Chapter 17
Sickle cell ulcers

Terry Allen Treadwell MD, FACS
Angela Colette Willis RN, CWS, CDE
Harold Brem MD, FACS
The contributions of Marc Gibber, Wound Care Center, The Mount Sinai Medical
Center, New York, New York; and Sharon Weinberger, The Mount Sinai Medical
Center, New York, New York, to the first edition of this chapter are greatly
acknowledged.

Objectives
After completing this chapter, you'll be able to:

understand the pathogenesis of sickle cell anemia (or sickle cell disease)
discuss the pathogenesis of sickle cell ulcers
differentiate sickle cell ulcers from arterial and venous ulcers
implement protocols for prevention and treatment of complications of sickle cell
ulcers (such as infection).

Sickle cell anemia
Sickle cell ulcers are a complication of sickle cell anemia, an inherited,
genetic disorder of the oxygen carrying hemoglobin in red blood cells. Sickle
cell anemia (or sickle cell disease) was first reported in 1910 by Dr. J.B.
Herrick.1 It is a disease primarily seen in black individuals and is more
prevalent in the United States and Africa. The disease is seen in two main
forms: when the individual receives a gene for the abnormal hemoglobin
(hemoglobin S) from both the mother and the father, the person has homozygous
sickle cell disease, which is the most severe form; when the individual receives
only one gene for the abnormal hemoglobin from either the mother or father and
the other gene is for normal hemoglobin, the person has heterozygous sickle cell
disease, which is the less severe form.

Prevalence and incidence
The patient with homozygous form of sickle cell disease is most likely to
develop the sickle cell ulcer. Studies have shown that males are more likely to
develop leg ulcers due to sickle cell disease than females.2 The same study
found that 5% of males with sickle cell disease who were over age ten had sickle
cell ulcers 2, and 75% of patients over age thirty had a sickle cell ulcer at
some time during the
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course of their disease.3 With over 80,000 patients in the United States with
sickle cell disease4, this makes the number of patients with sickle cell ulcers
significant.

Sickled cells
The diagrams below show a normal red blood cell and a sickled cell.

[image] 

[image] Practice point
Lower extremity ulcers in young black patients, especially males, could be due
to undiagnosed sickle cell disease.

Ulcer pathogenesis
The abnormal hemoglobin molecule in the red blood cell in the patient with
sickle cell disease does not affect the amount of oxygen the red blood cell can
carry. After the red blood cell and its hemoglobin give up the oxygen to the
tissues, the abnormal hemoglobin causes the red blood cell to distort and become
rigid. This results in the cell becoming deformed into a sickle shape (See
Sickled cells.)
When the red blood cell is reoxygenated, the cell resumes its normal shape.
Unfortunately, while the cells are in the sickled shape, they tend to increase
blood viscosity and become \"sticky.\" This causes slowing of the blood flow in
small vessels and subsequently clotting of the vessels, which results in
ischemia of tissues and organs. Over time the patient suffers repeated episodes
of pain, tissue damage, and, eventually, organ failure. Many times the cells
become damaged while they are in the sickled shape and have a shortened
life-span. Because these cells are removed from the circulation faster than
normal, anemia results. (See Conditions associated with sickle cell anemia.)
Although the exact cause of sickle cell ulcers is not clear, they have been
associated with trauma, infection, severe anemia, and warm temperatures6 and are
most likely to occur in the malleolar area of the lower extremities. Laboratory
evaluation has shown that sickle cell ulcer patients have lower hemoglobin
levels and higher levels of lactate dehydrogenase (LDH), bilirubin, aspartate
transaminase (AST), and reticulocytes than do patients with sickle cell disease
with no ulcers.7 It has been suggested that the sickle cells cause chronic
damage to the microcirculation in the skin at the ankle. This damage includes
injury to the capillary walls, thickening of the intima lining of the capillary,
and increase in permeability of the vessel wall, allowing macromolecules to
escape into the tissues.8 These changes result in the skin having a reduced
blood supply, being more susceptible to minor trauma, and being less able to
heal.9 As a result, these areas of involvement are more likely to be the sites
of skin breakdown and ulceration. It has also been suggested that a reduction in
the amount of the smooth muscle relaxant (nitric oxide) in the microcirculation
can result in unrestrained vasoconstriction of the small vessels, ischemia of
the skin, and skin necrosis.9

