Dr. Jane Little identifies hemoglobinopathies and presents on Sickle cell disease (SCD) as one such blood disorder caused by the abnormal hemoglobin that damages and deforms red blood cells.
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It is now my pleasure to introduce Dr Jane Little, professor of medicine and director of Comprehensive Sickle Cell disease Program at the University of North Carolina School of Medicine, who will speak on sickle cell disease and hemoglobin. APA these 2021 update for the practicing he Monk Healthcare Professional. Please welcome Dr Jane Little. If you have questions you would like to have her address, please use the chat function to ask your questions during the presentation. Questions will be addressed during the panel discussion session. Hello. My name is Jane Little. I'm from U. N. C. And I'm really delighted to be talking to you today about sickle cell disease. Um, it's really changed in the last 10 years, and it's becoming a much more optimistic situation. These are my disclosures, none of which are very relevant to what I'll be talking about today. Um, this is hemoglobin, which is the nut of the whole sickle cell disease. There to alpha subunits and two beta subunits. The beta subunits are the ones that are mutated in sickle cell disease. Both Hamas, I guess, and variant uh, and the beta subunits are also the ones that change in fetal hemoglobin, which we'll talk about as well. You never thought you'd have to see the oxygen Association curb again, and here it is. Um, it's worth discussing and sickle cell disease, because oxygenation of hemoglobin is so central to the path of physiology, this is the P 50 of hemoglobin. It's the P 02 at which the hemoglobin is 50% saturated with oxygen. When you shift to the right, it means you're giving up oxygen more readily. It's a lower affinity hemoglobin, and so the things that do that are more metabolically active. Red Cell hired to three D PG uh, and a more acidic environment. And that's not great in sickle cell disease. The things that shifted to the left are a lower to three D PG or more alkaline environment and in sickle cell disease. Vaccine later shifts the curve to the left as I'll show you and, uh, it increases the oxygen. The percent saturation of hemoglobin at a given appeal to, um, so the left shifted hemoglobin will give up oxygen less easily, and that's probably also important. This is a slide that I borrowed from Mitch Weiss at ST Jews and it's just a cartoon to show you how packed the red cell is with hemoglobin. And that's why the subtle changes subtle biophysical changes in sickle cell disease. Um, have such an impact, because when you get the polymer inside the red sale, it's so densely packed in there that you can have real, um, changes in the in the shape of the red cell. This is conceptually normal hemoglobin, in which the Alpha chain and the beta chains are balanced. And this is hemoglobin. A. As you know, sickle cell disease is a biological trade off. And there was a great story of Tony Allison in the sixties, um, driving across Africa with a van where he would get blood samples from just fingerprint blood samples and and reduce them. And he could visualize, um, cycling, even in people with sickle cell trait. And in that way, he was able to get prevalence estimates of trait as you went across Africa. And as you can see, it's really quite dense. In some areas, greater than 20% of the population has trait, Um, and as you can also see the places where there's trait is also where there is malaria, and it turns out that sickle cell trait protects you from the worst form of cerebral malaria. And that biologic tradeoff allows the people have trait to go ahead and reproduce, even at the cost of losing. Even to this day, Children who have Hamas IGA sickle cell disease. Again, this is the problem. The D N A. Is mutated as you know, it results in a mutated beta chain. The beta chain then can make this very rigid polymer inside the red cell which will distort it. And as I'll show you the net result of those distortions and Hamal, ASUs and abnormal red cell surface is both analysis and vascular apathy. This is sickle cell trait, which I alluded to a moment ago. One in 12 African Americans have sickle cell trait. Um, I draw the S as 40% here because it turns out that normal data has a higher affinity for Alpha than the sickle beta, and so that people who have trait will have 60% normal hemoglobin A and 40% hemoglobin s. And that's probably why they don't have a worse syndrome. Um, they about up to two million Americans have sickle cell trait. The blood counts are normal, but they are more prone to have him mature area, probably because of the acidic environment in the kidney is more prone to damage again because of that offloading of hemoglobin. That right shifting, Um and they're more prone to pulmonary ambala and probably renal disease. But we don't yet know how to integrate that into the care of people with sickle cell trait. People may know may not know they have sickle cell trait, but their Children might find out because one in 400 600 African American Children are born with hemoglobin SS one in about 850 with variant hemoglobin SC one in about 2500 Hispanics. Americans are born with hemoglobin s s. And again, often, these people adults will not know that they have trade because it doesn't have many consequences for them when they're young adults. 