Sickle cell pain syndromes include a triumvirate of acute, chronic and neuropathic pain that occur sequentially or simultaneously with age. Unlike other diseases associated with pain such as osteoarthritis, rheumatoid arthritis, fibromyalgia and complex sympathetic dystrophy, sickle cell acute pain manifests itself in infancy and continues to recur throughout the life span of the affected patient. With age, acute pain retains its unpredictable relapses and spawns chronic pain as a new partner in the rhapsody of pain and suffering. Persistent chronic pain may evolve into neuropathic pain. Acute pain, however, dominates the clinical picture and requires urgent treatment with parenteral opioids in the ER and/or the hospital. Pain that occurs between the acute episodes is usually milder and treated at home with oral analgesics and is often referred to as chronic pain. Although this classification is somewhat arbitrary, nevertheless management of sickle pain is based on these assumptions.
The painful crisis often precedes the onset of other complications of the disease such as acute chest syndrome and acute multi-organ failure. About 50% of cases of acute chest syndrome occur in patients a few days after admission to the hospital with acute painful crises. Moreover, sudden death is known to occur during a painful crisis or shortly after discharge from the hospital. The frequency of acute painful crises in patients varies within and between individuals from rare occurrences during a lifetime to many times a month. About 30% of patients have rare or no pain episodes, 50% have occasional episodes and 20% have weekly or monthly episodes requiring medical attention. The frequency of pain episodes increases late in the second decade of life and decreases in frequency after the fourth decade for reasons that are not understood. Frequency of more than 3 episodes a year is associated with a reduced life expectancy. A small number of patients account for the majority of patients requiring healthcare for acute pain episodes.
Moreover, the resolution of the painful crisis is associated with rebound thrombocytosis, elevated levels of fibrinogen, orosmomucoid, RBC deformability and plasma viscosity indicating the presence of a hypercoagulable state that may cause recurrence of the crisis. About 20% of the patients who discharged from the hospital after the resolution of a crisis had recurrent crises that required treatment with parenteral opioids in the ER or hospital within one week after discharge.
Thus it seems that the prevention of the occurrence of painful crises and the early aggressive treatment to abort a painful crisis could prevent or minimize the complications consequent to poorly managed painful crises. Approaches that may achieve this goal will be presented.
Samir K. Ballas, MD, FACP, FASCP, FAAPM, DABPM
Transplant versus Current Standard of Care for Sickle Cell Disease
The decision to perform a progenitor cell transplant (bone marrow transplant) for sickle cell disease is based on the historical context that sickle cell disease is life-threatening, and historically (prior to the use of hydroxyurea and chronic red blood cell transfusions) there have been no options for medical therapies that will decrease the progression of the disease and prolong life. Traditionally, myeloablative conditioning (using chemotherapy to completely kill all the hematopoietic dividing cells in the bone marrow and throughout the body) and matched sibling donor (full brother or sister of the person with sickle cell disease) progenitor cell transplant has been the primary option to cure children with sickle cell disease; however, successful transplantation has been linked to long-term toxicities for some survivors, including but not limited to, severe chronic graft-versus-host disease and sterility. The publication in 2015 of the multicenter, reduced-intensity, matched sibling donor transplantation trial conducted by Dr. Allison A. King and colleagues at eighteen centers has provided critical data which advances our knowledge about progenitor cell transplant and its role for selected children with sickle cell disease and thalassemia.1
This study was conducted to determine whether progenitor cell transplantation using immunoablative (using medication that would decrease an immune response without completely eliminating all of the hematopoietic cells) reduced intensity therapy along with a matched sibling donor. Over 12 years, a total of 43 children with SCD and nine with thalassemia received matched sibling donor with this reduced-intensity conditioning that included three drugs (alemtuzumab, fludarabine, and melphalan). The overall (sickle cell and thalassemia) survival was 94.2 % and the event-free survival (no major adverse complications) 92.3 %, with a median follow-up of 3.42 years. For sickle cell disease by itself, the survival was 93% and the event-free survival was 90.7%. After one year, no transplanted person was on immunosuppression and no graft versus host disease or rejection was noted. For sickle cell disease, there were no new events (strokes, vaso-occlusive pain episodes, or pulmonary complications).
This study offers promise for children with sickle cell disease and a matched sibling donor to be able to receive an immunoablative reduced-intensity transplant. Though this is encouraging the study falls short of becoming standard care for this population due to unanswered questions:
The median follow-up of 3.4 years prevents the assessment of long-term complications, such as infertility, and the absence of the evaluation end-organ function dampens confidence about long term end-organ disease progression after transplant.
