Jeffrey D. Lebensburger, DO, MSPH, and John J. Strouse, MD, PhD, comment on the serious complications of anemia and hemolysis caused by sickle cell disease and the impact on pediatric patients vs adults.
Jeffrey D. Lebensburger, DO, MSPH: Anemia and hemolysis are major contributors to the pathophysiology of sickle cell disease. There’s a multifactoral nature of sickle cell complications, but anemia and hemolysis, even separately in each situation, contribute markedly to the complications of sickle cell. For example, in the brain, anemia leads to a decrease in arterial oxygen saturation, and that places patients at risk for cerebral vascular events. Whereas in other organs like the kidney, hemolysis leading to the presentation of free hemoglobin to the kidneys, that in itself can cause acute kidney injury that can progress to chronic kidney disease. Both anemia, by itself, and hemolysis with the resultant free hemoglobin being presented to organs, can lead to severe organ complications. During acute events, we often see a drop in hemoglobin, which we believe is due to hemolysis. Hemolysis could contribute to kidney injury and to other complications. Hemolysis and free hemoglobin can also lead to sterile inflammation and its inflammatory milieu that patients with sickle cell have. We know thatanemia and hemolysis can contribute to that, and lastly, it can lead to oxygen distress. While we always think of sickle cell anemia as a vaso-occlusive disease, where we get occlusion of vessels, we cannot underestimate the contribution of anemia and hemolysis to the progression of both acute and chronic sickle cell complications.
John J. Strouse, MD, PhD: I think the VOC [vaso-occlusive crisis] pain gets more attention because pain demands attention. But we know that chronic anemia is associated with a number of serious sickle cell complications, and it’s more the end organ dysfunction. Patients with sickle cell disease who are anemic are more likely to have pulmonary hypertension. They’re more likely to have priapism, renal disease, and strokes. For some of these complications like renal disease, that’s something that occurs gradually over time. It’s painless. But over years, we have patients who develop progressive renal disease. This can lead to end stage renal disease, the need for hemodialysis, or renal transplant, certainly renal replacement therapies. People with sickle cell disease do particularly poorly when they’re on renal replacement therapies. These are generally younger people. It’s very different than the general dialysis population, where we’re mostly seeing in people in their 50s, 60s, or 70s. This is generally people in their 20s, 30s, and 40s who go into end stage renal disease in the setting of sickle cell. If they don’t go on to a renal transplant, their survival is less than that of that older population of people who have end stage renal disease. It’s both that they get it younger and seem to have an interaction between their renal disease and their sickle cell disease that shortens their survival notably.
Jeffrey D. Lebensburger, DO, MSPH: Anemia and hemolysis lead to serious sickle cell organ pathophysiology. One difference we see between pediatrics and adult is in pediatrics we have more resilience in some of our organs. For example, a patient with sickle cell disease in their kidney, they have millions have nephrons. If you get an acute kidney event due to hemolysis, you can get severe damage to the kidney. But in a setting of millions of nephrons, it’s not going to acutely show up as a rise in creatinine or injury, but that doesn’t mean injury isn’t still happening. With the heart, we know that pulmonary hypertension and elevated TRJ [tricuspid regurgitant jet] velocity has a component of anemia and hemolysis contributing to it. While we have elevated TRJ velocities, we don’t see as many complications in the pediatric side. The way I think about it is anemia and hemolysis significantly contribute to organ damage, yet the technology we have may not make it clear to a hematologist or a primary care provider that marked injury has occurred. In adults, they have much less reserve and, therefore, injury can become more clinically obvious. In both the acute and chronic complications of sickle cell disease, it’s going to be more obvious in an adult patient. For example, with the kidney, while we may not see a rise in creatinine in a child who’s having a pain crisis, who’s getting Toradol. In the adult population, it’s very prevalent. You give a patient some Toradol during a pain event, or they’re taking a lot of ibuprofen for their pain, those patients are much more likely to be developing acute kidney injury as defined by an increase in serum creatinine. With the pulmonary hypertension model, that anemia and hemolysis are leading to elevated TRJ velocities, and that is directly related to an increase in mortality. Both pediatrics and adult patients are going to be having organ disease due to anemia and hemolysis. It’s going to be more clinically prevalent in the adult patients because that’s the technology we have, and that’s when we can diagnose this organ disease.
John J. Strouse, MD, PhD: In general, we see a fair amount of severe anemia in younger children. Often, these younger children with severe anemia report little in the way of symptoms. If they have a sibling of a similar age, we’ll find that they might have some relatively decreased exercise tolerance. Generally, they are fine from day to day. As people with sickle cell disease get older, we see more impact of the anemia on their daily functioning. We hear more about fatigue and exercise limitation compared to what we see in children. As people get older, often their anemia will worsen. This reflects early kidney disease and decreased production of erythropoietin, and potentially some decreased responsiveness of the bone marrow. We see the anemia often worsening with age and having increased impairment for some of this chronic organ dysfunction and pulmonary hypertension. We can see some cardiac dysfunction; we can see the renal disease. We can often see cutaneous ulceration in patients who have more severe anemia, and the increased risk of priapism and stroke. We also see day-to-day impact, where that fatigue, that ability to get through a day of work, or a day of usual life activities, is impaired with the anemia. Another problem with the anemia as it becomes more severe is an increased incidence of as needed transfusion, which can lead to complications such as iron overload and alloimmunization. We think that by reducing the anemia, we may be able to improve people’s daily functioning, their physical activity functioning, and decrease their fatigue, and also hopefully the impact on chronic organ dysfunction.
Transcript edited for clarity.