100,000 Americans have sickle cell disease, and more than six million sub Saharan Africans have sickle cell disease. This is Hama Saugus, Um, sickle cell where you have to mutated Beta s. This is hemoglobin s s. And this is the dominant predominant form of sickle cell disease in the United States, about two thirds of Americans with sickle cell disease have Hamas. I guess, S s. But the number is lower in Africa, where they Children with him alone SS are prone to overwhelming infections. And it can die in childhood as they used to do in the US until about 40 years ago. As I'll show you. This is the problem stated again and again because I think it's so worth reminding you that when normal hemoglobin is deoxygenated, its biophysical properties are not significantly changed. But that is not true for Beta s. When you have Hamas ideas, Beta s and you d oxygenate, you'll get this polymer. Um, and you can even get it in trait as we discussed when the oxygen saturation is low enough. So this is proportion of polymer. This is oxygen saturation. And this is trade. And this is homicide. Assess says this is the original patient diagnosed in the U. S. With Hamas. I guess. S s It was a young dental student from Viana who, um, came to Chicago over 100 years ago, got sick with pneumonia, and when the doctors they're evaluated him. They found these oddly shaped sickle red cells. Um, but obviously, this had been known of in Africa for thousands of years. This is again the red cell, deforming in a low oxygen. Uh, this is a great side from Mark Gladwin and Elliot Bochenski. That really shows the underlying path of physiology. Um, on the arterial side, you can see the red cell exploding. And that's why patients with Homicide SS will have actress Why there are square electricity. Um, the free hemoglobin will bind and an activator? No. So you lose that sort of as a dilatory component and you also impair vascular health and really damage the vascular epithelium in a pure form. And it never turns out that way you can think of patients who have hyper Hamas is as being prone to these vascular to these, including pulmonary hypertension and a high TR jet truck hospital. Virgen and Jet, which has a poor prognosis, leg ulcers, priapism and stroke. Um, you see the red sale here? It's delivering its oxygen. It's cycling more. It's becoming more abnormal, and its surface and the white cells are likewise inflamed. And so you have a more adhesive genotype, which in its pure form would be characterized by pain, risk of acute chest, which is cycling in the lungs and osteonecrosis, or a vascular necrosis, which is a very morbid complication. Patients don't sort out in this way, but we do see patients who have very high all the age, have a low hemoglobin and don't have much pain. But we'll have a lot of vascular apathy and other patients with a high hemoglobin, lots of pain, and you can sort of think of them path of physiologically. In this way, this is variant disease. About a quarter of Americans with sickle cell disease have one gene that's beta s and one gene. That's beta C B two C is a dehydrating mutation. Um, and it will make the red cells shrink. Uh, I tell patients that it's like if you have gummy bears in a bag and then you make the bag smaller. It makes the gummy bears more able to find each other. And the S is the gummy bears. That's the sticky hemoglobin. In a way, this is s beta plus thalassemia. Uh, this is closer to SC disease than it is to S s but they can be prone to painful crises. Um, and it is a cycling syndrome most as well. And it's about 1/10 of the patient of patients we see in the U. S. Um, I tell the House staff that all pain is real and should be treated, so compassion is very therapeutic. These are patients who've been dealing with the health care system for all their life, and it can be very wearing. Um, in s s, uh, the cumulative damage from the vascular apathy can result in some subtle cognitive impairments that may make complicated. Um, expect, uh, instructions hard for patients to follow. So when you take care of any patient, but especially somebody who has sickle cell disease, you have to be very clear about what your priorities are and not overwhelmed them or yourself with a big, long list of things you want them to do. Um, I think the things I've learned and taking care of sickle cell patients are applied to all patients. You have to be clear and very focused about you. What you want them to do. Cycler is not a real world real word, and we do not use it anymore. Um, And while pain is critically important to the patients and the providers, it's the tip of the path of physiologic iceberg. And the more the patients understand that, the more they'll understand your desire to get them on disease. Modifying therapy. This is just a summary of what I think the major complications are in sickle cell disease. This is S s, which is again two thirds of Americans and then the variant disease, which is hemoglobin s C and S beta. Plus. You can sweep into this group to both have painful crises. Central nervous disease in S s is strokes and small Children, um, which has been prevented a lot by early screening and transfusions but is still a problem. Um, and CNS bleeds, which can happen in the 20 to 30 year old because of a fragile vascular system that evolved