Role of Unhealthy RBCs in Blood Disorders

Biree Andemariam, MD: This is an appropriate time to segue into talking about the characteristics of an unhealthy red blood cell. Matt, I’m going to let you continue where you left off. You were talking about hemoglobinopathies. Let’s talk a little about the conditions or diseases that result from a compromised state with respect to the red blood cells, including hemoglobinopathies, enzymopathies, and cytoskeletal abnormalities. Can you give us an overview of those disease states?

Matthew M. Heeney, MD: That’s like a 60-minute lecture in itself, but sure. As I said, the red blood cells are bags of hemoglobin and enzymes. It’s really pretty simple. It doesn’t have any of the organelles that Elna [Saah] talked about earlier. The diseases are in 1 of those categories. If you think about the membranopathies, the red blood cell membrane has a very complex multiprotein entity that’s bound to the bilipid membrane and provides incredible strength and durability to the red blood cells. It tours thousands of miles in its 120-day life span. If you have abnormalities in the interactions of those proteins, either connecting it vertically to the bilipid layer or horizontally between itself to keep the membrane together, those can result in different morphological changes in the red blood cell and shorten the red blood cell life span. Usually through the loss of membrane over time, the cell circulates and goes through the spleen frequently, in what we call splenic conditioning. Ultimately, that red blood cell becomes less deformable and is eventually cleared by the reticular endothelial system, macrophages in the spleen, and elsewhere.

Those membranopathies can be in that realm, but they can also have a role in terms of the hydration of the cell. Other transmembrane proteins that are integrated into the membrane are responsible for hydration, the flow of ions back and forth, and keeping the integrity of the membrane that way. There’s another family of membranopathies involved in hydration and ionic transport.

If you send signals to the enzymopathies, there are enzymes there that keep the membrane happy to some extent. There are some well-known enzymes involved, including Pyruvate kinase, which we touched on already. It’s important in the production of ATP, to keep the membrane happy, but there are several other enzyme deficiencies in that glycolytic pathway.

The other major pathway that’s important is to protect the red blood cell from the cargo that it carries. Some oxygen is extremely toxic, so you need to have enough ability to detoxify that. G6PD is the most common enzymopathy in our species, and it results in oxidative stress carrying all that oxygen. If you don’t have that pathway to try to reduce that oxidative stress and the damage it can do, then you end up shortening the red blood cell life span, which results in hemolysis. G6PD has a major role in that. These enzymes are important for both capacities: energy production and protection of the cell.

Finally, hemoglobinopathies are probably the most challenging group. I think of them as qualitative, so the body makes the right protein in adults, whether it’s alpha globin or beta globin, or it doesn’t make enough of them. There’s an imbalance in the alphas and betas together. Qualitative or quantitative, much like many type 1 or 2 protein, as some people describe them. Sickle cell is a classic qualitative hemoglobinopathy, meaning the protein is made but the protein is abnormal and leads to the downstream consequences we touched on. Thalassemia leads to an imbalance, and the coordinated production of alpha globin and beta globin in equal amounts is extremely important because excess alpha globin or beta globin within the red blood cell is highly toxic to that red blood cell, particularly in its precursor stages. In beta-thalassemia you have an excess of alpha globin, so those alpha globin precipitate inside the membrane, resulting in an apoptotic signal. Similarly, in alpha-thalassemia, an excess in beta globin results in ineffective erythropoiesis of the bone marrow, premature apoptosis, and all the downstream consequences of ineffective erythropoiesis. It’s an interesting large and heterogenous group of disorders of the red blood cell. That’s the overview in a simple way.

Biree Andemariam, MD: That was fantastic, Matt. Really fantastic. Some of that will spur our discussion here. You gave such a nice overview of how hemoglobin, enzymes, and membranes are so important to red blood cell health and where deficiencies or qualitative defects in various entities can lead to disease.

Transcript edited for clarity