The biggest limitation is the lack of a comparison group of children with sickle cell disease receiving current medical therapy. For children with sickle cell disease current advances in supportive therapy provide reasonable options to delay transplant until a clinical trial is completed comparing the short- and long-term complications of the transplant regimen to a comparable group of children receiving maximum medical therapy, the burden and progression of end-organ damage may justify transplantation when compared to current therapy.
When the trial by Dr. King and colleagues started in 2003, hydroxyurea had not been recommended as standard care for children with SCD, but it is now recommended to offer therapy at nine months. In 2003, many hematologists elected to offer hydroxyurea therapy to those children with severe disease, with criteria similar to entry criteria for the transplant trial.
Recently two large pediatric sickle cell trials using current therapy have been completed. In one prospective study, (prospective: children were enrolled, treated and followed over time), 185 children receiving hydroxyurea, with a median duration of treatment of 10.3 years, had a 15-year survival of more than 98 percent.2 In the second retrospective study, (retrospective: medical records are reviewed for children on therapy) 1,033 children with sickle cell disease were reviewed over an approximately 6.7 year period.3 They had a survival estimate over a five-year period of more than 98 percent. These two large pediatric sickle cell disease studies provide inconvertible evidence that sickle cell disease in children is no longer a life-threatening disease, but a chronic disease that may have life-threatening episodes.
The multi-institutional reduced-intensity conditioning and matched sibling transplant trial provides reasonable evidence for advancing the care of children with sickle cell disease. However, the results fall short of recommending that this transplant strategy should become the standard of care for sickle cell disease in children.
To advance the treatment of children with sickle cell disease, the next reduced-intensity conditioning transplant trial requires a longer follow-up duration, evaluation of end-organ disease, assessment of fertility, and a comparison group receiving maximum medical therapy. Questions regarding the optimal reduced-intensity transplant for children with sickle cell disease deserve to be answered in a comparison study. The work by Dr. King and colleagues brings us one step closer to finding that definitive answer.
King AA, Kamani N, Bunin N, et al. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol 2015;90:1093-8.
Le PQ, Gulbis B, Dedeken L, et al. Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment. Pediatr Blood Cancer 2015;62:1956-61.
Couque N, Girard D, Ducrocq R, et al. Improvement of medical care in a cohort of newborns with sickle-cell disease in North Paris: impact of national guidelines. Br J Haematol 2016;173:927-37.
Michael R. Debaun, MD, MPH
Vaso-occlusive pain episodes in sickle cell disease and menstruation: Is there a common connection?
I. Advancements in the Field of Sickle Cell Disease
The field of sickle cell disease has undergone many medical advancements over the past 40 years, including early detection of the disease with newborn screening, improved management of vaso-occlusive events, such as acute pain episodes and acute chest syndrome, early identification of neurological complications, and widespread vaccination against life-threatening infections such as Streptococcus pneumoniae. Because of these breakthroughs, this previously designated “disease of childhood” has now become a chronic “disease of adulthood.”
II. Vaso-Occlusive Pain Associated with Periods in Adolescents and Women with Sickle Cell Disease
Strong clinical evidence indicates that adolescents and women with sickle cell disease have vaso-occlusive pain episodes immediately prior to or during their periods. As more children with sickle cell disease become adults, health care providers have shifted their focus to improve the care of the most common complication of sickle cell disease: vaso-occlusive pain. The largest natural history study on sickle cell disease demonstrated that women have more vaso-occlusive pain than men throughout their lifetime, which may be explained by differences in hormones over the course of a woman’s menstrual cycle. Additional studies have indicated that women who use contraception have lower rates of vaso-occlusive pain, possibly as a result of menstrual cycle regulation. However, the biological basis between vaso-occlusive pain and menstruation in sickle cell disease is unknown.
III. Hormones in the Menstrual Cycle and Nitric Oxide
Certain hormones are involved in different phases of the menstrual cycle. Estrogen is higher in the beginning of the menstrual cycle (called the follicular phase). Progesterone, a hormone that is involved in maintaining the uterine lining for implantation, is higher later in the menstrual cycle (the luteal phase). If no implantation takes place, progesterone levels decrease, causing the uterine lining to shed in the process menstruation.
IV. What We’ve Learned Thus Far
Vaso-occlusive pain associated with menstruation (VOPAM) demands more attention in the research field, as further knowledge about the frequency and biological basis for this association may lead to improved management of vaso-occlusive pain for women during their menstrual cycles. Preliminary evidence from our pediatric sickle cell clinic suggests that as many as 50% of adolescents experience VOPAM. We will continue to collect information about VOPAM in both adolescents and adults and plan to investigate its biological basis, with the ultimate goal of improving therapeutic modalities for VOPAM.
V. How Can You Help Us Understand Pain Associated with Periods
If you or someone you know has experienced vaso-occlusive pain around your period, then we invite you to participate in our online survey about VOPAM, which can be found at: Questionnaires about Sickle Cell Pain during your Menstrual Period.
