Sickle-cell anemia (SCA) is an inherited condition in which some of the subject’s red blood cells contain an abnormal form of hemoglobin, the molecule that carries oxygen to the body's tissues.
This form of hemoglobin carries less oxygen. The cells containing the hemoglobin tend to become abnormally shaped (sickled) and much less flexible, and thus can block blood flow through the capillary beds of key organ systems such as the lungs, heart and brain. Large-scale sickling can occur unpredictably and lead to “vaso-occlusive crisis” (VOC), which can result in stroke, heart attacks or acute pain in the chest or bones.
Normal blood cell (left), and sickled blood cell (right).
Recent research by an interdisciplinary team of investigators including Professor Michael C.K. Khoo of the USC Viterbi School of Engineering's Department of Biomedical Engineering has found increasing evidence that autonomic nervous system (ANS) activity has a distinct pattern in SCA patients, which may be involved in precipitating these strokes.
Dr. Khoo has worked with his former graduate student, Suvimol Sangkatumvong, as well as Drs. Thomas Coates, John Wood and Herbert Meiselman of the USC Keck School of Medicine and Children’s Hospital Los Angeles on the study, which involved a number of patients of different ages diagnosed with SCA.
Since low oxygen levels in the blood are known to predispose to VOC, the Viterbi-Keck team’s experimental procedure compared the pattern of heart rate response of SCA under these conditions to the pattern in normal controls. These responses are controlled by the autonomic nervous system (ANS), an involuntary, unconscious control system that regulates body functions such as salivation, heartbeat, perspiration, respiration, and others.
For the experiment, which was supervised by Children’s Hospital staff, experimenters had SCA subjects take five deep breaths of nitrogen, filling their lungs but not putting oxygen into their blood.
In a preliminary safety check, none of the SCA subjects showed any significant short- or long-term results from the nitrogen inhalation. But careful comparison of their reactions revealed significant differences between the SCA subjects and controls. The ANS reaction, which the investigators deduced from the heart rate and breathing patterns by using a computational model, was substantially more exaggerated in the SCA group.
Another observation from the study involved sighing, technically defined as taking a breath twice as deep as the average breath, within two minutes after a stimulus. For each sigh, the team carefully measured heart rate and blood flow to the finger, looking for subtle changes in pattern compared to the control group.
Analysis of the results, according to a 2011 paper, showed that sighs stimulated the sympathetic branch of the ANS much more in the SCA subjects than in the controls. Further analysis suggested a more important tie. Before, it had been thought that the severe VOC was a direct result of lowered blood oxygen content. What the results seem to indicate is that the neural response may be the direct trigger of VOC, or as an independent reviewer analyzing the results put it, “that autonomic nervous system dysfunction is part" of the sickle-cell conditon.
Professor Michael C.K. Khoo
Khoo and his colleagues hope to further pursue the research in order to develop ways to use the insight to refine treatment techniques. “While there is no outright cure for sickle cell disease,” he says, "there are two major forms of therapeutic interventions that can lower the probability of VOC."
One intervention is administration of a drug, hydroxyurea. The other is blood transfusion to reduce the percentage of sickled cells. “What we're trying to do is to determine reliable biomarkers of the vaso-occlusive crises - and these biomarkers should also provide feedback as to how we can optimize the treatments. Our next steps are indeed to determine which are the most reliable biomarkers and how we can use them to optimize therapy.”
