Long-Term and Adult-Onset Health Challenges of Sickle Cell Disease

An expansion of research interest in adult-onset complications of SCD, meaning secondary symptoms that are likely to first appear after childhood, has revealed new information. On June 16, 2018, Dr. Caterina Minniti of the Albert Einstein College of Medicine led a panel discussion on chronic complications of sickle cell disease at the 12th Annual Foundation for Sickle Cell Disease Research (FSCDR) Symposium. Along with Dr. Umar Mian of Montefiore Medical Center, Dr. James Taylor IV of Howard University, and Dr. Gregory Kato of the University of Pittsburgh, she presented latest findings from research on eye disease, pain, painful or sustained erections also called priapism, and on slow-healing wounds called leg ulcers. Although much remains to be discovered on these topics, attendees were left with concrete best practices to consider for each of these health concerns.

Retinopathy: Sickle cell can affect the eyes in ways that only a specialized doctor can detect

Hypoxia (low oxygen availability) caused by vaso-occlusion (blocked or decreased blood flow) can damage an important structure inside the back of the eye called the retina. This collection of special cells and nerves is critical for your sense of sight, and very sensitive to the oxygen deprivation that can occur during a crisis or from chronic anemia. The retina cannot be seen by looking at the eye without special equipment used by eye doctors called ophthalmologists. A standard eye exam for glasses is not enough screening to detect SCD-related eye complications. Damage to the retina can cause vision problems or even blindness.

Dr. Mian gave an overview of how sickle cell related retinal damage can be detected, monitored, and the current progress made in treating it. He also stressed the importance of yearly eye screening by an ophthalmologist who has received specialized training to look for two things: 1) formation of unusual blood vessels that may cause retinal detachment and 2) areas of the retina that have perished from a lack of blood flow (also called ischemia)1. Not all opthalmologists are retina specialists, so it is important to check the credentials of your eye doctor before scheduling screening. When signs of SCD retinopathy are detected, additional medical imaging like a fluorescein angiogram can help doctors clearly measure the extent of the damage.

Although the exact causes of retinopathy in people living with sickle cell disease is unknown, Dr. Mian highlighted a few trends:

  • People with SC are more likely to develop retinopathy as compared to people with the SS genotype (SS genetic makeup).
  • The prevalence, or percentage, of people affected by SCD retinopathy is higher among older patients. This complication usually arises in adulthood, although it can sometimes affect children too.
  • Hydroxyurea may protect some people from sickle cell related retinopathy.
  • Some sickle cell patients naturally have higher levels of fetal hemoglobin (HbF), which also lowers the risk for this complication2.

Treatment options for sickle cell patients with retinopathy are limited. The standards for treating ocular (relating to the eye) complications in sickle cell are still under development. More research is needed to learn the underlying causes and best treatments for this potentially life-changing consequence of SCD. These are points to keep in mind:

  • Compared to diabetes, a disease that causes similar changes to the retina over time, the changes related to sickle cell are very difficult to detect due to their location on the outer edges of the retina. Specialized procedures are used to get a clear view of this part of the eye.
  • Additionally, it’s hard to predict if retinopathy caused by SCD will spread to affect more of the retina, if it will affect both eyes, or if laserpexy will preserve the affected patient’s vision.
  • Laserpexy is a surgery that uses lasers to create a barrier of scar tissue between the dam aged cells and the rest of the retina, it carries significant risks and is usually considered a last resort in treating eye problems in sickle cell patients. The surgery itself could cause sickling and vaso-occlusion in the affected eye, potentially making the condition worse.
  • Dr. Mian advises SCD patients who must have the surgery to ask their doctor whether a transfusion prior to surgery could make the procedure safer.
  • Medications called VEGF (define acronym in parenthesis here) inhibitors may be used to delay the need for surgery to treat SCD retinopathy. These prescription drugs lower the amount of a compound called VEG-F in the body. This signal molecule normally encourages the growth of new blood vessels, and by limiting its activity, the medications can provide temporary protection in an affected eye3. Each medication must be injected directly into the eye to be effective, and each injection lasts for about one month.

Both Dr. Mian and Dr. Minniti strongly recommended that ALL people living with sickle cell disease have their eyes screened by an ophthalmologist every year. People who develop SCD retinopathy should still have yearly imaging during these visits to track progression of the condition.

Pain: How can we describe acute pain and chronic pain in sickle cell disease?

