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770 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 771

to that of age-matched controls. 224–226 It tends to decrease with age but
is still prevalent in adults. Social and environmental factors, decreased
functional bladder capacity, and decreased arousal during sleep appear
to be contributing factors.

Musculoskeletal System
VOE is commonly manifested by marrow infarction causing mus-
culoskeletal pain, swelling at involved sites, fever, and leukocytosis.
Marrow hypercellularity is thought to predispose to this phenomenon
by causing a decrease in local blood flow and oxygenation.
Dactylitis Dactylitis is a painful swelling of digits of the hands
and feet (“hand-foot syndrome”). It occurs early in infancy as hemato-
poietic marrow is still present in these bones at this age. Most episodes
resolve within in 2 weeks. 227–230 Epiphyseal infarction can result in joint
pain and swelling mimicking septic arthritis. Use of hydroxyurea in the
BABY HUG trial resulted in significant reduction of rate of dactylitis. 161
Osteomyelitis, Septic Arthritis, and Bone Infarction Impaired
cellular and humoral immunity together with infarction of bone con-
tribute to this complication with an estimated prevalence of 12 percent.
Atypical serotypes of Salmonella, S. aureus, and Gram-negative bacilli
are the principal infectious offenders. No single lab or imaging test
reliably differentiates osteomyelitis from infarction. 227,229,231–235 Culture
results may be nondiagnostic as patients usually receive antibiotics on
presentation with fever; therefore, the presence of leukocytes in bone Figure 49–9. Avascular necrosis of the right hip in a 31-year-old
126
and joint aspirates should evoke a high suspicion for osteomyelitis. female with sickle cell disease depicting a patchy lucency and sclerosis
and irregular contour of the femoral head and loss of the joint space.
Septic arthritis tends to occur in joints involved with avascular necrosis,
also seen following hip arthroplasty. Multiple joints may be involved.
An elevated C-reactive protein should raise suspicion for septic arthri- Avascular necrosis has been treated with a number of modali-
tis and prompt intervention with appropriate antibiotics as needed to ties including core decompression, osteotomy, bone grafting, surface
227
prevent joint deterioration and collapse. Vertebral body infarctions arthroplasty, and joint replacement. Two randomized trials in avascu-
with subsequent collapse causes the classic “fish mouth” appearance of lar necrosis compared core decompression and physical therapy ver-
vertebrae on radiographs of the spine. sus physical therapy alone and did not show a difference in outcome
Osteopenia and Osteoporosis Osteopenia and osteoporosis are between the two arms; however, followup was short, a significant
prevalent (30 to 80 percent) in patients with sickle cell anemia, with a number of stage III hip joints were included in one study, and sample
predilection for the lumbar spine. Presence of avascular necrosis with size was limited. In our experience, core decompression is a useful
249
local bone remodeling may lead to false-negative results on a bone option in early stage avascular necrosis. Several studies associate total
mineral density test at the femoral neck. Fractures of the long bones hip replacement in SCD with a higher rate of orthopedic and medical
126
are commonly underdiagnosed and self-reported rates of fractures in complications. However, other studies show a lower rate of orthopedic
young adults with SCD are high. Etiology of osteoporosis is multifac- complications. Structural bone diseases in SCD make joint replacement
torial with hypogonadism, hypothyroidism, nutritional deficiencies, challenging. 250–252 Hydroxyurea and chronic transfusion therapy have
and iron overload interfering with osteoblast function being the major not been shown to reduce the risk of avascular necrosis. 243
causes. 126,236–238 More than 50 percent of patients are vitamin D deficient
with the majority (>80 percent) having less-than-optimal levels. High Leg Ulcers
doses of vitamin D supplementation have resulted in improvement in Leg ulcers occur in 2 to 40 percent of cases with SCD and varies geo-
chronic pain and higher levels of physical activity. 239 graphically with the highest rate being reported in Jamaica. 1,253 In the
Avascular Necrosis Vasoocclusion resulting in infarction of United States, leg ulcers are seen in 4 to 6 percent of patients with SCD
articular surfaces of long bone occurs most commonly in the femur and are most common in patients older than 10 years of age. They
254
followed by the humerus. It was previously thought to occur with occur on the lower extremities, especially on the malleoli, and cause
increased frequency in HbSC disease as opposed to patients with HbSS. chronic pain and disability. Venous stasis is a predisposing factor while
However, with increased longevity of HbSS patients, its prevalence is coinheritance of α-thalassemia appears to have a protective effect. The
greater in patients with HbSS. 240–242 As per the CSSCD estimates, 50 relationship between hydroxyurea use and increased occurrence of leg
percent of patients by age 33 years will have avascular necrosis of the ulcers is controversial. Polymorphisms in KLOTHO, TEK, and sev-
255
femoral head (Fig. 49–9). The presence of concurrent deletional α- eral other genes in the transforming growth factor (TGF)-β and bone
thalassemia (–α ) and a history of frequent VOEs are classic risk factors morphogenic protein (BMP) pathways are associated with leg ulcers.
3·7
245
for avascular necrosis. Other risk factors include male gender, higher Once established, ulcers are recalcitrant and significantly impair quality
Hb concentration, low fetal Hb, and vitamin D deficiency. 126,243,244 Poly- of life. 256
morphisms in BMP6, ANNEXIN A , and KLOTHO genes are associated Treatment of leg ulcers is largely empiric. Leg elevation, bed rest
2
with avascular necrosis. 245 when practical and feasible, wet-to-dry dressings, gentle debridement,
Patients present with chronic joint pain with progressive decrease Unna boots, and treatment of infection and topical or systemic antibiot-
in range of motion of affected joints. Multiple joints are commonly ics are commonly used. The peptide encoding integrin-interaction site
involved. The vast majority of untreated patients will progress to fem- of many extracellular matrix proteins (RGD peptide) enhanced healing
246
oral head collapse within 5 years. 247,248 of the ulcers in preliminary studies, but, unfortunately, it never came to

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