Characteristics of an Unhealthy RBC

Biree Andemariam, MD: Nirmish, let’s start with you. This is a broad question. What attributes would you assign to an unhealthy red blood cell?

Nirmish Shah, MD: Matt [Heeney] did a great job summing things up and not spending a 60-min lecture on it. It’s a complicated topic. It really is. To start, an unhealthy red blood cell is just having things that go wrong in all of what Matt just said. [Sometimes] the hemoglobin is abnormal and unable to dissociate from the oxygen in the correct way—for example, in sickle cell disease, it’s dumping oxygen too quickly because the curve is shifted to the right. [Sometimes] the red blood cell is rigid and sickling, and there’s an increase in exposure to sticky proteins, P-selectin…and different proteins on the surface because you don’t have access to energy like ATP [adenosine triphosphate] to try to bring those things back in. All of the above lead to an unhealthy red blood cell.

Unfortunately, in sickle cell disease, which is the topic today, they have all of the above. They have everything as a cascade of events occurring. It starts with polymerization. The polymerization— [which is like] LEGOs sticking together—then causes this cascade of issues where the red blood cell is unhealthy, and you have all these signs with not enough enzymes, not enough healthiness to the red blood cell health on the surface of the cell. Thus, it’s a constellation of things. In the end, it’s all of what Matt just said together in 1 package. It’s unfortunate, but it’s what we focus on to try to correct that.

Biree Andemariam, MD: Exactly. Elna, let’s talk about some other terms people use when they talk about an unhealthy red blood cell in somebody with sickle cell disease, like red blood cell sickling, hemolysis, the resultant vasocclusion—simply put, the shortened life span, right? These are things that we’ve talked about among one another as colleagues and also with our patients and families. What are some of the pathophysiological underpinnings that lead to sickling, hemolysis, and vasocclusion?

Elna Saah, MD: Matt and Nirmish have done an elegant job and made my work easy. They’ve laid the foundation for everything that happens, starting with the polymerization in the membrane from the outside and hemoglobin on the inside. That’s what has been a little difficult for us to translate even in conveying a message to our colleagues. Sickle cell [disease] is a progressive disease. Nirmish is a life span hematologist, and pediatricians have historically focused on the … sickle cell, forgetting that this constellation of things happening is what makes sickle cell a progressive end-organ disease.

The mechanical distortion of the red blood cell causes the occlusion, but the interaction with the vascular endothelial lining, the release of all these adhesive molecules, and the increased stickiness in the sterile inflammation that happens is the result of hemolysis and free radicals. As Matt said, oxygen itself is very toxic. You have to have other molecules to help that.

First, oxygen is bound to hemoglobin and iron. It’s not supposed to be left walking around freely. Once you have hemolysis in you, and you have free hemoglobin in the plasma, you deplete nitric oxide, and you have these direct toxicities to the endothelial membrane. This further cascades downstream all your other inflammatory cytokines, making the whole process of the white blood cells, platelets, red blood cells, and vascular endothelium, causing that interaction that promotes end-organ dysfunction. The heart, the kidneys, microalbuminuria…increased pulmonary hypotension. Even if patients haven’t had an acute chest obstruction to the lungs, how do they develop pulmonary hypotension in the absence of having had a chest crisis. Understanding this pathophysiology makes it more important or easier for us to introduce the names of disease-modifying agents, even in an otherwise well-appearing person who’s doing OK.

Transcript edited for clarity