Elna Saah, MD, provides an overview of sickle cell disease and comments on disease pathophysiology.
Biree Andemariam, MD: I think this discussion on quality of life has been so important and particularly for our audiences to really understand the impact of sickle cell disease on the day-to-day life of those living with it and their families that they’re there to support them. And thus, I think we can segue now into another important topic, which is how do we treat individuals with sickle cell disease? And thinking about that question, what are the unmet needs? But before we get to that, Elna, can you give us a brief overview of sickle cell disease and its pathophysiology?
Elna Saah, MD: Absolutely. I think I’m liking this 60-minute sessions cracked down into 2½ minutes. But we’ll do our best to see if we can give a complete overview and a summary of sickle cell disease. I would mention, even talking about the normal in the sickle cell, you have a hemoglobinopathy where the beta gene is mutated. And for you to have sickle cell disease, you must sickle—you must have a sickle hemoglobin and not that abnormal hemoglobin. And patients with sickle cell disease will have homozygous hemoglobin SS, 2 abnormally sickle mutated hemoglobin genes from each patient parent, or they have a sickle mutated gene from 1 parent and another abnormal sickle mutated gene from the other parent. And thus, the compound heterozygous would be SC, the more common ones, you can have hemoglobin SC, hemoglobin S beta-zero thalassemia where your other gene isn’t thalassemia major and you’re not producing any thalassemia, any normal sickle A hemoglobin.
And subsequently, the predominant gene that you have is a sickle; the predominant hemoglobin. The second is the sickle beta-plus thalassemia where you have a sickle and in beta minor where you’re making some, a little bit of normal hemoglobin, and in addition to that, they’re just making a much-decreased quantity. And then, we do not think about the other abnormal hemoglobins, which depend geographically. You might see coinheritance of some of these other rarer genotypes. Our friends on the West Coast in California see a little bit more S inherited with E, so you’d have hemoglobin SE. And then, I came from the Midwest, we had quite a few patients who had S inherited with D-Punjab, and S inherited with O-Arab. But when we talk about the sickle mutations, the more common ones are the SS, the SC, the S beta-plus … the S beta-zero thalassemia, more commonly is what we see. Those are the genotypes.
Then, how does that translate to what we see phenotypically? As Dr Nirmish Shah said earlier, it is a very, very variable disease. Thus, even though genotype-wise, we expect that SS under S beta-zero to be the most severe genotypes, even within each of those genotypes, the variability of a disease is very wide. The patients will present, the key sentinel event is polymerization of the sickle hemoglobin because the valine is hydrophobic. And on the polymerization, the hemoglobin itself polymerizes to a point where it cannot revert. And the membrane and things we talked about eventually becomes irreversibly deformed into that sickle shape. Now, that is just the beginning. The hemolysis, the adhesion, the other things that happened and the sterile inflammation that happened between that distorted, deformed erythrocyte and all the other select components around it give that pathophysiology both a decreased risk of survival anemia hemolysis and all the sequelae of hemolysis and the painful vaso-occlusive episodes which may or may not be present.
Some people have more, and some people do not have that pain phenotype. But because of the hemolysis and all the other things, you still find the pathophysiology of the sterile inflammation in the vascular endothelial dysfunction that happens. And hence, understanding that, that one patient can have the pain phenotype and appear otherwise well, but will suffer the sequelae of the vascular endothelial dysfunction and the sterile inflammation. And we’re sure you have a teenager completely disappear from clinical service for 3, 4 years and has albuminuria, nephropathy, retinopathy, and cardiovascular complications. And thus, understanding all of that makes us less comfortable. Now, adult colleagues are trying to caution us to not say “this sickle cell is mild, that sickle cell is mild,” that way, you don’t have severe sickle cell because you do not come very often with pain. Hence, the whole paradigm in approach and in looking at this patient’s missed to … that you cannot have hemolysis and free radicals and still call it a friendly disease.
Biree Andemariam, MD: I think that was well said, Elna, thank you very much. And I just want to pick up on your mentioning of the genotypes and how oftentimes, someone like me who is an adult hematologist, I transition individuals with sickle cell disease between the ages of 18 and 21 over to the adult practice from the pediatric program. And they’re oftentimes categorized as having mild sickle cell disease if they have S beta-plus or SC. And severe disease if they have SS or S beta-zero thalassemia. And it’s always perplexing to me because in my experience, taking care of a lot of adults with sickle cell disease, genotype begins to matter less and less, in terms of the phenotype of sickle cell disease in the adult space. And one of the things that concerns me is oftentimes, the young adults, at the time of transition, also believe that they only have a mild form of the disease if they have SC or S beta-plus thalassemia. Thus, they may not come to their comprehensive visits as much. They don’t see the need for disease-modifying therapy. They don’t see the need for certain screening examinations. And as we try to push hydroxyurea into more and more individuals, it’s harder to have that discussion, which is probably a discussion we can have in and of itself.
Transcript edited for clarity