Diagnosis

Medical history
Evaluation of the patient with a suspected sickle cell ulcer is of utmost
importance so that the correct diagnosis can be made and appropriate treatment
planned. The patient's medical history should be recorded, and the events
surrounding the ulcer development
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should be investigated. Is this the first ulcer the patient has had? How long
has the ulcer been present? How did the ulcer first develop? Was there trauma to
the area? How did the area first look? Any history of lower extremity edema,
unexplained swelling of the hands, feet, or knees, osteomyelitis, episodes of
abdominal or joint pain, episodes of severe unexplained pain, recurrent urinary
tract infections or pneumonia, or anemia should be noted. Sickle cell patients
are prone to develop unexplained episodes of fever which tend to resolve without
therapy. These patients may carry a diagnosis of FUO (fever of unknown origin).

Conditions associated with sickle cell anemia

Complication
Cause

\"Crisis\" with fever and pain
Sickling of cells due to abnormal hemoglobin

Pain in bones, joints, and back
Sickling of cells and ischemia of tissues

Severe abdominal pain
Sickling of cells and ischemia of tissues

Pregnancy problems" "" "Fertility problems
Uncontrolled sickling of cells

Increased infections" "" "Pneumonia" "" "Urinary tract
Deficient immune response

Salmonella osteomyelitis
Ischemia of bones, bone infarcts, sepsis

Chronic leg ulcers
Sickling of cells and ischemia of tissues

\"Hand-foot\" syndrome
Sickling of cells and ischemia of bones

Avascular necrosis of femoral or humeral head
Ischemic necrosis of bones due to sickling

Visual problems
Ischemia of retina due to sickling

Pulmonary infarction
Ischemia of lung due to sickle cell emboli

Congestive heart failure" "" "Cardiac murmurs" "" "EKG abnormalities
Myocardial ischemia

Jaundice
Hemolytic anemiaGallstone production and obstructive jaundice

Cirrhosis of liver
Ischemia of liver and cell necrosis

Hepatitis
Multiple blood transfusions

Enlarged spleen (infancy only)
Increased blood production

Splenic infarction (late teens, adult)
Ischemia of tissue due to sickling of cells

Renal dysfunction" "" "Hematuria" "" "Infections
Ischemia of kidney with infarction of tissue

Renal vein thrombosis
Sickling of cells

Priapism (especially in children)
Sickling of cells

Impotence
Damage of penis by priapism and ischemia

Anemia
Hemolysis of abnormal cells

\"Aplastic crisis\"
Failure of bone marrow to produce cells due to infarction of marrow

Folate deficiency
High folate requirement of hemolytic anemia

Adapted from Conley, C. Lockard, \"The Hemoglobinopathies and Thalassemias\" in
Textbook of Medicine, eds. Beeson, PB, McDermott, W, 13th Edition, W.B. Saunders
Co., Philadelphia, pp.1501-1503, 1971.

Physical examination
A complete physical examination should be part of the evaluation of the patient.
Vital signs, especially temperature, should be taken because, as mentioned
above, unexplained fever may be a sign of sickle cell disease. Abdominal
examination can detect enlargement of the liver and spleen. Examination of the
extremities is also important to evaluate the ulcer and for the presence and
degree of edema.
The presence of scars or other skin problems of the extremities may indicate
previous ulcer incidence. The location of the ulcer or ulcers is important as
most sickle cell ulcers are found on the lower one third of the leg and usually
over the medial or lateral malleoli (or both) of the ankle6. The size of each
ulcer should be measured by determining the length and width or by using one of
the more advanced measuring modalities described elsewhere in the book. (See
chapter 6, Wound assessment.)
The presence of an ulcer in a patient with varicose veins, venous insufficiency,
and sickle cell disease can be especially troublesome as it may lead to
misdiagnosis. (See Undiagnosed sickle cell ulcer treated initially as a \"venous
ulcer.\") In addition, venous incompetence in the patient with sickle cell
disease may predispose him for ulcer development and is highly correlated with
the development of a recurrent sickle cell ulcer.10 Noninvasive venous studies
can be helpful in establishing the correct therapeutic approach in these
patients.

