Advocating for Drug Adherence in

Patients with Sickle Cell Anemia

Easha Qasba
Independent Research II GT
May 26, 2017

Advisor: Dr. Anupama Narla

Instructor: E. Leila Chawkat
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Abstract

Sickle Cell disease is caused by the sickling of hemoglobin which results in the hardening

of the red blood cell ultimately distorting the shape and flexibility of the cells. Several treatments

and supportive medicines exist including hydroxyurea therapy, penicillin prophylaxis, [U1] and

bone marrow transplants. The goal of the current project is to answer the question: How can

researchers increase the use of available treatment protocols in order to better the quality of life

for pediatric patients with sickle cell anemia? By evaluating the extent to which current treatment

protocols are adhered to in correlation to the observed results, one can discern which

improvements could be most effective for resource dedication.

Introduction

Sickle Cell Disease is a debilitating, genetic blood disorder which primarily affects

people of African American (about 1 in 12) or Middle Eastern descent. Patients are affected from

birth, and their life expectancy is greatly impacted. The sickling of hemoglobin prevents organs

and muscles from receiving oxygen. Over time, this lack of oxygen causes an extra strain on the

body as a whole which eventually leads to organ damage and possibly death. Children are often

the most resilient when it comes to medical procedures; however, damage to key organs such as

the spleen will leave them extremely susceptible to bacterial infections. When the brain is not

getting enough oxygen this can also result in stroke; however, the body is programmed to insure

that the brain gets priority when there is a lack of oxygen. Depending on the level of available

health care, this disease can be fatal within the first several years of life; however, with proper

treatment, life expectancy has been greatly increased from an average of 12 years to almost 60.
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The way sickle hemoglobin is shaped makes clotting much more common which prevents

blood and oxygen from reaching the organs. When this occurs with vessels leading to the brain,

stroke can occur. Individuals with SCD are at risk of ischemic and hemorrhagic stroke,

especially those with HbSS or HbS-beta0 thalassemia. It has been estimated that without

intervention, 11 percent of patients with SCD will have a clinically apparent stroke by age 20

years, and one-fourth of patients with SCD will have a stroke by age 45 (Acute Stroke in Sickle

Cell Disease). Strokes add an additional aspect of complexity as it must be determined if the

symptoms of that of a stroke or another cerebrovascular manifestation.

One of the problems in managing the disease lies in the lack of consistency of adherence

to the available treatment protocols. While bone marrow transplant has been found to be

curative, there are many complications associated with finding a donor and managing afterwards.

Adherence to treatment with hydroxyurea as well as penicillin prophylaxis can lead to a

substantially better quality of life with fewer incidents of pain crisis and organ damage. Sickle

Cell Anemia is not fatal on its own, but the ramifications of the anemia, organ damage, and

susceptibility to infection create an extremely dangerous situation, especially for children.

Over the past 30 years, both government and university research institutions have

dedicated millions of dollars towards treatment and a cure for Sickle Cell disease. For current

patients, hematologists focus on improving their quality of life through specific treatments that

decrease the frequency of the adverse reactions that occur as a result of the disease. This study

focused on identifying the most common treatment protocols, examining their effectiveness, and

assessing possible ways to improve the quality of life for patients by improving adherence to

these treatment protocols. Since the researcher did not have access the necessary lab equipment

to conduct a new experiment, the data was collected through meta-analysis. Through the analysis
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of these following four articles, the researcher concluded that the most important aspect missing

from the current treatment protocols is the funding for further research as well .

Literature Review

Since Sickle Cell disease has become a priority disease for treatment within the United

States, life expectancy around the world has increased substantially due to available treatments.

While life expectancy is still nearly thirty years below the average, the rise shows that these

treatments can be effective. Through the research by various research universities and

institutions, penicillin prophylaxis has become a staple in the care of SCA patients along with

hydroxyurea therapy and/or bone marrow transplantation.

