CASE HISTORY
Patient history
The patient is a 26-year-old African America male with a history of
homozygous sickle cell anemia with multiple secondary complications. He
was diagnosed in 1983 near the time of birth. His family history
includes sickle cell disease in two cousins and sickle cell trait in
both of his parents and one of his two brothers. The patient's
second brother, other than being a type II diabetic, is considered
healthy.
He was initially seen at the University hospital in the hematology
clinic in 2000 as a 16-year-old with at least II-B and possibly III-A
Avascular Necrosis (AVN) in his left hip. Avascular Necrosis is a
gradual wearing of a weight-bearing surface, in this case the femoral
head, which can lead to the collapse of the hip. (1) The stages of
necrosis range from stage I to stage IV, with stage IV being a
completely flattened femoral head. This patient had progressed to stage
III-B, meaning that his femoral head was aspherical and was beginning to
show signs of collapse. Upon his first visit, the physician also learned
of a past history of sickle cell disease, a Cerebrovascular Accident
(CVA), or stroke around the age of seven, development of hypertension,
migraine headaches, and chest fracture repair.
Complications secondary to sickle cell disease and occurring from
2000 to the time of admission in 2009 included AVN, sickle cell pain
crises of approximately 25 times per year, musculoskeletal chest and
back pain at rest and also during activity, night pain, as well as
priapism. Other health complications included Type II diabetes,
depression, and Tinea-like skin lesions on the upper left extremities
and face.
Prior to hip replacement in 2002, the patient was noncompliant in
using crutches and other therapy. He received a total left hip
replacement due to AVN. He has also been receiving numerous units of red
cells, typically in the form of red cell exchanges, since December of
2000. The transfusions are usually performed once a month; these have
led to iron overload. The patient has multiple port abscesses as well as
port infections. He is in and out of the hospital frequently due to
sickle cell pain crises.
The patient has been treated with a variety of medications for
migraine headaches, pain, hypertension, iron overload, depression, and
diabetes. Hydroxyurea, a cytoxic drug, was used in order to increase the
percentage of hemoglobin F in an attempt to lessen his hemolytic and
pain crises. However it was found that the patient was allergic to this
agent. He was also allergic to penicillin, vancomycin and
cephalosporins.
Results from physical examination
Over the years, the patient's physical examinations have
generally been unremarkable, other than the musculoskeletal chest and
back pain due to sickle cell pain crises. His physicians have noticed
mild scleral icterus, Tinea-like lesions on the face and left, upper
extremities, and occasional fatigue.
Significant diagnostic laboratory tests
Table 1 presents his laboratory values from 2002. Most notable are
the data from hemoglobin S quantitation and elevated ferritin levels.
The patient's CBC in 2009 (Table 2) shows a normocytic,
normochromic anemia. With red cell exchange for patients with sickle
cell disease the concept is not to replace hemoglobin because the
patient is "anemic" it is to replace the altered/abnormal
hemoglobin (SS) with physiologically active hemoglobin (AA) in large
amounts. Typically the patients end up at the hemoglobin they started
with which is around 9 and no higher than 10. Throughout the years, his
white blood cell counts and platelet counts have usually been increased.
Hemoglobin evaluation by electrophoresis shows increased hemoglobin S,
generally around 35% pre-transfusion and 10% post-transfusion. His
hemoglobin solubility screen is consistently positive. The
patient's current conditions require monthly monitoring of
ferritin, due to iron overload that is being treated with Deferasirox.
His liver and kidney function tests, although slightly elevated, are
generally fairly stable. Overall, his bilirubin is generally between 3
and 4 mg/dL, with his direct bilirubin being around 0.5 mg/dL. The
patient's LDH level is usually around 300 units/L and his
creatinine about 0.35 mg/dL.