[image] Practice point
Misdiagnosis-and thus, mistreatment-of sickle cell ulcer as a venous \"stasis\"
ulcer makes it imperative to get the differential diagnosis correct.

Ulcer assessment
Examination of the wound bed is essential to determine the presence of
granulation tissue or fibrinous material (\"slough\"). (See photographs in the
color section, pages C10 and C11.)
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In addition, the presence of cellulitis or peri-ulcer erythema should also be
documented and the presence and character of any drainage noted. Tenderness of
the lower extremity to palpation or the presence of pain in the ulcer or
surrounding area should be also recorded. A brief vascular examination should
always be performed to be sure the patient has adequate blood flow to the area.
The presence of dorsalis pedis and posterior tibial pulses should be noted. If
there is a question about the adequacy of the circulation, the patient will need
to be referred for noninvasive vascular studies or arteriography. The microcirculation
in the periwound area can be evaluated with the laser Doppler and TcPO2
measurements, if available.

[image] Practice point
A complete history and physical examination are vital when evaluating a patient
with a sickle cell ulcer.

Laboratory assessment
Laboratory evaluation depends on the condition of the patient. If the patient
does not have a diagnosis of sickle cell disease, but it's suspected the
clinician should order blood tests that check for anemia, sickle cells, and
abnormal hemoglobin. This usually involves a complete blood count (CBC), sickle
\"prep,\" and a hemoglobin electrophoresis. However, although hemoglobin
electrophoresis is considered the diagnostic tool of choice, it has its
limitations especially if the patient has had recent blood transfusions.5 In
such a case, referral to a hematologist may be necessary. If the patient with
known sickle cell disease has an ulcer, the laboratory workup should consist of
a CBC with differential white blood cell count and reticulocyte count.
Patients with sickle cell disease are especially prone to developing infections;
therefore, it is important to obtain a wound culture using appropriate technique
if the wound appears infected or is covered by a biofilm. We have found that a
significant number of patients with sickle cell ulcers have wounds covered by
biofilm, which must be removed before the ulcer can heal. (See photographs in
the color section, page C23.) The most frequent way to remove a biofilm is with
sharp debridement, but recently we have turned to ultrasonic debridement
techniques, which are less painful for the patient. (See photographs in the
color section, page C23.) Currently, although other methods for removing
biofilms are still considered experimental, it's hoped that they will be
available in the near future. (See chapter 7, Wound bioburden.)

Undiagnosed sickle cell ulcer treated initially as a \"venous ulcer\"

[image] 

Infection and osteomyelitis
Patients with sickle cell disease and a deep, painful ulcer should be evaluated
radiologically for the presence of osteomyelitis especially if the patient has
fever or leukocytosis. In particular, patients with sickle cell disease are
prone to developing salmonella osteomyelitis. 5 Radiologic evaluation can be
done by several methods. Plain film X-rays are the least sensitive method and
usually don't any evidence of osteomyelitis until late in the course of the
infection. In addition, they can be especially confusing in the patient with
sickle cell disease as the disease can result in periosteal elevation and other
bone changes mimicking osteomyelitis.5 Nuclear medicine bone scans are slightly
more helpful,
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but it must be remembered that routine bone scans only detect areas of
inflammation.
Also, if the patient has an ulcer overlying the bone in question, the bone scan
is virtually useless. Magnetic resonance imaging appears to be the imaging
modality of choice in terms of sensitivity and specificity. It has been
suggested that bone biopsy and culture may be the only definitive way to
determine if osteomyelitis is present6, but it should be done with great care so
as not to cause an infection in the bone. Biopsy of the wound bed and wound
margin may be advisable if the ulcer has been present for over three months,
does not respond to therapy, or just doesn't \"look right.\" This should be done
to rule out the possibility of malignancy and can help with the diagnosis.12