over 30 years. Um, and these are patients who present with the worst headache of their life. Um, the CNS disease in the variant disease is really retinal diseases. Eye disease. You can have retinal disease and S s, but it's more of an A trophic, um, vascular problem in SC and Espada Plus, it can be proliferated, and it can result in retinal detachment, you know, Flashers and floaters. And so we send every SC patient every year an espada plus to the eye doctor to make sure that they don't need preventive laser treatments. Lung disease can be very dangerous for both types of sickle cell. Um, and s s is a little more prone to having a high try. Custom rig. Urgent jet velocity suggesting cardiopulmonary disease and a worse prognosis. Bone disease and more than a third of all patients with sickle cell disease can be extremely debilitating in the shoulders and the hips with a vascular necrosis infection is what used to kill Children and still does in resource limited regions. And that's why prophylactic penicillin and immunizations have become so important. Kidney disease afflicts many of our patients more than two thirds of adults. And again, it can be very subtle because, especially in S s as Children, they'll have create needs of 20.5 or 0.4 because of hyper filtration. And, uh, then as they age, they have a crowning of one, and everyone will think it's normal. But it turns out they've lost some significant renal function. Um, since childhood, and that may happen in their twenties or thirties. And similarly, hypertension isn't much lower blood pressures in S s than it is in SC or in people with hemoglobin. A symmetrical complications can be difficult. Priapism is a debilitating problem for young men, where they'll have a very inclusive prices in their Penis, and it can result in impotence. Espana, Uh, and hyper Spahn is, um, both result in functional immune deficiencies. And hyper Spahn is, um, can be a painful problem for adults With these variant disease blood clots. Again, they often gonna be pulmonary emboli, or most most likely, pulmonary emboli. And Trump Ophelia is a risk in up to a quarter or more of patients with sickle cell disease. During their life, people with S s have a shortened by probably 10 to 20 years or more. Life expectancy and people with various disease have a near normal life expectancy. But all of these patients can have sudden life threatening complications as young people. Um, there are more disease modifying therapies for homicide S s s disease than there are for the variant diseases. And I'll go into those a little more detail in a moment. Excuse me. This is just to remind you that 50 years ago, the median life expectancy in the U. S. For people with sickle cell disease was under 15 years of age. And it's only incrementally with this national sickle cell act with penicillin with hydroxyurea, which we'll talk about in a minute and transfusion for strokes that you see the life expectancy begin to go up. But even though this curve is a very optimistic and a wonderful thing, these Children and young adults are not cured, and we don't really fully understand what's happening under this curve. What kind of complications are emerging in these? These young adults who have survived childhood but but still have active disease? I'm going to show you a number of different metaphors for treatments and sickle cell disease, So forgive me, but I think of disease modifying therapy as those treatments that affect the mouth of the river rather than downstream primarily, um, so they will have a more widespread effect than if you just affect a branch. Um, so if you think of sickle cell disease having a parent adhesion, inflammation, oxidant stress, it's from Ophelia. You can affect each of these downstream branches, but we expect, and we see that those treatments that are targeted further upstream have more, more dramatic effects in more regions than targeting each of these separately. Although these this individual targets are also very important, I think for the mouth of the river you can. And this is the Amazon. By the way, you can think of stem cell transplants gene therapy that that fix the approximate problem in the DNA hydroxyurea and box A litter affect the hemoglobin protein and primary ization. Chris and Chris and lose a mob affects adhesion, so it's more downstream, like likewise gloomy and probably affects more downstream as well. These treatments probably have other effects across and these other branches, but they're not, as obviously, going to affect more downstream effects, as these approximate therapies are mhm. Pain is, in most patients lives, the most important and most dominant symptom that they have, and the treatments we have for that are poor there, opioids and their anti inflammatories. But as you can see, pain doesn't really affect the approximate problem. It probably does have some. Treating pain probably does have some disease modifying effects, but you can see that it's not as powerful is something that can treat up here at the mouth of the river. And this is another way of saying that same thing if you think of it as a pyramid with disease, modifying therapy at the top and symptom modifying therapy at the bottom there all important. But they have slightly different implications and our ability and our willingness to tolerate risk changes as well. So gene therapy