Patient outcomes
The patient benefited from an earlier total left hip replacement
due to AVN, as well as stroke rehabilitation in his early years. To help
deal with his numerous sickle cell crises, the patient was initially
administered hydroxyurea, but he was found to have an allergy towards
the drug. He is currently dealing with sickle cell disease with chronic
exchange transfusions of Kell negative red cell units every four weeks
instead of every six weeks, due to a long interval free of pain crises
resulting from the more frequent red cell exchanges. Replacing the ports
and allowing the infections to heal with associated antibiotic therapy
has been effective in treating the port infections.
In terms of the pain caused by the sickle cell pain crises, the
patient is undergoing physical therapy and taking pain medications,
which lower his daily resting pain level.
His immunizations are kept up to date to prevent further
complications with his disease. The Tinea-like skin lesions have been
cleared with medications and visits to his dermatologist.
The patient is evaluated by his family doctor every four to six
weeks in order to monitor his ferritin levels and liver function tests
due to the risk of iron overload from the constant red cell exchange
transfusions. He is also receiving Deferasirox, an iron chelator, to
ensure that secondary hemochromatosis does not occur.
Quality of Life
This patient, initially diagnosed at birth with sickle cell
disease, has finished high school and is attempting to earn a degree in
broadcasting and business. However, due to his chronic medical
conditions, the patient has had to postpone his studies several times.
He is single, unemployed, lives at home with his parents, and has an
eight-year-old son. His conditions generally keep him from participating
in many activities of everyday life, such as school and work, as he has
been known to have as many as twenty-five pain crises per year.
When asked questions regarding depression, the patient states that
he is depressed due to his conditions, as well as the death of one of
his brothers. He was being treated synergistically for depression with
both psychiatric counseling and medication; however he notes that no
change had been seen with the use of medication and that he didn't
care for his psychiatrist. He was encouraged to locate a new
psychiatrist to continue his treatment of depression.
The patient's physicians have spoken with him about a possibly
shortened life span due to his disease and complications. He understands
the situation and has been educated on possibilities to prolong his
life, such as a bone marrow transplant. A brother has been identified as
a possible donor and he and his family are considering the options.
EXPLANATION OF HOMOZYGOUS SICKLE CELL ANEMIA
Homozygous sickle cell anemia is an autosomal codominantly
inherited disorder that results in chronic hemolytic anemia. It is one
of the most common genetic disorders in the world, seen most frequently
in Sub-Saharan Africa, but also in geographic locations that are
associated with the presence of malaria, or have immigrants from these
locations. (2) The genetic defect, a single point mutation resulting in
the substitution of valine for glutamic acid at the 6 position on the
beta globulin of chromosome 11, causes a sickling of hemoglobin in red
blood cells. The sickled hemoglobin, referred to as Hemoglobin S, in the
absence of oxygen, polymerizes, forming rods that develop the sickle or
crescent shape of the red blood cell. (See Figure 1). Within the
microcirculation, these cells stimulate a cascade of events that cause
serious complications.
[FIGURE 1 OMITTED]
The current median survival for sickle cell disease patients is 42
years for men, and 48 years for women, up from less than 20 years in the
last three decades. (1-3) The increase in survival rates for sickle cell
patients has been due to increased screening in newborns, increased
prophylaxis for the prevention of infections, advanced technology for
detection and monitoring, and sustainable treatments for sickle cell
anemia and its secondary complications. (2,3) Although an increase in
life expectancy with sickle cell patients has been seen, this does not
mean that the complications have diminished.
These patients live with a wide range of symptoms that vary in
onset, severity, type and location. (1) Due to the complexity of the
variation in sequelae related to sickle cell disease, the management and
treatment for the disease and accompanying conditions also vary from
person to person. Individualized plans, including management of
secondary conditions through various treatments and medications, allow
the patient, physicians and scientists to determine possible strategies
for dealing with this serious and long-term condition. (1)
COMPLICATIONS OF SICKLE CELL ANEMIA
The blockage of the small blood vessels by sickled cells causes
episodes of vaso-occlusion, and pain crises, which characterize sickle
cell disease clinically. (1) However, sickle cell patients show a wide
range of complications other than pain crises, including stroke,
bacterial infection, sequestration of the spleen, avascular necrosis
(AVN), leg ulcers, end-organ damage, renal disease, hypertension (HTN),
acute chest syndrome (ACS), and priapism. (2) As previously mentioned,
these symptoms can come on all at once or gradually. They may occur
frequently or sporadically, and can vary in type and location of pain.
