher hemoglobin and slightly modulated pathophysiological events in end-organ dysfunction. [There are] other things, like epigenetics. In patients who have a concurrent iron deficiency, this can make the red blood cells somewhat stiffer. Iron overload, on the other hand, is when patients have overloaded from the transfusion 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 it may not be as strong an epigenetic or genetic biomarker as we thought. All red blood cell and white blood cell microantigens, such as Duffy [antigens], also correlated with a slightly low white blood cell count. These indirect elements can modulate the severity of sickle cell disease. But overall, very few have been validated as potential biomarkers of disease severity or healthy behavior in sickle cell disease.

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

Nirmish Shah, MD: I’ll start by pointing out that even if you have hemoglobin SS or sickle cell SS, there is a lot of variation. There are patients who have SS and have high hemoglobin…. We have SS patients who historically have a lot of problems. There are sub-phenotypes, 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 are many things that are not understood. There is an effort to do whole genome sequencing. Look at these small mutations to try to find the sub-phenotypes. It’s essential because when you find these sub-phenotypes, it would be nice to be able to find – it’s almost the holy grail – sub-phenotypes of patients who have, for example, the SS type but who would be more susceptible to this type of therapy compared to another type. Right now we’re throwing it all on the patients, and I’m so thankful we have options. But we don’t have this sub-phenotyping yet. Genetics is part of the puzzle. I’m glad it’s raised because that’s where we need to go.

Transcript edited for clarity

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