and stem cell transplants are up here. Things that affect the polymer are here and then adhesion inflammation from affiliate oxidant stress. So gene therapy effects DNA, the accelerator and Piquet activators, which are an emerging family of treatments that affect the oxygen affinity of hemoglobin and are being tested currently in trials, will affect the hemoglobin hydroxyurea, which increases fetal hemoglobin, which is an anti cycling hemoglobin. Hemoglobin A will participate in the sickle, as you can tell in Espada plus thalassemia that hemoglobin F, which is fetal hemoglobin, will not participate in this cycle, and so is a much more disruptive and more potent anti cycling hemoglobin than hemoglobin. A glutamine affects the oxidant stress in the red cell and Chris and lose a mob affects the adhesion. These were some of the original sort of data that suggested that fetal hemoglobin was ameliorated and sickle cell disease. This was a collection of lab data on people who had Hamas. I guess S s from, you know, 35 years ago, where hemoglobin and this is still true. The main hemoglobin and SS is about eight. The percent f is higher than people who don't have sickle cell disease. So it's about 5%. The ridiculous I count is elevated. You look at someone with trait who's essentially normal, the their hemoglobin is normal, the hemoglobin f is normal, and the ridiculous account is normal. In Saudi Arabia, there were people who had straight up SS disease who did not have the dramatic sick well a that people in Africa had. And it turned out that really associated with these high levels of fetal hemoglobin. Their hemoglobin are higher, They have less analysis, less red cell breakdown, less vascular apathy. And it's really because of this anti cycling hemoglobin. Additional proof of or suggestion of this came from epidemiologic studies again from 30 years ago, where they looked at large populations of Children and young adults with sickle cell and found that mortality and some older adults mortality was less in people had the high hemoglobin F as part of their makeup. They had a mutation that naturally made their F levels higher. That 25% of patients had a much lower mortality that than did the rest of the patients. And so in 1995 they tested hydroxyurea, which increases fetal hemoglobin and found that it really dropped the pain crises. It increased the time before you had the 1st and 2nd pain crisis. And, importantly, it cut back on acute chest syndrome, which we know is one of the things that is really lethal for people with sickle cell disease. And that's cycling in the lungs. Um, so if you think of our pyramid again, hydroxyurea is fairly high up in the pyramid, and so we'll have effects downstream in all of these areas. And we believe now is really good at organ preservation and at lengthening life. It does have side effects. You'll gain weight. Your hair might fall out in adults, which I know better than Children. Um, and we're not sure quite what it does to some aspects of fertility. But it's been around for a long time, and it seems right now to be pretty safe and pretty effective. Um, the second approach is a recent one is prison lose a mob, which blocks some of these adhesive interactions between white cells. Um, there are some other drugs that can affect red cell interactions with epithelium, but the one that just was approved was one that blocks the interaction between peace selected, which is the bright blue one here and the white cells. And it turned out in studies of crystal is a mob. They found that the time to crises was much longer. So if you look at the cumulative event rate, it happened. The base inclusive crises. The first crisis happened much sooner in the patients on placebo, on lower dross Christian lose a mob. And that was also true for the second pain event, and this probably is an effective more time on drugs. But Chris Journalism AB is fairly low down the pyramid. It probably does have some effects in these other regions, and it may be disease modifying, but conceptually, you can see how it isn't as approximate to the gene problem as hydroxyurea is, for instance, but it has been very important in symptom management. Um, you can also try to directly inhibit polarization, and that gets us back to oxygen dissociation box. Alatorre, another recently released drug that's a very important addition to our armamentarium, favors the our state or relaxed state or Oxy. Hemoglobin continued figuration advised about 30% of hemoglobin in a sickle red cell, and it was it was tested in people. Hemoglobin is greater than seven, mostly with SS disease. Prison lose. A mob is used in both s and and in variant disease. But packs shelter is probably most useful in people with Hamas, I guess, SS, who are more anemic. Um, And sorry, This was the study from 2019, uh, and this is the high dose therapy. Over two thirds of patients or two thirds of patients had a good hemoglobin response. You can see some of them are really amazing. Um, even lower dose had a 40%. Almost had a hemoglobin response compared to placebo. And you can see it happens pretty fast. It happens. This is two weeks, four weeks. The hemoglobin started to rise quite rapidly. Um, this is, as I say, a great addition to our armamentarium. Um, and it's quite proximate, so it affects politicization. So it's likely to have, um, good outcomes for