Berry Andemariam, MD: This is the perfect part of a question I want to ask Matt. How are 2,3-DPG levels increased [diphosphoglycerate] The effect of red blood cells?
Matthew M Heaney, MD: An increase in 2,3-DPG shifts the sigmoid-shaped oxygen dissociation curve to the right. This increases the p50 we use in the lab, 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 went for a run. The acidity in the muscles will increase, and the temperature in the muscles will increase. You can also increase 2,3-DPG to allow more oxygen to be delivered to that muscle. It works and needs more oxygen and more energy delivery. This is the only way the body can change how it responds physiologically to certain situations.
Pharmacologically, another way to tackle this curve is to try to find a way to reduce 2,3-DPG. This is why there is a great deal of interest in pyruvate kinase activators — allosteric activators that increase the activity of one of the final steps of the glycolytic pathway — to increase flow through this pathway and produce more ATP. [adenosine triphosphate] energy, which may make the cell healthier but also reduce some of the shunt yield of 2,3-DPG. By doing so, by using or not allowing 2,3-DPG to build up, you can increase your oxygen affinity and thus have potentially beneficial effects in some cases of red blood cell disease. It’s an interesting molecule, and it’s one of the ways we’ve developed over time to modulate the delivery of oxygen to our tissues when needed. We can manipulate it pharmacologically.
Berry Andemariam, MD: It is exciting to talk about pharmacological manipulation of these important biochemical pathways. I want to focus a little. I will get back to you, Elna. Talk about some of the genetic and genetic factors that play a role in the health and well-being of red blood cells. Where will there be some diseases that lead to unhealthy red blood cells in terms of genetics and epigenetics?
Elna Saah, MD: This is another 60 minute discussion. in the sickle cell [disease] And red blood cells, we’ve looked for endpoints and biomarkers over the past two or three decades to give us an indication of the severity of a patient’s sickle cell disease. Few are validated and known. The first of them is fetal hemoglobin. With patients’ fetal hemoglobin, if you keep it after switching from fetal to adult hemoglobin, it should be gone completely by 6 months of age. Patients with hemoglobinopathy retain some of this fetal hemoglobin, and this depends on a lot of genetic inheritance patterns. Some people retain more, others lose almost all of it – and they only have 3%, 5%, 7% – and others retain slightly higher fetal hemoglobin. It stimulates fetal hemoglobin, and so we discovered that hemoglobin stimulation as a pharmacological method – as a disease-modifying agent – is of great value. We have 20 years to validate the proof of principle.
The other thing genetically modified is the heredity associated with the trait alpha thalassemia. We are talking about disorders of beta-hemoglobin. If you have inherited alpha thalassemia trait and more microcytosis, it modifies the disease and intends to have slightly higher hemoglobin and slightly modified pathophysiological events in end-organ dysfunction. [There are] Other things, like epigenetics. In patients with concomitant iron deficiency, it may make red blood cells more stiff. On the other hand, iron overload occurs when patients are overloaded from our blood transfusions.
Which hasn’t been validated over time and…is a slightly elevated white blood cell count. Genome Center [at The University of Texas at Dallas] demonstrated that this may not be as powerful for an epigenetic or epigenetic biomarker as we thought. All the exact antigens of red blood cells and white blood cells, such as Duffy [antigens]It is also associated with a slight decrease in the number of white blood cells. These indirect things may modify the severity of sickle cell disease. But overall, very few potential biomarkers of disease severity or the correctness of sickle cell behavior have been validated.
Berry Andemariam, MD: Thank you, Elna. Nearmesh or Matt, would you like to talk more about some of the other epigenetic factors that are becoming more famous?
Nermesh Shah, MD: I’ll start by emphasizing that even if you have hemoglobin SS or sickle cell disease SS, there is a lot of difference. There are patients who have SS and have high hemoglobin…. We have patients with MS who have historically had a lot of problems. There are subtypes, some of which are hereditary. I don’t think we have a complete understanding. Some are well described, Elna said, as having abnormalities of hemoglobin or alpha globin. But there is a lot that is not understood. There is an effort to do whole genome sequencing. Look at these small mutations to try to find the subpatterns. This is critical because when you find these subtypes, it would be nice to be able to find – which is almost the holy grail – subtypes of patients who have, say, type SS but would be more responsive to this type of treatment versus another type. . Right now, we’re throwing everything at patients, and I’m so grateful we have options. But we don’t have this subtype yet. Genetics is part of the puzzle. I’m glad he’s being bred because that’s where we need to go.
Text edited for clarity