February 17, 2018
4 min read

Stress, fear may increase risk for vaso-occlusive crisis in sickle cell disease

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Thomas D. Coates

Mental stress and the anticipation of pain decreases microvascular blood flow, which may trigger episodes of vaso-occlusive crisis among patients with sickle cell disease, according to study results presented at American Physiological Society’s Physiological and Pathophysiological Consequences of Sickle Cell Disease conference.

“This type of research draws a direct connection between vague concepts like emotional stress and measurable changes in human physiology,” Thomas D. Coates, MD, section head of hematology at Children’s Center for Cancer and Blood Diseases, and professor of pediatrics and pathology at University of Southern California Keck School of Medicine, told HemOnc Today. “There is an idea in the medical community that emotional stress is somehow not real when, in fact, it may be directly connected to health outcomes through provable and measurable disease mechanisms.”

Coates and colleagues assessed the effect of emotional stress on the risk for vaso-occlusive crisis among patients with sickle cell disease.

Study participants performed computer-based mentally stressful tasks that tested their ability to remember sequences of numbers or letters, and quickly identify the color of a word. In an attempt to elicit natural fear anticipation response, researchers told participants they would experience pain through a device on their arm. However, researchers never exposed study participants to any pain.

Investigators observed a 20% decrease in blood flow when patients experienced stress in anticipation of feeling pain.

HemOnc Today spoke with Coates about the study findings and their potential implications.


Question: How did you conduct the study?

Answer: In the course of experiments related to blood flow changes secondary to pain in sickle cell anemia, we noted in a study published in American Journal of Hematology that significant decreases in blood flow occurred before the painful stimulus was applied. The decrease in blood flow occurred when we told participants they were about to feel pain. For the current study, along with Payal Shah, MS, and colleagues, we recruited participants with sickle cell anemia. Devices on the participants’ fingers measured blood flow in small blood vessels. They also had continuous electrocardiogram recording and monitoring of their respiratory rate to allow us to monitor autonomic nervous system activity.

After several minutes of acclimating to the system and making sure they were comfortable, participants were presented with various scenarios on the computer screen. For example, a patient saw the word ‘red’ but it was in green letters and they had to provide the color of the text.

This is a standard psychological test, which is known to be extremely annoying for participants. Finally, we told them that the device on their arm would be turned on and they would feel pain; however, we did not actually turn on the device.


Q: What did you find?

A: We found that having to think hard to remember sequences of numbers caused an approximate 20% decrease in blood flow. Being exposed to the annoying word or color identification schema caused even more decreases in blood flow. However, when the patients thought they were about to feel pain, this caused the most significant decrease in blood flow. This blood flow change occurred simultaneously in both hands and the forehead. We also noticed that different individuals had dramatically more blood flow decrease response than others. The pattern of these responses seems to be characteristic of the individual.



Q: Can you explain how this could happen?

A: The autonomic nervous system is the part of our nervous system that controls bodily functions, such as blood flow to all regions of our body, temperature, respiratory rate and heart rate. All of these are important functions that need to be constantly and automatically regulated. We blush in response to certain situations because our brain causes an increase in blood flow to our face by dilating blood vessels. Other things like cold temperature and mental stress can cause decreased blood flow. The body is able to control blood flow in the extremities in order to regulate the body’s temperature, as well as to regulate blood pressure under certain conditions.


Q: What are the potential implications of the se results for patients with sickle cell disease?

A: The fact that blood flow changes under various conditions has been known for a long time. However, the specific responses to these types of stimuli had not been studied in this matter. These decreases in blood flow may be very significant for individuals with pre-existing types of blood vessel disease — in particular, sickle cell anemia. These processes or stressors would markedly increase the probability that red blood cells would become stuck in the small blood vessels if the patient significantly decreases blood flow in response to mental stress or pain. Patients with sickle cell anemia have told us for years that emotional stress and cold temperature can bring on painful sickle cell vaso-occlusive crisis. Until we made the connection between this stress-induced blood flow process and the fundamental mechanism of sickle basal occlusion, we had no real explanation for the most common crisis trigger our patients told us about. We have already published a paper with Lonnie K. Zeltzer, MD, and colleagues from UCLA, showing that we can modulate this blood flow process with hypnosis. Thus, there may be nonpharmacologic ways to help these patients. With the technology we have developed, we now have an objective way to measure these responses.


Q: What are the potential implications of these findings for the health care system?

A: We suspect these vasoconstriction patterns are characteristic phenotypes of individuals with different autonomic nervous system reactivity. These may help identify individuals who may be more likely to benefit from cognitive-based therapies and other nonpharmacologic approaches. These vasoconstriction parameters also may be amenable to modulation with various drugs. We think the approaches to monitoring may be important in diseases other than sickle cell disease in which small vessel blood flow and reactivity are important.


Q: What must be confirmed in future research?

A: The next directions will be to make these measurements using wearable devices. Ultimately, we need to see if modulation of these vaso-occlusive crisis phenotypes ultimately alters sickle vaso-occlusive crisis rates. Hopefully, this type of thinking will bring a new legitimacy to cognitive-based therapies. We will not cure sickle cell disease this way, but we may be able to significantly modulate the symptomatology of the disease. – by Jennifer Southall



Bhatt RR, et al. J Pain Res. 2017;doi:10.2147/JPR.S131859.

Kaleel M, et al. Am J Hematol. 2017;doi:10.1002/ajh.24858.

Shah P. Abstract #4.4. Presented at: American Physiological Society’s Physiological and Pathophysiological Consequences of Sickle Cell Disease; November 6-8, 2017; Washington D.C.


For more information:

Thomas D. Coates, MD, can be reached at Children’s Hospital Los Angeles,

4650 Sunset Blvd. MS 54, Los Angeles, CA 90027; email: tcoates@chla.usc.edu.


Disclosure: Coates reports no relevant financial disclosures.