Impact of Anemia & Hemolysis in Sickle Cell Disease - Episode 6

NHLBI Guidelines for Anemia-Related Disease Manifestations

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Experts in hematology discuss NHLBI guideline recommendations for the screening and monitoring of anemia-related disease manifestations as well as goals of therapy for patients with sickle cell disease.


John Strouse, MD, PhD: In children with sickle cell anemia, the recommendation is to screen annually with Transcranial Doppler ultrasound, using the methods that were evaluated in the STOP studies. The STOP studies were looking at stroke prevention and began at age 2 and continued annually till age 16 with screening by Transcranial Doppler ultrasound. This involves using Doppler ultrasound to measure the cerebral blood flow velocities in the distal internal carotid artery and the middle cerebral artery. If these velocities are increased for the standards for children with sickle cell disease, then the recommendation is to refer that patient to a sickle cell expert for treatment.

In practicality, most places that do Transcranial Doppler ultrasound for children are pediatric centers for sickle cell disease. They’re getting their screening done in the setting of that program. If we see very high velocities greater than 200 cm/sec, when you average it over systole and diastole, we generally recommend transfusion, which reduces the risk of stroke from about 30% over the next 30 months to about 3%. If people are conditional, then velocities are generally in the 170 to 199 cm/sec range; we generally increase the frequency of monitoring.

For children not already on hydroxyurea, we’ll use this as a reason to recommend hydroxyurea, because hydroxyurea has been shown to decrease the cerebral blood flow velocities. For children that are on chronic transfusions and doing well, if they don’t have evidence of severe vasculopathy by magnetic resonance angiography, or MRA, we’ll often recommend that they transition to hydroxyurea over that with their transfusions. We can often keep them from having elevation of their Transcranial Doppler ultrasound and reduce their risk of stroke. This has been a huge change in the care of children with sickle cell disease. Before we had routine screening for stroke, we used to see stroke in 11% of children with sickle cell disease in the first 2 decades of life. By the time they’re age 20, 11%, 1 of 9 children, would have a stroke. With regular Transcranial Doppler ultrasound, that’s down to 2% to 3% percent of children. This is just the standard for children who have sickle cell anemia: hemoglobin SS, or hemoglobin S-beta plus, S-beta thalassemia. For people with more, with phenotypes of sickle cell disease where they have less anemia, we generally don’t recommend screening unless there’s something different about them.

As far as cardiopulmonary complications, the NHLBI [National Heart, Lung, and Blood Institute] guidelines recommended that we assess children and adults with sickle cell disease for signs and symptoms of respiratory problems, such as asthma, chronic obstructive pulmonary disease, restrictive lung disease, or obstructive sleep apnea by history and physical exam. If there were concerning factors identified, then we evaluate those children and adults. They did not recommend universal testing for cardiopulmonary complications.

Once they have that sign or symptom, further assessment may include pulmonary function testing and echocardiography as we evaluate for pulmonary hypertension or for tricuspid regurgitant jet velocities that are elevated. In general, if it’s elevated 2.5 m/sec or higher, then the recommendation is to consider additional evaluations, such as the 6-minute-walk test, to look at their functional status. Or a potentially right heart catheterization, particularly in people who have higher tricuspid regurgitant jet velocities, recommending that they have the right heart catheterization to evaluate for pulmonary hypertension or for increased right atrial pressures, which could be a sign of congestive heart failure as a cause of their symptoms.

In addition, we recommend that patients have evaluation for renal disease. For renal disease, the recommendation is that all people with sickle cell disease at age 10 be screened for microscopic albuminuria. In our program, we do a microalbumin-to-creatinine ratio, beginning at age 10 and repeating it annually. If we identify someone with microalbuminuria, we consider therapies that might reduce that. Those therapies include hydroxyurea as a disease-modifying therapy for sickle cell disease and then either an ACE inhibitor or an angiotensin receptor blockade. If someone has increased proteinuria, or if they have macroscopic proteinuria, we generally refer them to a nephrologist as well.

The third complication is retinopathy. The recommendation is that we screen people with sickle cell disease for retinopathy beginning at age 10, and if they have any evidence of retinopathy, then they should be referred to a retina specialist. If they have normal findings on that initial evaluation, the recommendation is to rescreen every 1 to 2 years. I prefer to have the screening done by an ophthalmologist. It can be done by an optometrist as well, but it really needs to be a dilated retina exam. Much of the retinopathy we see in people with sickle cell disease is peripheral, but in the general population, where we see a lot of diabetic retinopathy, that’s often more central. It can sometimes be diagnosed without doing a dilated exam. It’s hard to do it without doing a dilated funduscopic exam in people with sickle cell disease.

Sophie Lanzkron, MD, MHS: The goals of therapy for sickle cell disease are dependent on what the patient wants. Many times you talk to a patient, and they’re like, “I didn’t drink enough. That’s why I got a crisis.” The goal of therapy is to allow patients to live their lives without having crises that interrupt them at every step along the way. They shouldn’t blame themselves for developing a crisis. It should be our job to find a therapy that allows them to jump into a pool of water, to go to the beach—to do all those things—and to have life stresses and not end up in the hospital with a vaso-occlusive crisis. The goal of therapy is to allow patients to live as normal a life as possible and to do the things we all do. None of us, certainly recently, has been able to escape stress in our lives. We want patients to be able to deal with the common cold, having stress, going without fluid for a few hours without ending up having a vaso-occlusive event.

For patients with hemoglobin SS disease, when you’re thinking about therapy, the primary and first-line therapy that we should consider is hydroxyurea. Hydroxyurea has been in use for sickle cell disease for a long time, and we know it offers a lot of benefit. It decreases crisis frequency, the risk of acute chest syndrome, the need for transfusion. Two long-term observational trials suggested that people on hydroxyurea live longer than people not on hydroxyurea. Before I consider the new therapies that are now available for patients, the first thing I always consider is whether they’re appropriate candidates for hydroxyurea. That should still remain first-line therapy for people with sickle cell disease.

Jeffrey Lebensburger, DO, MSPH: NIH [National Institutes of Health] Guidelines don’t directly comment on the need to prevent anemia or prevent hemolysis, but clinically it’s clear that patients who are anemic—those patients with hemolytic phenotypes—are at increased risk for morbidity and mortality. The guidelines may not address this, but most sickle cell clinicians would agree that patients who are severely anemic or patients who have a hemolytic phenotype should be on a disease-modifying therapy. Some patients who have severe anemia or a hemolytic phenotype may not accept sickle-modifying therapies because they may not be having pain events. I can’t understate the importance of how anemia and hemolysis impact organ disease. Therefore, if you have a patient who has anemic but not a lot of clinical severity, please don’t disregard the fact that they may be having more subclinical organ injury. These patients, just like those who are having chronic pain events, deserve sickle cell–modifying therapy.

Transcript edited for clarity.