Penicillin prophylaxis was one of the first available treatments, and it has proven to be

crucial to the treatment of nearly every patient with Sickle Cell Anemia. A study conducted by

the Prophylactic Penicillin group, PROPS, which was established by the Sickle Cell Disease

Branch, Division of Blood Diseases, and Resources of the National Heart, Lung, and Blood

Institute, assessed the efficacy of the treatment. Penicillin prophylaxis has proven helpful in the

prevention of severe bacterial infections in children with SCA (NHLBI). The researchers

designated two groups; one group received the treatment while one received a placebo, a neutral

substance that is meant to test if the drug has actual results beyond what a patient believes should

happen. No child within the tested group became infected during the time period of the study

while 13 children from the placebo group did. Of those infected, 4 patients went from onset of

infection to death within 9 hours. These results demonstrate the extent to which the drug can

improve a patients chance for survival.

Based on this data, The authors concluded penicillin prophylaxis would drastically

reduce the risk of pneumococcal infection while they added the caveat that the earlier
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penicillin prophylaxis begins, the more likely it is to be effective since the risk of infection is

inversely related to age (NHLBI). The results from this study and others like it led to newborn

screenings for sickle cell disease to become standard. This not only allows patients to

immediately begin receiving treatment, but it also allows the caregivers to become aware of the

amount and type of care the child will require. Also, since the disease is genetic, parents may

simply be carriers who were unaware of this prior, and they can make further family decisions

with more information.

The treatment itself is relatively simple consisting of a twice daily oral pill. While

adherence to the drug had not been studied at the time, even minimal adherence yielded

statistically significant results. For those allergic to penicillin, amoxicillin is an equally viable

option.

Hydroxyurea Therapy is a drug therapy which has been coupled with other treatment

protocols in order to better the chances of event free living. Hydroxyurea is the only effective

drug proven to reduce the frequency of painful episodes. These episodes known as pain crises

are caused by the blockage of arteries that occurs due to the rigid, sickled shape of sickle

hemoglobin. While normal hemoglobin moves smoothly through the vein and arteries, sickle

hemoglobin becomes stuck, preventing the organs and body tissues from receiving the oxygen

they need. Hydroxyurea therapy Raises the level of [fetal hemoglobin] and the haemoglobin

level. It usually decreases the rate of painful episodes by 50% (Agrawal). These increased levels

of fetal hemoglobin decreases morbidity from vaso-occlusive complications in patients with

sickle cell anemia (SCA) Steinberg).

These vaso-occlusive events, or pain crises, are one of the most debilitating parts of

Sickle Cell disease. They occur due to a lack of oxygen caused by clotting hemoglobin in the
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arteries. A trial regarding the efficacy of hydroxyurea therapy was closed earlier than expected,

after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per

year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and

numbers of transfusions were also lower in patients treated with [hydroxyurea] (Charache, S, et

al). By reducing these events, both quality of life and health is improved.

Furthermore, Recent evidence documents sustained long-term benefits with prevention

or reversal of chronic organ damage (Agrawal). By preventing or reversing this organ damage,

people with Sickle Cell Anemia will be better suited to manage infections and survive longer. By

helping to reduce the occurrence of the vaso-occulusive events, this also reduces the risk of

stroke which occurs in 11% of patients with Sickle Cell Disease. Challenges in management

[and diagnosis of stroke] include distinguishing acute stroke from other cerebrovascular

manifestations of the disease such as meningitis, cerebral malaria, or seizure disorder, and

distinguishing acute ischemic stroke from hemorrhagic stroke (Acute Stroke in Sickle Cell).

These are crucial in determining which therapies are needed/ would be most effective.

