Anemia-Related SCD Manifestation: Monitoring and Screening

Ifeyinwa Osunkwo, MD, MPH: Abdullah, can you discuss the recently published NHLBI [National Heart, Lung, and Blood Institute] recommendations for screening and monitoring of sickle cell disease complications, including anemia regarding stroke, pulmonary adrenal dysfunction, and retinopathy? What do we know that we should be doing in the year 2021?

Abdullah Kutlar, MD: As was pointed out by Wally, you, and Pat, we are having an increasing recognition that sickle cell [SC] disease is not just pain crisis, and when the pain crisis is gone, they are fine. No. The organ damage starts very early. Based on a long period of accumulation of data from clinical trials and everything, the National Heart, Lung, and Blood Institute and more recently ASH [American Society of Hematology] have come up with guidelines on how to identify and prevent or treat organ damage. 

Let’s take stroke, for example. Stroke is another complication. The natural history study, the CSSCD [Cooperative Study of Sickle Cell Disease], identified that about 11% of patients with sickle cell up to age 20 suffer from stroke; it’s a little higher in SS [sickle cell anemia] and a little lower in SC. We have no way of identifying stroke, but in the landmark trials STOP 1 and STOP 2, done by my colleague Dr Robert Adams, transcranial doppler was a very useful predictor of cerebrovascular disease. If you have high velocities in major intercranial arteries, such as the carotid, anterior cerebral, and middle cerebral, that presents a highly increased risk of stroke. With the STOP studies, screening with TCD [transcranial Doppler ultrasound] was established as a means of detecting stroke risk. The current recommendation in the guidelines is to start screening everybody at age 2, and at least until age 16 or 17, a window with the highest frequency of cerebrovascular disease. 

Normal velocities are less than 170 cm/s. Those who have velocities over 200 cm/s have a significantly higher risk of stroke, like 10-fold or so, over the next 4 years. The standard has been established to identify these individuals and put them on transfusion. That’s why it’s important in prevention. There is a category of 170 to 200 cm/s, which is called conditional. Conditionals can be treated with transfusion, but now we have evidence that hydroxyurea is effective in reducing velocities. We could use those. In secondhand prevention, transfusions are necessary. That’s for stroke risk. In terms of cardiopulmonary, it’s very important—and this has been shown in many studies—to screen the patients clinically and symptomatically for the presence of pulmonary complications like asthma… 

Ifeyinwa Osunkwo, MD, MPH: That’s true.

Abdullah Kutlar, MD: And restrictive lung disease and so forth. As you become older, the issue of pulmonary hypertension becomes significant. The recent recommendations for monitoring include echocardiograms on all adults and looking at the tricuspid regurgitant velocity. Normally, it should be 2.5 m/s. If anybody is at 2.5 m/s, repeat that and optimize the sickle therapy, whether it’s hydroxyurea or any other disease-modifying agent. But if the velocity is over 3 cm/s, then they must be referred for a right heart catherization to identify pulmonary hypertension. This has been proven to have pulmonary arterial hypertension, which requires treatment. Those are the recommendations in a nutshell. 

Sickle cell involves kidneys from a very early age. I’m not going to talk about the hyposthenuria, which some people say starts in the intrauterine life. The more clinically significant aspect of sickle nephropathy is the sickle cell of high penetration, microalbuminuria, albuminuria, and then chronic kidney disease, end-stage renal failure. It’s a sequence that is very similar to the evolution of diabetic nephropathy. These 2 diseases have a lot in common. 

The microalbuminuria can be seen in children but sharply increases with increased age. The recommendation…is to start screening for microalbuminuria at age 10. Any albumin or creatinine ratio of 30 mg/g or over should be taken seriously. In children, there are some studies that have shown hydroxyurea to be effective in reducing nephropathy. In adults, you must start either an ACE inhibitor or an ARB therapy in patients with microalbuminuria. The guidelines also recommend that anybody with albuminuria that is greater than 300 mg protein excretion in 24 hours should be referred for a nephrology evaluation and work-up and likely be put on ACE inhibitors and ARBs. For retinopathy, recently it has been found to be a little more common in SS than originally thought. The recommendation is again starting at age 10, do a dilated retinal exam. If it’s normal, repeat it every year or 2. If that’s abnormal, then they should be followed by a retinal specialist, and necessary treatment should be instituted.

Transcript Edited for Clarity