(1)
The patient introduced in this case study illustrates sickle cell
anemia that includes several of the aforementioned complications.
Although each individual case will present differently, complications
are not all necessarily inevitable. The collection of secondary
complications to sickle cell anemia that are unique to this patient,
including stroke, pain crises, avascular necrosis of the left hip,
hypertension, priapism, Tinea-like skin lesions on the upper
extremities, and iron overload will be discussed next in order to gain
greater understanding of the pathophysiology of sickle cell anemia.
At the age of seven, the patient experienced a cerebrovascular
accident (CVA), or stroke, evidenced by multiple white matter lesions
seen with Magnetic Resonance Imaging (MRI). Young children with sickle
cell anemia are at very high risk for strokes because of the vascular
occlusion and intravascular hemolysis seen with sickle cells. These
abnormalities in the microvasculature eventually reach the brain,
causing the child to have a stroke. Currently, abnormalities in the
cerebral vasculature can be detected using Transcranial Doppler
Ultrasonography (TCD) by measuring the velocity of blood flow in the
brain. However this patient suffered a stroke 19 years prior to his
current situation. It has been suggested that once a pediatric sickle
cell patient has been considered at high risk for stroke, red cell
transfusions can significantly reduce that risk when performed
regularly. (4)
Sickle cell pain crises, which are responsible for the
patient's back and chest pain, are known as the hallmarks of sickle
cell anemia. (2) These episodes of pain, such as acute chest syndrome,
can be explained by a difficult mechanism resulting in red cell
adherence to the vascular endothelium and activation of coagulation
factors. When pain accompanies sickle cell anemia, tissue injury is
being reflected. (3) This patient has had a history of pain crises,
occurring as many as 25 times per year and usually taking place two or
three weeks post-transfusion. These episodes have led to as many as 50%
hospitalizations throughout a year. In fact, vaso-occlusive pain is the
most common reason for hospitalization among sickle cell patients. The
pain itself is not life threatening, but secondary complications due to
inadequate treatment can be fatal. Current studies are examining at ways
to develop long-term management plans for pain crisis patients to
recognize and manage their pain from home, without having to be admitted
to the hospital. (1)
Hypertension and priapism can both be explained as manifestations
of a hemolysis-related syndrome. Pulmonary hypertension (PHT) has
emerged as a new complication for patients with various kinds of
hemolytic anemia. The rationale behind this issue may be due to a high
cardiac compensating output related to the anemia. Correction of the
anemia by way of exchange transfusion, or administration of hydroxyurea
in order to increase Hemoglobin F, may allow the patient to develop
healthier red cells with normal function in relation to the vascular
endothelium. In children with PHT, acute chest syndrome, asthma, and
bacterial sepsis are common, while in adults, renal and liver
dysfunction can be seen. (2) When the patient presented here was seen by
a hematologist, he was already taking medication to lower his blood
pressure. Priapism, which is the inability to return an erect and often
painful penis to its normal state, found in 10 to 40% of adult males
with sickle cell anemia, is also associated with hemolytic disorders.
Its mechanism is not fully understood. (2,3) This patient occasionally
presented to his physician with priapism, which required surgical blood
extraction from the penis at least once.