Sarah-Jo Stimpson, MD
Melissa Day, BS
Michael R. DeBaun, MD, MPH
Hydroxyurea Management in Patients with Sickle Cell Anemia
While sickle cell anemia was first reported by Dr. James Herrick more than 100 years ago1, there remains only one U.S. Food and Drug Administration (FDA)-approved drug for patients with sickle cell anemia, hydroxyurea. Sickle cell anemia is caused by an inherited mutation where the red blood cells are transformed from a flexible donut-shaped cell to a rigid banana-shaped cell. These cells get clogged in small blood vessels and can cause problems such as severe pain crises and organ damage. Fetal hemoglobin is the type of hemoglobin that we all make when we are in our mother’s wombs. Fetal hemoglobin is not affected by the sickle cell mutation and is protective against changes in the hemoglobin. Fetal hemoglobin decreases the chance that the red blood cells will transform into the banana shape and become clogged in the blood vessels. Months after we are born, our fetal hemoglobin levels usually decrease to very low levels. That is why people with sickle cell anemia typically don’t experience symptoms until they are more than 6 months old.
Hydroxyurea has many potential benefits. First, hydroxyurea significantly increases fetal hemoglobin levels in most patients. In fact, if you look at a patient’s red blood cells under the microscope, you can see that unlike before taking hydroxyurea, many of the cells will look normal. Hydroxyurea decreases the stickiness of the red blood cells to the blood vessels. And hydroxyurea helps the red blood cells to live longer; it also decreases the numbers of white blood cells that also contribute to the clogging of blood vessels. Hydroxyurea use was first reported in adults with sickle cell anemia, and it was found to decrease the number of hospitalizations for pain crises, decrease the frequency of acute chest syndrome, and decrease transfusion requirements2. Based on this study, hydroxyurea was FDA-approved for the treatment of adults with sickle cell anemia in 1998. Subsequently, studies were reported in children and infants with sickle cell anemia with similar findings, showing that hydroxyurea was safe for use in even very young children3,4. Hydroxyurea has not been tested in children to determine whether it is as effective as taking no medication, this would be unethical knowing that hydroxyurea is beneficial and safe in children; because of this, hydroxyurea has never been officially approved for use in children. There have also been multiple studies that show that patients with sickle cell anemia who take hydroxyurea live longer than those who do not take hydroxyurea5-7. Therefore, the recommendation has now been made that most adults with sickle cell anemia should take hydroxyurea and that hydroxyurea should be offered to children as young as 9 months of age, including those who don’t have symptoms8.
The main side effects associated with hydroxyurea are that white blood cells (the cells that help to fight infection) and platelets (the cells that help prevent excessive bleeding) can decrease too much. Therefore, patients who take hydroxyurea must have their blood counts monitored, initially every 2-4 weeks when the medicine is first started and then every 2-3 months when the dose is stable. Some patients are more sensitive than others, so a lower dose is initially started, and the dose can be slowly increased every 8 weeks until the ideal dose is reached. Occasionally patients who take hydroxyurea for long periods of time will notice darkening of their fingernails. Rarely, patients may experience nausea and vomiting and very rarely rash and diarrhea. Also, because of the theoretical risk that hydroxyurea can have a negative impact on the fetus, appropriate contraception should be used and patients should talk to their physicians if they are interested in either getting pregnant or getting their partner pregnant.
While we have been treating patients with sickle cell anemia for now more than 20 years, there is no evidence that hydroxyurea increases the risk of leukemia. In fact, we feel that the benefits of hydroxyurea greatly outweigh the risks in most patients with sickle cell anemia. Therefore, anyone with sickle cell anemia (HbSS or HbSb0-thalassemia disease) should talk to their hematologist about hydroxyurea management. Although hydroxyurea has been show to be potentially effective in hemoglobin SC9, the data are not as clear in patients with other types of sickle cell disease and patients should talk to their doctors about whether hydroxyurea is the right choice for them.
Herrick JB. Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia. Arch. Intern. Med. 1910;6(5):517-521.
Charache S, Terrin ML, Moore RD, et al. Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia. The New England journal of medicine. 1995;332(20):1317-1322.
Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377(9778):1663-1672.
Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood. 1996;88(6):1960-1964.
Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am. J. Hematol. 2010;85(6):403-408.
Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010;115(12):2354-2363.
Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of hydroxcarbamide therapy on survival of children with sickle cell disease. Br. J. Haematol. 2013;161(6):852-860.
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048.
Luchtman-Jones L, Pressel S, Hilliard L, et al. Effects of hydroxyurea treatment for patients with hemoglobin SC disease. Am J Hematol. 2016;91(2):238-242.