some of these downstream affects as well. Um, these are less studied yet we don't really know that, but it's plausible, and quite likely that will have good outcomes for these things. Um, the thing that I think we're all gonna watch for with these oxygen affinity agents is, um, whether over time we need to in any way modify them. Um, for those organs that really need to get oxygen, they don't want a hemoglobin that's holding tightly to its oxygen. You can imagine that might be a problem. They didn't see a problem when they looked at the kidney. But the other organ that I think we're all going to keep our eyes on is the brain, because we know in sickle cell already, there are subtle. There's subtle damage. There's silence, cerebral infarction in Children. Excuse me. Um, 30% of 15 year olds have evidence for silent cerebral infarction, and this is the most severe form the S s form and maybe up to half of young adults, um, can have silent, cerebral infarction. So again, with these agents who alter oxygen delivery, we're really going to have to watch what happens to them in the coming decades. Um, allergenic transplant has been adopted widely in pediatrics, especially in kids who have matched sibling where the risks are lower. Um, still, most of the current transplants, uh, will make can make people infertile. Uh, and the strategies that you have to adopt too prevent that are relatively complicated. When these algebraic transplants were first done 30 years ago, they had CNS bleeds and seizures. But that's been pretty well mitigated recently by high platelet counts and putting patients on Capra prophylactically. There's a 10 per cent mortality quoted in recent literature, but I think that's dropping rapidly as transplants get more and more effective in this population. Um, there are certain things particular to transplant and sickle cell like Attacker LIMAs is associated with some CNS complications and tends to be used less nowadays. Um, the other problem is that many of us do not have matched sibling donors and in sickle cell disease. It's estimated that less than a quarter of patients have a match. Sibling donor and unrelated donors are not very feasible, in part because of some tricks of the H L A system in people from in the African diaspora. Um, so at Johns Hopkins and other places, they adopted a happily identical strategy because everybody has, you know, a mother who's happily identical. But there are still problems with those bone rows transplants being rejected by recipients. And so I think, uh, allergenic transplants are a really important consideration, but have their nuances and have their complications. In addition, when you think about it, um, I think in pediatrics again, I'm talking to you about adults. The adults I've seen, they have Children, they're going to school, they're trying to work. And so the thought of taking two or three months out of your life to go through a procedure like a transplant is really a daunting, a daunting thing for them to consider. Um, gene therapy is emerging, um, and is really an exciting avenue as well. Um, however, the bone marrow of people with sickle cell disease is a stressed marrow. And so there is some. There may be some additional preparation that's needed before you can use that autologous bone marrow. There's only one site that I know of. Now that's doing a non Milo, a blade of approach where there's, um, less infertility. Um, and shorter time with pants I Dapena. Most sites are doing milo blade of transplants. Um, and so the applique of the applicability in the third World of these strategies is really going to be limited. Um, and the expense is quite high. Currently, over a million and a half is estimated for the most recent bluebird vector for one patient, and you can't use growth factor because it stimulates all the inflammatory million and sickle cell disease and can really be deleterious. But, you know, stem cell transplants and gene therapies, which are going to be adopted more widely, I think, are at the very tip of the pyramid at the very mouth of the Amazon and are likely to have really profound effects on all of these downstream problems. Just I'm going to conclude by by saying how I am thinking myself about risk benefit in Stratton and these emerging strategies for sickle cell disease. It's incredibly exciting. The new treatments that are that are being tried in sickle cell disease, and I think it's a very hopeful time for the sickle cell community in general. For myself, I think that those strategies that address the tip of the of the pyramid or the mouth of the river or the D N A, as it were, are the ones for which higher risk is more acceptable. Um, and so I sort of think of risk trying to risk figure out the risk tolerance that those that go closer to the heart of the problem. One can think about a higher risk than those those that are, um, treating downstream symptoms Now for patients. Those downstream symptoms are a big deal, and so their risk tolerance may be different, and you have to incorporate that into any decisions made about these new treatments. But it's great that we're able to have these discussions now, and I think it's going to be a really exciting next decade to see where all these treatments sort out. And I'm looking forward to it, and I'll come back in 10 years and tell you what's happened. Thank you so much