Avascular necrosis (AVN) occurs in sickle cell patients due to the
increased intramedullary synthesis of blood cells of the bone marrow in
an attempt to compensate for the hemolytic anemia. Necrosis typically
occurs at the femoral head due to increasing pressure on the femoral
head and a decrease in tenuous blood supply. A lack of blood supply to
the bones, especially the femur, causes bone death to the weight-bearing
surface of the head of the bone. (3) At the age of 18, this patient
underwent a total left hip replacement because of AVN. Recent studies
show that physical therapy can protect the hip from collapsing just as
effectively as surgery if it is followed with persistence. Although AVN
is certainly not a new finding with sickle cell patients, its prevalence
is increasing. (3)
Tinea-like skin lesions were seen on the upper extremities and face
of this patient on several occasions, in which case he was referred to a
dermatologist for treatment. He also experienced several transfusion
port infections, which required the removal of the port and
reinstallation at a different site. The infections were treated with
intravenous antibiotics. Sickle cell patients are generally susceptible
to infections because the spleen in the first organ damaged by the
sickle cells in the microcirculation. Bacteria such as Streptococcus
pneumoniae are a common cause of bacteremia, while Salmonella sp. and
Staphylococcus aureus are common causes of osteomyelitis in sickle cell
patients. Infants are now screened at birth for sickle cell anemia not
only for diagnostic purposes but also to prevent early death by
bacterial sepsis. Children with sickle cell disease are kept up to date
with immunizations and are treated with penicillin prophylaxis no later
than three months of age. (2) This type of prevention can be maintained
throughout life. Unfortunately in this case, the patient was allergic to
penicillin, vancomycin, and cephalosporin, so treatment for bacterial
infections has been difficult.
In this case, an indirect secondary complication to sickle cell
anemia has been iron overload. Due to chronic transfusions, (in order to
reduce risk of stroke and to treat symptomatic anemia), priapism,
hypertension, and chronic pain, macrophages are overloaded with iron in
the form of non-transferrin bound iron (NTBI). As units of transfused
blood increase, iron storage increases proportionately. In order to
prevent iron toxicity in sickle cell patients, iron overload must be
evaluated and managed as the major long-term problem with transfusing
these patients. (3,5) Physicians administered, to the patient in this
case, two different types of drugs that act together to reduce iron
levels, that will be discussed in the treatment section.
CORRELATION OF LABORATORY TESTING
A complete blood count (CBC) and bone marrow examination need to be
run to evaluate a suspected person with sickle cell anemia initially.
The CBC usually shows a normocytic, normochromic anemia in a patient
with sickle cell anemia. The bone marrow examination will show erythroid
hyperplasia, since the bone marrow attempts to compensate for the
hemolytic anemia. (6)
Hemoglobin solubility tests are done when the clinical
presentation, CBC and bone marrow examination imply a diagnosis of
sickle cell anemia. If the patient has sickle cell anemia, the
solubility test will be positive, meaning Hemoglobin S is present in the
individual. With this patient, the physician requested the hemoglobin
solubility test, which gave a positive result.
Hemoglobin electrophoresis can be performed using both alkaline and
acidic mediums. Performing electrophoresis on cellulose acetate at pH
8.4 for a patient with sickle cell anemia will result in a band
migrating in the Hemoglobin S region on the gel. However, Hemoglobin D
and Hemoglobin G also migrate with Hemoglobin S on cellulose acetate, so
electrophoresis should be performed on a second gel using citrate agar
at pH 6.2. The acidic agar will separate Hemoglobin S from Hemoglobin D
and Hemoglobin G, confirming the source of sickle cells in a patient.
(6) Electrophoresis on both cellulose acetate and citrate agar in this
patient showed the presence of Hemoglobin S in higher than normal
proportions, confirming sickle cell anemia.