Pain
Because of the painful nature of sickle cell ulcers and the need to do biopsy
cultures, the practitioner must be aware of recent studies about the use of
topical and local anesthetics. Berg, et.al. have shown that EMLA cream, a
topical anesthetic agent commonly used before doing wound biopsies, is highly
antibacterial.11 Within one hour of exposure to EMLA cream, most common bacteria
were killed. This included strains of Staphylococcus aureus (both methicillin-resistant
and methicillin-sensitive strains), Streptococcus pyogenes, Escherichia coli,
and Pseudomonas aeruginosa. Injected solutions of 1% lidocaine were also found
to be antibacterial for the same organisms but at greater than two hours after
local injection. It is the recommendation of the authors that EMLA cream not be
used for anesthesia when biopsy cultures are being done. Local injection of
preservative-free 1% lidocaine would be satisfactory to use if the biopsy
culture is done within two hours of the injection.11
Although sickle cell ulcers tend to be extremely painful, pain assessment is an
area that can be easily overlooked as, often times, the patient is fearful of
experiencing even more pain and may not want you to look at the ulcer much less
touch it. This makes debridement and treatment of these ulcers very difficult.
(A useful pain assessment tool for evaluating a patient's pain is outlined
elsewhere in this book [see chapter 12, Pain management and wounds]). It has
been the author's experience that if the provider does not address the pain
problem many of the patients will not return for follow-up care. Indeed, most
patients would rather keep their ulcer than deal with potentially being in more
pain than they already are. For this reason, significant debridements must by
done with some type of anesthesia, either topical anesthesia (xylocaine
ointment), injectable local anesthesia, regional anesthesia, or general
anesthesia. Some of these techniques will require hospitalization of the
patient.
Pain control can be managed with topical anesthetic agents. Topical xylocaine
ointment or EMLA cream can be used on a regular basis for pain control. Applied
every four to six hours, these agents can make the patient's daily activities
much more manageable. It also makes dressing changes more comfortable. Other
therapies, including opioid analgesics and regional medications (xylocaine
patches), are useful but many times have to be managed by a pain specialist.
(See chapter 12, Pain management and wounds.)

[image] Practice point
Sickle cell ulcers are extremely painful. Evaluation and treatment of the
patient's pain should be a top priority and should be the first steps in
instituting therapy for the ulcer.