Despite the promising results of hydroxyurea therapy, physicians are inadequately

informed about the treatment which leads to patients and guardians not even being offered the

option or refusing out of unwarranted fear (Agrawal). The studies mentioned earlier were

published during the late 1990s, but few newer studies of the kind have been conducted. Studies

conducted recently to determine the effectiveness of available treatments demonstrated that while

there is still progress to be made, treatments improve quality of life; however, increased

adherence will be necessary in order to reap all of the possible benefits from the existing

treatments.
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The consequence of Sickle Cell disease is further exacerbated by the rate at which the red

blood cells hemolyze. Since Sickle hemoglobin destroys itself at a substantially faster pace, these

patients are often anemic. Rather than hemolyzing at a rate of once every 90 to 120 days, the red

blood cells of a patient with sickle cell disease hemolyze every 10 to 20 days. This prevents the

body from producing enough red blood cells to supply the body with the oxygen it needs. Blood

transfusions help to combat this. Healthy blood gives their body and organs a better chance of

receiving enough oxygen, if only for a temporary period. Bone marrow transplants, on the other

hand, are curative.

Bone marrow transplants are less common for patients with sickle cell disease because of

the possible complications and difficulty in finding a donor, but this is the only cure for SCD at

this point. While marrow is very difficult to type and match, transplantation can help rejuvenate

the body with fresh red blood cells which clot, process, and work in the correct manner. To begin

the process, patients are given chemotherapy in order to destroy their bone marrow and infection

fighting system. This is done to reduce the chance of rejection. The best option for a donor is

often a sibling or family member, but a donor can have normal or hemoglobin with sickle cell

trait (Barrett). Engraftment, the process in which the patients body begins producing healthy

cells, indicates the beginning of the road to recovery. Patients may also receive growth factors in

order to expedite the bodys production of blood cells. A common growth factor for white blood

cells is granulocyte-colony stimulating factor or G-CSF. Some patients may also receive growth

factors to stimulate the marrow to make more red blood cells or platelets (Engraftment). If this

process is successful, the patient will no longer suffer the symptoms of sickle cell disease. While

some patients do not suffer any complications, those undergoing transplant risk further

hospitalization due to complications.

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The various complications which can occur following a transplant vary based on several

factors. The risk can depend on the type of disease or condition, the type of transplant, and

the age and health of the person receiving the transplant (Mayo Clinic). One possible

complication is graft versus host disease, GVHD, which can occur when stem cells from the

donor are used. This sort of transplant is known as an allogeneic transplant. This result is not

rare, and the chances are higher when the donor is unrelated. GVHD can be acute, meaning it

occurs within several months of transplant and affects specific organs, or chronic GVHD can

occur. Chronic GVHD can occur at any point following the transplant, affects many organs, and

can result in persistent cough, joint pain, vision or skin changes, diarrhea, or nausea.

The risk for complications is highest during the first 100 days following transplant (Early

Recovery). Due to the chemotherapy administered prior to transplant, the immune system is

weaker than normal which leaves the patient vulnerable to infections. Without the ability to fight

infection, minor infections can spiral into something far more serious. The medication used to

treat GVHD can also further weaken the immune system.

A trial of unrelated donor marrow transplantation for children with severe sickle cell

disease was conducted in order to determine the correlation between adherence and better

outcomes. By coordinating with the multiple checkpoints for care, researchers were able to

determine the level of bias in the self-reporting of adherence as well as observe the correlation

between higher adherence and better outcomes. The researchers found that adherence was

substantially lower than expected, at around 60-70%. They also found that for those who

reported better adherence, as corroborated by physicians and pharmacists, these patients reported

fewer incidents and better overall quality of life.

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Clearly, treatment for sickle cell disease is multifaceted, and this makes it difficult for

general physicians, caregivers, and patient to manage. A study was conducted using primary

physicians, pharmacists, primary caregivers, hematologists, and patients in order to determine

the level of adherence to the prescribed treatment plan to determine if the events were due to a

lack of adherence or a need for improvement in the treatment itself.

This information was gathered through meta-analysis in order to prove the hypothesis set

forth by the researcher. Adherence is among one of the main issues facing the treatment of sickle

cell disease as it is difficult to discern the effectiveness of treatments which are not being carried

out to the fullest extent. Furthermore, if the general public, as well as the families of patients, are

given the information, resources, and support they need, then the adherence to detailed treatment

protocols will increase. This increased awareness will also allow the American Society for

Hematology to improve fundraising leading to a greater dedication of funding towards research

for treatment therapies.