Dr. James Taylor VI presented the latest updates on his work to document and measure the types of pain that people living with SCD experience. He groups the pain into three categories:

  • Acute: pain brought on by a short-lived event, such as during a vaso-occlusive pain crisis.
  • Chronic pain: pain that occurs on most days over a 6-month period.
  • Aftersensation: acute pain that is noticed immediately after a painful event stops and takes time to go away. Dr. Taylor’s measurements show that this happens when the nerves that sense pain remain activated instead of returning to a state of rest4.
  • To an observer, aftersensation pain appears to have no cause.
  • This type of pain is related to how messages received from your nerves are processed by the brain. Aftersensation pain also happens to people who have other painful chronic health problems. It is also described as neuropathic pain.

Dr. Taylor’s work reframes chronic pain as resulting from progressive damage to the nervous system. Researchers now believe that repeated bouts of acute pain re-train an affected person’s central nervous system to be more sensitive to painful sensations or misinterpret normal sensations as painful. This process is known as central sensitization. For people living with sickle cell disease, this means that the central nervous system (which is the brain and spinal cord together) begins to amplify the sensation of pain so that it feels more intense, and lasts longer than what another person would perceive. Over several years, Dr. Taylor’s team used instruments to measure perceived pain and nerve activity in people with sickle cell disease as compared to others without a chronic disease. Highlights from the presented results are below:

  • Sickle cell patients with higher fetal hemoglobin (HbF) levels had less central sensitization (chronic pain damage to central nervous system) than patients with SS or SC genotypes and less than 15% HbF measured on a blood test.
  • Narcotics, also called opioids, could also alter the nervous system in ways that cause chronic pain.
  • Sleeping disorders and in general lack of adequate rest was associated with higher pain scores.
  • Sickle cell patients with depression also felt more pain.
  • The coping mechanisms that we all use to deal with challenges in life have a direct effect on how the central nervous system processes pain. Catastrophizing (showing strong negative emotional reactions like despair or panic when in pain)5 is linked with higher levels of pain and disability for SCD and other chronic conditions.
  • Compared to unaffected participants, participants with SCD reached their limit for pain caused by ischemia (lack of blood flow to part of the body) sooner (shorter pain tolerance time) and felt higher levels of pain lasting after the ischemia was reversed (longer recovery time).
  • Dr. Taylor and his team are still working to refine the scientific understanding of pain related to sickle cell disease. This type of research, called an observational study, focuses on measuring your body’s physical or biochemical responses. Patient participation in observational studies helps researchers understand the many ways that SCD affects the body. The results of these studies are used to refine current and developmental therapies for the disease. You can learn about chronic pain, acute pain, the science behind what we feel when in pain in this book: Explain Pain by David Sheridan Butler and G. Lorimer Moseley (NOI Group Publishing).

Priapism: Best practices in treating long-lasting or painful erections caused by vaso-occlusion

Vaso-occlusion due to SCD can affect any part of the body, including the genitals. Men and boys with sickle cell can experience vaso-occlusion in the penis which may lead to an unexpected, long-lasting erection. These events are called priapism and can be very painful. At other times an erection due to priapism is simply inconvenient, however, even priapism that is not painful should be reported to your healthcare provider. Without enough blood flow in this delicate area, tissue damage can occur leading to other effects and possibly causing erectile dysfunction. Dr. Gregory Kato presented his observations and conclusions regarding this important complication. There are two types of SCD-related priapism:

  • Acute, severe priapism comes on rapidly and is often very painful. These events are medical emergencies if they last more than 4 hours.
  • Stuttering priapism occurs more frequently, often without pain, and resolves on its own in less than 4 hours.

Dr. Kato and others observed that male SCD patients who have ongoing hemolysis (when the body breaks down red blood cells) are more likely to experience priapism. A set of four blood tests measure hemolytic activity and its impact on the body:

  • Hemoglobin test: measures the amount of hemoglobin protein carried in the blood. This molecule is concentrated inside red blood cells and collects oxygen in your lungs to release it to other parts of the body. It is the same protein that is altered in sickle cell disease. Low hemoglobin levels usually mean that the amount of functional red blood cells is also lower.
  • Bilirubin test: measures a molecule created as your body takes apart damaged or old red blood cells. Normally, it is cleared from the body by the liver and kidneys. When a person is rapidly hemolyzing blood, bilirubin can accumulate and cause dark-colored urine and jaundice, a noticeable yellow tint to the skin and whites of the eyes.
  • Lactate dehydrogenase (LDH) test: measures an enzyme (protein that converts one thing into another) in the blood that increases when cells or tissues are damaged. LDH is contained inside of our cells but can be released into the blood when cells are destroyed and burst open. Usually, levels in the blood are low, but when cells are destroyed LDH levels in the blood increase sharply.
  • Reticulocyte count: reticulocytes are freshly produced red blood cells. Your bone marrow releases more reticulocytes to the bloodstream when it is compensating for a loss of functional red blood cells. Someone who has higher baseline red blood cell hemolysis would be expected to have a higher reticulocyte count. These results help doctors gauge if a person’s bone marrow production can keep up with their need for new blood.

These lab tests are essential during an acute SCD-related health event (including pain crisis), and some hematologists track the laboratory values for each of these tests along with a complete blood count (CBC) at regular office visits.

Comparisons of currently available therapies for both acute and stuttering priapism show penile aspiration (removal of the trapped blood) combined with irrigation (injection of saline solution mixed with a drug to open the blood vessels) as the recommended first treatment6. Phenylephrine is the recommended drug for irrigation because it has a lower risk of cardiac side effects compared to the others in its class (α-agonists). This combination procedure currently has the best chances of preserving erectile function. It must be performed by a urologist, a doctor with specialized training in male urinary and reproductive health.

Dr. Kato also highlighted two drugs that men and boys with sickle cell disease should avoid: cyamemazine and phenothiazine-based drugs. These medicines are often used to treat severe emotional or psychological conditions and have been shown to cause priapism in some men with SCD7. Dr. Kato’s team and several groups of researchers are working cooperatively to discover the reasons why this complication occurs.

Dr. Kato laid out a hopeful vision for the future of priapism treatment, saying that multiple developmental drugs are in testing. Until the safety and efficacy (ability to create an expected effect) of these new approaches are documented, patients and their healthcare providers can stay updated with the latest recommendations from the American Urological Association regarding ischemic priapism.

Leg Ulcers: Taking a broader view on early detection and prevention of slow-healing wounds

The session chair, Dr. Caterina Minniti, presented a new perspective on leg ulcers in sickle cell disease. More of the people who develop this complication have the SS genotype (genetic makeup). Leg ulcers come in three forms, one-time ulcers, stuttering or recurrent minor ulcers, and long-standing ulcers that last for months or years and can be disabling8. She and her team consider the following risk factors for this condition:

An important risk factor for SCD-related leg ulcers is a chronic catabolic state where the body uses dietary protein for energy first instead of building lean body mass (like muscle) with it. When we need energy, our bodies use fats, carbohydrates, and protein to generate it. Under normal conditions it is optimal to:

  • Use available carbohydrates first for short-term energy needs
  • Store and “burn” fat for long-term energy needs or under extreme conditions (e.g. during a severe illness, during endurance sports like running a marathon)
  • Preserve protein for building up or repairing muscles and other tissues in the body.

Some people have an alteration in the way their hormones regulate this metabolic order that leads to chronic catabolism (using too much of the dietary protein as fuel). People with this condition experience low body-mass index (BMI) and unwanted weight loss because their body burns the protein that would be used to build muscle. This can also happen to people experiencing a severe illness or injury (severe burns, lung infection, premature babies, etc.)9,10. Anyone with this type of metabolism would have a harder time healing from cuts, scrapes, and other wounds because there are fewer available protein “building blocks” for their bodies to work with. In people with sickle cell disease, this type of metabolic “programming” can increase the risk to develop slow-healing wounds on one or both legs.

Some risk factors are related to hemolysis and other clinical test features11. Individuals who routinely have high blood test results for LDH, bilirubin, and other markers of hemolytic (red blood cell breakdown) activity have a higher risk to develop leg ulcers. Other factors that can be measured with hospital laboratory tests include thrombophilia (high platelet counts) and poor kidney function.

Other clinical features that can predispose someone to developing these potentially debilitating wounds include chronically low levels of oxygen in the blood (measured by pulse oximetry) and injury to the lower leg like an insect bite or scrape. Even without an injury, many patients say that they felt pain or itching at the site of the ulcer just before it developed. There is some evidence that the local nerves of the lower leg play a role in ulcer formation and progression. Severe or long-standing ulcers may cause chronic pain along with nerve damage that prevents the person from using their feet normally.