Treatment
Treatment of sickle cell ulcers can be challenging and frustrating. Even in this
day of evidence-based therapies, it is noteworthy that there are no published
trials of treatments of sickle cell ulcers. 6 One of the more interesting
findings about the treatment of sickle cell ulcers is that most ulcers will heal
with prolonged bed rest 6 Obviously, this is not a practical therapy as
hospitalization is no longer possible and complete bed rest at home is not
realistic. However, any therapy that results in a long period of immobilization,
such as from operative intervention, must take into account that the bed rest is
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healing the ulcer, not the treatment. With this in mind one must begin with the
basics of what we know constitutes good wound care.
The basics of good wound care include debridement of devitalized tissue, control
of infection, assurance of adequate circulation, and maintenance of a moist
wound environment. The major addition in the treatment of sickle cell ulcers is
control of wound pain. Many times the ulcers are so painful that manipulation of
the wound is impossible. Treatment of the wound with topical anesthetics has
been previously addressed and must not be overlooked. If the therapy for the
wound is painful, most people will forgo your advice and treat the ulcers
themselves in ways that do not cause more pain. It is unfortunate that many of
these patients are labeled as \"noncompliant\" when it is a poor choice of
therapy by the clinician and not the compliance of the patient that should be in
question. Once the pain is controlled, the wound can be debrided and treated, as
indicated.
The evaluation of sickle cell ulcers for infection and the evaluation of the
patient for circulation problems have been covered previously. The importance of
moist wound care has been known since Winter's publication in 1963.13 It is now
known that wounds treated with wet-to-dry dressings do not heal well and
removing a dry dressing that adheres to the wound causes pain and wound
reinjury.14 Wounds treated with moist wound healing heal faster, are less
painful, and have less scarring. There are numerous wound dressings currently
available which will maintain a moist wound environment. (See chapter 9, Wound
treatment options.)
If the wound is felt to be infected, topical antimicrobials should be considered.
Oral or I.V. antibiotics are only indicated if the patient has a leukocytosis,
cellulitis, or fever. Silver dressings have become popular in the treatment of
the wound with a clinically significant bacterial burden (critical colonization)
or with frank infection. There are numerous silver dressings available for use
on these wounds. It is these authors opinion that, at this time, one should pick
the silver dressing that best meets the patient's needs instead of debating the
amount of silver in the dressing. It there is excess drainage present, a silver
alginate, hydrocolloid, or foam might be indicated. If there is significant
odor, then a silver dressing with odor control properties might be most
beneficial. If only a bandage delivering silver ions is needed, those are also
available. It is suggested that once the bacterial burden is under control, the
silver dressing should be discontinued and other moisture control dressings
used. This is because of the potential for toxicity of the silver to the growing
tissues.15,16 Dressings containing Cadexomer iodine are useful in treating
wounds critically colonized with bacteria or wounds which are infected.17,18
Other therapies that may be helpful include oral zinc sulfate (200 mg three
times/day)19 and zinc oxide impregnated Unna boots. An Unna boot applied to the
lower extremity and covered with an ace wrap has been especially beneficial for
patients with edema. The bandages are changed weekly until the ulcer has
healed.6 A recent series of patients treated with the topical growth factor,
molgramostim (GM-CSF), reported some degree of success in the treatment of these
very difficult wounds.20
The revival of the use of natural honey, a therapeutic product as old as
Egyptian medicine, for treatment of sickle cell ulcers has been tried and has
met with mixed results.21 Because natural honey is unsterile, some important
implications must be considered for treatment of wounds, the most serious of
which is the presence of clostridial spores which could cause wound botulism.
However, the introduction of the sterilized honey product, Manuka honey from New
Zealand, opens new opportunities for the treatment of sickle cell ulcers.22
The use of the human tissue-engineered skin in the treatment of sickle cell
ulcers has met with some degree of success. 23 Prior to applying any advanced
therapy product the wound bed must be well prepared, which means assuring that
the wound bed has been debrided to remove all necrotic tissue, that infection
has been controlled, and that the wound environment has been optimized.24 To
achieve the goal of wound environment optimization, one author recommends
pretreating the wound with a protease modulating
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agent for two to three weeks to reduce the abnormal protease levels.27 These
agents include oral or topical Doxycycline or an oxidized, regenerated cellulose
(ORC) collagen product.25,26 His early data show that pretreatment of any
chronic wound with these protease modulating agents prior to application of
human skin equivalent improves the healing rate.27 Once treated with the
tissue-engineered skin product, the patients experience significant relief of
their pain as well as healing of their ulcer. (See photographs in the color
section, page C24.) One patient's ulcer healed within 8 weeks of one application
of the human tissue-engineered skin. Over eighty percent of our patients treated
with human skin equivalent will heal with only one application.27 It is also of
note that sickle cell ulcers treated with tissue engineered skin seem to have a
more \"normal\" appearing and stable scar. (See photographs in the color
section.)
One of the treatments of sickle cell disease is hydroxyurea, which is known to
improve symptoms associated with sickle cell disease. Unfortunately, hydroxyurea
is known to cause leg ulcers in patients taking this medication.29,30 The
medication must be stopped before the ulcer will heal.31 Fortunately, it has
been found that ulcers related to hydroxyurea therapy respond promptly to
treatment with tissue engineered skin.31
The use of the split-thickness skin graft to treat patients with sickle cell
ulcers may be a reasonable therapeutic alternative. However, the procedure
requires hospitalization and anesthesia, thus making it less cost-effective. It
has also been reported that split-thickness skin grafting has a very low success
rate in healing sickle cell ulcers and in those that do heal, the recurrence
rate is very high.28 Success has been noted with the use of muscle flaps,
myocutaneous flaps, and free flaps to cover large lower extremity sickle cell
ulcers32,33 but not uniformly. 34
Transfusion therapy has been tried in the treatment of patients with sickle cell
ulcers who have been resistant to all other therapies. The goal of the therapy
is to keep the hematocrit between 30-35 volume percent and the percentage of
normal hemoglobin (hemoglobin A) greater than 70% of the total.28
Another interesting approach to treating sickle cell ulcers has been the use of
I.V. arginine butyrate. The concept is that the arginine butyrate will change
the concentration of abnormal hemoglobin, thus allowing the wounds to heal. Two
studies have shown reasonable success with this method35,36, but no randomized
controlled trials have been done as of this time.
Other therapies for sickle cell ulcers include medications, such as pentoxifylline
(Trental); negative pressure wound therapy; hyperbaric oxygen therapy;
electromagnetic stimulation; and nitric oxide stimulation. Others therapies are
still considered experimental, and their utility in treating these patients with
difficult wound problems will be determined by future studies.
It is our impression that sickle cell ulcers will respond better to any therapy
if the sickle cell disease is under control. If the patient's anemia is profound
(below 5 grams Hg/ 100 cc) or if the abnormal hemoglobin-containing cells
represent greater than 50% of the total volume of red blood cells, the chance of
any therapy working is problematic. This has recently been supported by work
reported by Eckman and Platt.28

