Biree Andemariam, MD: Elliott, we heard about the influence of the red cell and the red cell contents, the altered hemoglobin that people inherit that lay the pieces for the pathophysiology of the disease and enhanced sickling, especially hypoxia. We’ve heard about other cells that are involved. You mentioned white cells. You mentioned endothelium.
Just for the panel, what is your understanding of where we are in the present day in terms of the influence of not only the red cell and sickling but all the other cellular elements that contribute to vaso-occlusion, for example?
Julie Kanter, MD: One of the things that Elliott pointed out that’s so important is how different each person is and how different the phenotype can be. Some of that is about the red cell, but some of it is also the blood vessel. A lot of what happens in sickle cell disease is that it becomes a blood vessel disease as much as it is a blood disease. There are likely other mutations and coinherited changes that affect the flexibility and the longevity of those blood vessels.
While it is incredibly important that the red cell is the primary focus where the sickling occurs and the abnormal membrane and the interactions are there, we also know that downstream, all the ongoing inflammation really impairs the blood vessels. When you look at treating this disease, we have to look at not just the blood cells but the blood vessels.
Biree Andemariam, MD: Thank you, Julie. That’s so important, and it really does segue nicely into our next discussion.
Michael, Wally [Smith] did a nice job of giving us a brief overview of some of the clinical manifestations of sickle cell disease. Keeping in mind what Julie said about the role of cells and blood vessels in the manifestations of the disease, tell us some of the more common or more concerning acute and chronic complications that individuals with sickle cell disease experience.
Michael DeBaun, MD, MPH: Clearly, the hallmark of the disease is vaso-occlusive pain episodes. This is characterized by unremitting pain, to the extent that women who have delivered children have gone into labor ignoring the labor pain because it is less severe than their sickle cell pain. This is not anecdotal. This is routinely reported when you talk to many women with sickle cell disease who have delivered children.
It also sets up a tremendous challenge for structure of their life because these events can occur spontaneously with no forewarning. There clearly are environmental factors that can precipitate pain. Work done out of the University of Southern California by Tom Coates and his team have shown quite nicely that even anticipation of noxious stimuli will cause vaso-constriction, which sets up the pattern of ischemia-reperfusion injury that Elliott [Vichinsky] so nicely described a few minutes earlier.
Vaso-occlusive pain is clearly the hallmark. Other complications include the predisposition to infectious disease in infancy, in particular encapsulated organism. For this reason, every newborn should be screened for sickle cell disease and started on penicillin prophylaxis as a standard approach. This is to decrease life-threatening streptococcal pneumonia infection that occurs in this population. Prior to the era where we started penicillin and the use of conjugated pneumococcal vaccine, you could expect almost 20% of the children to die in the United States or Europe. The rate is much higher in low-income settings.
The third complication that occurs on an acute basis is acute ischemic injury of the brain. We call them strokes. They can occur as young as a year of age, and they clearly occur in older individuals as well. These are ischemic strokes as well as cerebral hemorrhagic strokes. Both occur in this population. We have luckily, because of some breakthrough work by Bob Adams and his group, been able to identify a biomarker for which group of children are likely to have strokes. In the absence of this technology and intervention, about 11% of the children will have a stroke before their 18th birthday. With this screening, as well as with the intervention of initial blood transfusion therapy for at least a year, we’ve dropped this rate down to less than 1%.
Another complication that occurs in children and adults, for men and young boys, is priapism. This is an unrelenting pain in the penis where the penis stays erect for several hours and is not relieved by detumescence. It’s very embarrassing. About a third of the young men have this complication. It can lead to sexual dysfunction, erectile dysfunction, as well as altered self-esteem and altered interaction with their significant others.
Pregnant women with sickle cell disease have a much higher rate of pain and acute chest syndrome. Essentially, every complication that occurs in sickle cell disease occurs at a much higher rate in pregnant women who have sickle cell disease. It’s very important to mention that in low-income countries, 10% of the pregnant women with sickle cell disease—this is not a made-up number—will die during their pregnancy.
This is clearly an opportunity for us to address some of the acute complications of the disease. In terms of chronic complications, I believe No. 1 on my list would be mental health. Because of these myriad complications I just described, many of the adolescents and adults with this disease have significant markers for depression. Even using something as straightforward as a PHQ-9 [Patient Health Questionnaire-9], Wally has shown quite nicely that in a survey of adults using a pain diary, about a third had evidence of depression that would require evaluation and, ultimately, treatment. There’s clear evidence that in the general population, which is substantiated in the sickle cell population, the presence of mental health, specifically depression, is a major predictor for frequent acute and chronic pain.
I would be remiss if I didn’t mention post-traumatic stress syndrome occurs in this population. That is also associated with significant onset of acute and chronic pain. Our ability to understand how post-traumatic stress contributes to their disease, particularly in our black, poor population, is paramount in understanding how to manage this disease chronically.
In addition, there’s pulmonary hypertension. A proxy for that is elevated TR [tricuspid regurgitation] jet velocity. About 10% of the adult patients who have an elevated TR jet velocity have a risk of death within 12 to 24 months of their diagnosis, so it’s clearly an important biomarker for mortality in this population.
Avascular necrosis of the hip is a major chronic problem. We’ve not addressed who’s at risk for avascular necrosis. We are subject to somewhat anecdotal experience about how to best manage avascular necrosis. Replacing the hip with artificial hips is not optimal for a disease where blood supply is quite limited. We’re still basically at a rudimentary level in how to optimally detect or screen and manage avascular necrosis, which can be quite debilitating.
Leg ulcers are another severe problem for adults with this disease, more commonly in low-income settings. This is another problem where we are pulling at straws for the best evidence to identify the subgroup at risk and then the management strategies to prevent extension of these leg ulcers. They can become quite debilitating. They become very embarrassing, particularly in regard to having significant-other relationships and having an open wound in your lower extremity for years at a time.
Kidney disease is a major complication; a chronic complication in this population. Research that was done about 10 years ago indicated that within a year of a diagnosis of end-stage renal disease in the adult population, using a national sample from the United States, 25% died. Clearly, this is a major complication that deserves more attention—from not just the hematologist but also the nephrologist, so we can work together to understand the precursors, biological markers, and genetic variance associated with progressive renal disease in this population.
I would be remiss if I didn’t talk about the brain specifically as it relates to overt strokes. As I just mentioned, in the United States with appropriate health care screening and follow-up, we can drop the stroke risk down to less than 1% for children. For adults, the stroke risk is still very high when compared with years gone by. Somewhere in the neighborhood of 7% to 8% of adults will have an overt stroke over their lives.
Then there are silent strokes, which is a misnomer. Silent strokes occur in 30% of the children roughly before their 5th or 6th birthday. The prevalence increases with each passing decade, to the extent that by the time they’re 30 years of age, you can expect 50% of the adults to have silent strokes. We know from the work that has been done that silent strokes are associated with a 5-point drop in IQ, as well as challenges in academic performance and simply managing their disease, which has already been stated is extremely complex and requires multiple different management strategies.
Transcript Edited for Clarity