Dr. Minniti’s recommendations for treatment are comprehensive:

  • Nutritional support for all affected patients: Many people with leg ulcers also have unique nutritional needs associated with chronic catabolism. Also, the presence of a large wound can induce or worsen a catabolic state. Your doctor may be able to refer you to see a dietitian (licensed specialist in nutrition and meal planning) for guidance.
  • Professional psychosocial support: Needed to help people with this condition overcome depression, stigma, and other social consequences of living with one or more leg ulcers.
  • Physical therapy: Patients with severe or long-standing leg ulcers are at risk of losing function in their feet, ankles, and legs. Dr. Minniti believes that an experienced physical therapist can help reduce the impact that leg ulcers have on mobility.
  • Topical treatment: the current best practices for treating leg ulcers include keeping the area clean and disinfected. It is also strongly recommended to avoid actions or locations that may expose the area to infection.

Take the next step

Educate yourself and loved ones about the potential complications of sickle cell disease. When you understand your health concerns and goals well, you will have an easier time speaking with your doctor to develop a satisfying health care plan. Recent progress in both basic biomedicine and translational (directly addresses a medical need) research has uncovered new insights about the internal processes set in motion by sickle cell disease and increased appreciation for the resilience of people affected by it. Judicious addition of screening and treatments related to this knowledge could empower physicians as well as individuals living with the disease to achieve better outcomes.

This blog article was sponsored by Global Blood Therapeutics Inc. GBT logo, used with Permission, the views expressed by the author are her own.

References

1 Pahl DA, Green NS, Bhatia M, Chen RWS. New Ways to Detect Pediatric Sickle Cell Retinopathy: A Comprehensive Review. J Pediatr Hematol Oncol. 2017 Nov;39(8):618-625. doi: 10.1097/MPH.0000000000000919. Review.

2 Estepp JH, Smeltzer MP, Wang WC, Hoehn ME, Hankins JS, Aygun B. Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children. Br J Haematol. 2013 May;161(3):402-5. doi:10.1111/bjh.12238.

3 Cao J, Mathews MK, McLeod D, Merges C, Hjelmeland L, Lutty G. Angiogenic factors in human proliferative sickle cell retinopathy. The British Journal of Ophthalmology. 1999;83(7):838-846.

4 Darbari DS, Vaughan KJ, Roskom K, et al. Central sensitization associated with fetal hemoglobin levels in adults with sickle cell anemia. Scandinavian journal of pain. 2017;17:279-286. doi:10.1016/j.sjpain.2017.08.001.

5 Quartana PJ, Campbell CM, Edwards RR. Pain catastrophizing: a critical review. Expert review of neurotherapeutics. 2009;9(5):745-758. doi:10.1586/ERN.09.34.

Levey HR, Segal RL, Bivalacqua TJ. Management of priapism: an update for clinicians. Therapeutic Advances in Urology. 2014;6(6):230-244. doi:10.1177/1756287214542096.

Quint R, Lillo-Le Louet A, Pouchot J, Arlet JB. Priapism in sickle cell disease: Beware of neuroleptics. Am J Hematol. 2018 Jun 8. doi:10.1002/ajh.25156.

Senet P, Blas-Chatelain C, Levy P, Manea EM, Peschanski M, Mirault T, Stankovic-Stojanovic K, Debure C, Debbache K, Girot R, Bureau JM, Bachmeyer C, Baldeschi C, Galacteros F, Lionnet F, Gellen-Dautremer J. Factors predictive of leg-ulcer healing in sickle cell disease: a multicentre, prospective cohort study. Br J Dermatol. 2017 Jul;177(1):206-211. doi: 10.1111/bjd.15241.

Nilesh M. Mehta, Chapter 75 – Nutrient Metabolism and Nutrition Therapy During Critical Illness, Pediatric Critical   Care (Fourth Edition), Mosby, Editor(s): Bradley P. Fuhrman, Jerry J. Zimmerman, 2011, Pages 1073-1088, ISBN 9780323073073, https://doi.org/10.1016/B978-0-323-07307-3.10075-8.

10 Molnar JA, Underdown MJ, Clark WA. Nutrition and Chronic Wounds. Advances in Wound Care. 2014;3(11):663-681. doi:10.1089/wound.2014.0530. 

11 Minniti CP, Delaney K-MH, Gorbach AM, et al. Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia. American journal of hematology. 2014;89(1):1-6. doi:10.1002/ajh.23571.

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