High-pressure liquid chromatography (HPLC) is a more recent method
for determining the relative portion of specific hemoglobins found in
whole blood, measured in percentages. Automated systems, such as The
Variant[TM] II Hemoglobin Testing System, used in the laboratory where
this patient was evaluated, combine sample preparation, separation, and
determination into one instrument. The hemoglobins are measured
according to their retention times from injection of the sample into the
instrument to their peak concentrations. Each type of hemoglobin has its
own characteristic retention time window that is used in the
determination of hemoglobins present in a whole blood sample. (7)
TREATMENT
The administration of hydroxyurea, long-term transfusions, and bone
marrow transplants are three of the primary treatments associated with
sickle cell patients. Hydroxyurea, a pharmacological agent, is commonly
used in adults with sickle cell anemia. It is the only medication that
has been approved for the treatment of these patients. Hydroxyurea acts
to increase the levels of fetal hemoglobin, or Hemoglobin F, in sickle
cell patients. Hemoglobin F has a higher affinity for oxygen than does
normal hemoglobin and especially Hemoglobin S. Increasing fetal
hemoglobin increases total hemoglobin while decreasing hemolysis and
vaso-occlusion. (8) Hydroxyurea treatment was started with the patient
in this case; however he was found to have an allergy towards the agent,
so treatment was ceased.
Transfusions are used not only to increase the levels of normal
hemoglobin in these patients, but also to reduce risk of stroke and to
treat some of the symptoms involved in the anemia, such as fatigue. (3)
In this case, the patient has been transfused every four to six weeks in
order to reduce his agonizing pain crises. However, chronic transfusions
add a life-threatening complication to the mix, known as iron overload,
often requiring iron chelation. Since iron overload is an important
long-term complication in patients receiving chronic transfusions,
maximizing iron chelation efficiency is a topic that has received much
attention among medical scientists and pharmacologists. (5) The FDA has
approved two drugs to treat iron overload in transfusion patients.
Deferoxamine, which requires continuous infusion, is used in combination
with deferasirox, an oral iron chelator have recently emerged as highly
effective drugs. (3) In this particular case, the patient has been
treated with both deferoxamine and deferasirox. The goal of iron
chelation is to maintain an iron balance by matching the amount of the
iron excretion through chelation and the amount of iron that is loaded
during transfusion. Deferasirox is highly effective in maintaining these
results because it allows continuous chelation over a 24-hour time
period by simply having the patient take a once-daily oral medication.
(5)
While hydoxyurea and chronic transfusions are helpful in managing
the symptoms of sickle cell patients, bone marrow transplantation may be
the only current cure for sickle cell anemia. In order to free sickle
cell patients from the numerous manifestations of hemolytic anemia, bone
marrow transplant candidates must have a suitable donor, who is usually
a primary family member. In order to find a suitable donor, HLA matching
must be performed on family members and the patient in order to
determine if the patient is a good candidate. In those patients who do
not reject the graft, this procedure increases patient survival, free
from usual clinical manifestations. However, only 14 to 18% of sickle
cell patients are able to find a suitable donor. The procedure is often
limited to younger patients with severe complications in order to reduce
the risk of graft rejection. Currently, treatment developments are
focused toward less intense procedures and more immunosuppression, which
would be beneficial for older patients who generally would not be
considered for transplant. (3,9) The patient in this case was referred
to a bone marrow transplant center and his brother has submitted a blood
specimen for HLA typing. However, the family of the patient and his
brother are reluctant to go ahead with the procedure.
CONCLUSION
Patients with sickle cell anemia, such as the patient in this case,
are diagnosed and treated by a team of health care professionals in
order to establish a diagnosis and to manage the anemia and secondary
conditions that can be difficult to control in everyday life. Since the
average life expectancy of sickle cell patients has increased, current
research regarding sickle cell anemia and its complications is focused
on an aging population of those with sickle cell disease as well as
their long-term management. (2,3) Individualized management plans in
terms of treating complications are anticipated to continue to show
signs of increased effectiveness and efficiency. Home management of
complications such as pain crises may be in the near future for these
patients. (1) An increase in newborn screening for sickle cell disease
or trait, advanced technologies for detection, increased prophylaxis for
prevention of infections in those diagnosed, and sustainable treatments
contribute to an increase in life expectancy and perhaps quality of life
of sickle cell patients. (2,3)
REFERENCES
(1.) Wright K; Adeosun O. Barriers to effective pain management in
sickle cell disease. Br J Nurs. 2009;18:158-61.