Data Collection

A meta-analysis was used to gather data from various scholarly sources regarding the

characteristics of Sickle Cell Disease as well as the various treatment options. Between the

various sources, different information regarding the adherence of caregivers to prescribed

treatment protocols was given, and theories regarding improving patient care presented differing

perspectives.

In order to combat the organ damage and decrease the frequency of pain crises and other

incidents, treatments such as hydroxyurea and prophylactic penicillin are proven to be useful. In

source 1, The National Heart, Lung, and Blood Institute found that a daily dose of penicillin in

SCD patients between the age of 3 months and 3 years can reduce the incidence of infection by
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84%. The success of prophylactic penicillin in such young children encouraged scientists and

legislators to push for newborn screenings for blood disorders in order to start treatment earlier.

Over the course of several years, in the late 1900s, 44 states [U4] made newborn screenings

available or mandatory versus the previous 14 states. Now, these screenings are universal. In

1991, a trial testing hydroxyurea found that this treatment reduced by half the following: pain

crises, hospitalizations, acute chest syndrome episodes, and units of blood needed. It was even

found that, in patients between 5 and 15, hydroxyurea therapies increased fetal hemoglobin

levels and decreased complications along with the other benefits mentioned earlier. Bone marrow

transplants, while risky for the patient and only considered in certain cases, has been extremely

successful in some cases. New research indicates the use of the umbilical cord could be a better

option since it negates the need for chemotherapy.

While the National Institutes of Health seem highly optimistic about the future of

treatment for the disease, the other sources expressed concern about the inconsistency in patient

care which was essentially undermining the treatment plans and best possible outcomes.

Considering the awareness for this disease in relatively low and the fact that it only received

government funding for research about three decades ago, the progress made has been

substantial. The progress would be greatly improved by greater adherence.

Overall, researchers [U5] are working towards improving several treatments that offer a

longer life expectancy and a better quality of life than before. While the researcher began this

investigation under the impression that there were insufficient treatment, this assumption was

incorrect as transplantation is curative; however, a large amount of money was needed to make

this progress and more will be needed in order to progress towards a cure. This data revealed

what is truly missing from the field, what progress has already been made, and what realistic
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possibilities still exist within the research community. It is important to acknowledge what has

been accomplished thus far; however, the standard of care is not consistent which is something

that can be improved.

Conclusions

The various treatment protocols are rendered less effective without consistent adherence,

and since the majority of Sickle Cell patients are children, the burden falls to the parents. A

greater level of awareness, standardization, and adherence would greatly improve the quality of

life and life expectancy for patients with sickle cell disease. Treatment protocols vary from

patient to patient; however, the more common treatments/drug regiments include hydroxyurea

therapy or penicillin prophylaxis. Supportive care with penicillin prophylaxis is critical to

reducing the occurrence of vaso-occlusive events. Bone marrow transplant is curative for Sickle

Cell Disease, but a donor must be found and there are many possible complications which range

in severity. Transplant allows a patients body to begin producing its own, healthy red blood

cells. While the risk for complications are daunting, transplants offer the only cure for Sickle

Cell disease. From studies conducted over the past two decades, it is clear that while the quality

and expectancy for life has greatly improved, the adherence to treatment protocols falls at around

60-70%.

The success of bone marrow transplants indicates the progress which has been made

since the beginning of research for Sickle Cell Disease; however, transplantation presents many

risks. That is considering a patient is able to find a donor within his or her own family or through

donation organizations such as UNOS. In order to move towards more consistent and readily

available care, additional funds and awareness must be raised. By raising awareness,

organizations such as the American Society for Hematology will be able to raise funds to
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dedicate to the research and treatment of Sickle Cell Disease. The average life expectancy for

someone with Sickle Cell Disease is still almost 30 years below that of the average American.

That is what these resources are being dedicated towards: closing that gap.
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