Preventing ulcers
Prevention of sickle cell ulcers is of utmost important. The patient with sickle
cell disease must be instructed in the importance of good skin care and methods
to keep the skin moisturized and to avoid trauma to the lower legs and ankles.
For example, the patient should use insect repellants to avoid insect bites. It
has been noted that edema is the single most common occurrence prior to
recurrence of an ulcer.28 For this reason, the importance of treating lower limb
swelling should be emphasized including the use of support hose or elastic
wraps. The patient should also be instructed to treat any minor injury to the
lower extremities aggressively and seek medical care promptly. The clinician
should inspect the lower extremities of sickle cell patients at
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each visit and review the preventative measures with them routinely.

[image] Practice point
Always look for edema on the lower extremities of patients with sickle cell
disease as it is a critical indicator prior to ulceration.

Summary
Sickle cell ulcers are a potential reality for any person with the inherited
disease-sickle cell anemia. The success of therapy is multifactorial, which
involves optimizing the patient's sickle cell disease and using several
therapeutic modalities to treat the ulcer. It is the hope that in the near
future, research will provide more satisfactory therapies to treat these
difficult wounds.

Show what you know
1. Which of the following is NOT correct?
A. Sickle cell disease is an inherited disease of the blood's hemoglobin
molecule.
B. Sickle cell disease is seen primarily in black individuals.
C. Higher risk of developing an ulcer is seen in individuals with heterozygous
sickle cell disease.
D. The most severe form of sickle cell disease is seen when an individual
inherits an abnormal hemoglobin gene from both parents.
View AnswerAnswer: C. Persons with heterozygous sickle cell disease receive only
one gene for abnormal hemoglobin from one of their parents and are at less risk
of ulceration than persons who have abnormal hemoglobin genes from both parents
(homozygous). A, B, and C are true statements.
2. Sickle cell ulcers are more likely to develop in males with sickle cell
disease than females.
A. True
B. False
View AnswerAnswer: A
3. Which one of the following can signal that a patient with sickle cell disease
might ulcerate?
A. Edema
B. Hemoglobin A1C of 7
C. Absence of fever
D. Resolution of pain in the leg
View AnswerAnswer: A. Edema is a key indicator that a person with sickle cell
disease may get an ulcer. B is incorrect as hemoglobin A1C is not related to
sickle cell disease but to diabetes mellitus. C is incorrect as patients with
sickle cell often have fever of unknown origin. D. Pain is frequently part of
sickle cell ulcers.
4. Which one of the following is not part of the evaluation of the patient with
a sickle cell ulcer?
A. History including a family history
B. General physical examination
C. Assessment of wound bed and pulses
D. A bone scan
View AnswerAnswer: D. A bone scan is virtually useless in diagnosing osteomyelitis
while MRI is preferred. A, B, and C, are all correct and should be part of the
assessment of a patient with a sickle cell ulcer.
5. Comprehensive treatment of the patient with sickle cell ulcer could include
all of the following except:
A. Restrict dietary iron intake
B. Debridement of the ulcer
C. Wound pain management
D. Compression modalities
View AnswerAnswer: A. There is no reason to restrict iron in the diet of persons
with sickle cell disease. B, C, and D are all important parts of the holistic
plan of care of patients with a sickle cell ulcer.

References
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