(2.) Driscoll MC. Sickle cell disease. Pediatr Rev. 2007;28:259-68.
(3.) Hagar W, Vichinsky E. Advances in clinical research in sickle
cell disease. Br J Haematol. 2008;141:346-56.
(4.) Adams RJ. Big strokes in small persons. Arch Neurol.
2007;64:1567-74.
(5.) Porter JB. Concepts and goals in the management of
transfusional iron overload. Am J Hematol. 2007;82(12 Suppl):1136-9.
(6.) McKenzie SB, Williams JL. Clinical Laboratory Hematology. 2nd
ed. New Jersey: Pearson; 2010.
(7.) LaRue H, Gewirtz A. Variant II Hemoglobin Testing System for
Quantifying Normal and Abnormal Hemoglobins. OSUMC Department of
Clinical Laboratories. 2009.
(8.) Strouse JJ, Lanzkron S, Beach MC et al. Hydroxyurea for sickle
cell disease: a systematic review for efficacy and toxicity in children.
Pediatrics. 2008;122:1332-42.
(9.) Bhatia M, Walters MC. Hematopoietic cell transplantation for
thalassemia and sickle cell disease: past, present and future. Bone
Marrow Transplant. 2008;41:109-17.
Christopher J. Yontz, The Ohio State University, Columbus, OH
Kathy V. Waller, Ph.D., CLS, The Ohio State University, Columbus,
OH
Address for Correspondence: Christopher J. Yontz, The Ohio State
University, 535 Atwell Hall, 453 W. 10th Avenue, Columbus, OH 43210,
419-357-5031, yontz.17@buckeyemail.osu. edu
Table 1. Significant laboratory values from one of the patient's
earlier visits on 08/21/2002.
Analyte Result Reference Ranges
Red Blood Cell Count 4.01 x [10.sup.12]/L 4.30-5.60 x [10.sup.12]/L
Hemoglobin 125 g/L 133-162 g/L
Hematocrit 0.365 L/L 0.388-0.464 L/L
MCHC 342 g/L 323-359 g/L
MCV 91.1 fL 79-93.3 fL
Platelets 412 x [10.sup.9]/L 165-415 x [10.sup.9]/L
Hemoglobin A 73.8% 95-98%
Hemoglobin A2 3.0% 1.5-3.1%
Hemoglobin S 22.7% Absent
Ferritin 1650 ug/L 29-248 ug/L
Hemoglobin Solubility Positive Negative
Screen
Table 2. Pre- and post-transfusion lab values
from 10/09/2009 and 10/12/2009, respectively.
(9 Red cell units of type B+, Kell negative
blood were transfused on 10/12)
Pre-transfusion
Analyte Result
Red Blood Cell Count 3.39 x [10.sup.12]/L
Hemoglobin [10.sup.9] g/L
Hematocrit 0.32 L/L
MCHC 332 g/L
MCV 95.6 fL
Platelets 475 x [10.sup.9]/L
Hemoglobin A 57.9%
Hemoglobin A2 3.02%
Hemoglobin S 35.9%
Ferritin Not done
Hemoglobin Solubility Screen Positive
Post-transfusion
Analyte Result
Red Blood Cell Count 3.50 x [10.sup.12]/L
Hemoglobin [10.sup.9] g/L
Hematocrit 0.32 L/L
MCHC 342 g/L
MCV 91.6 fL
Platelets 153 x [10.sup.9]/L
Hemoglobin A 83.5%
Hemoglobin A2 3.1%
Hemoglobin S 10.5%
Ferritin 6142 ug/L
Hemoglobin Solubility Screen Positive