HEMATOLOGY

By admin Last updated Dec 17, 2022

Ovid: Pediatrics

Editors: Tornetta, Paul; Einhorn, Thomas A.; Cramer, Kathryn E.; Scherl, Susan A.

Title: Pediatrics, 1st Edition

> Table of Contents > Section III: – Specialty Clinics > 26 – HEMATOLOGY

HEMATOLOGY

26.1 HEMOPHILIC ARTHROPATHY

Daniel W. Green

Cemil Yildiz

Hemophilia is a sex-linked genetic coagulation disorder
that occurs primarily in males, resulting in clotting factors that are
nonfunctional or absent. Intraarticular hemorrhages in patients with
poorly controlled hemophilia can lead to progressive joint arthropathy.
The natural history of the disorder has changed significantly over the
past several decades, due to the development of factor replacement
therapy, but considerable orthopaedic morbidity still occurs.

PATHOGENESIS

Epidemiology and Etiology

The incidence of hemophilia is estimated to be 1 per 10,000 male births in the United States.
Approximately 95% of cases are caused by a variable lack of factors VIII or IX.
Hemophilia A (factor VIII deficiency) is the most common (about 80% of cases).
- □ Several different mutations cause the disorder, which accounts for the variable clinical severity.
- □ It is an X-linked recessive disorder that affects males.
- □ Hemophilia A is the result of a new mutation in approximately 33% of patients.
Hemophilia B (factor IX deficiency), also known as Christmas disease, is the next most common.
- □ Clinically indistinguishable from hemophilia A.
- □ Also transmitted as an X-linked disorder.
The third most common inherited
coagulation disorder is von Willebrand disease, caused by a variable
lack not only of factor VIII coagulant activity but also of factor
VIII-related activity responsible for adhesion of platelets to exposed
vascular subendothelium.
- □ This form is characterized by abnormal
  bleeding from mucosal surfaces, therefore major hemophilic arthropathy
  is relatively uncommon.

Pathophysiology

The exact pathophysiology of hemophilic arthropathy remains controversial.
Both the inflammatory cascade and iron deposition have been implicated in cartilage destruction.
The degree of hemarthropathy does not always directly correlate with the number of joint bleeds.
Hemarthrosis probably starts as a subsynovial, intramural hemorrhage that then ruptures into the joint cavity.
Spontaneous hemorrhages without antecedent trauma commonly occur in patients with a severe deficiency.
With repeated exposure to blood, the
synovium of joint hypertrophies and becomes hypervascular, leading to a
progressive cycle of synovitis and more bleeding.
Histology of the hypertrophic synovium is
characterized by villous formation, markedly increased vascularity, and
chronic inflammatory cells.
Hemosiderin deposits accumulate in the
lining cells of the synovial villi, and the inflammatory cells
congregate around the vessels and hemosiderin deposits.
In summary, the result of repeated hemorrhage into a joint with chronic synovitis
Proteolytic enzymes released by the inflamed synovium attack both cartilage and bone.

P.295

As the hypertrophied synovium continues to expand, and the articular cartilage erodes, the joint space narrows.
Osteoporosis occurs from disuse, and the joint becomes immobile.
Grading of articular involvement can be seen in Table 26.1-1.
In children, chronic synovitis may also
cause asymmetric physeal growth, or early physeal closure, leading to
angular deformities or leg length discrepancies.

TABLE 26.1-1 GRADING OF SYNOVITIS AND ARTICULAR INVOLVEMENT IN HEMOPHILIC PATIENTS

Grade	Classificaiton	Description
I	Transitory synovitis	No bleeding sequelae, and no more than 3 episodes in 3 months. No evidence of chronic inflammation remains after treatment.
II	Permanent synovitis	Persistence of increased joint size/volume, synovial membrane thickening, and joint range limitation. Muscle atrophy cannot be detected in 1st week. However, vastus medialis is 1st muscle to become atrophic and quadriceps volume reduction becomes noticeable in 2nd week.
III	Chronic arthropathy	Grade II findings are present in grade III together with axial deformities and severe muscular atrophy. Joint changes are irreversible.
IV	Ankylosis
Adapted from Battistella LR. Maintenance of musculoskeletal function in people with hemophilia. Haemophilia 1998;42:26-32.

DIAGNOSIS

Clinical Features

A history of similarly affected males on the maternal side of the family, or typical behavior
A history of hemorrhage from major surface wounds and musculoskeletal sites.
Hemophiliacs rarely experience bleeding during the first years of life in the absence of trauma or surgery.
- □ Hemarthroses usually begin after the child starts to walk.
The frequency and severity of bleeding
episodes commonly increase as the child attends school and becomes more
physically active and socially interactive.
Patients with severe hemophilia typically develop their initial joint pathology between the ages of 5 to 15 years.
Abnormal bleeding may occur in any area of the body, but joints are the most frequent sites of repeated hemorrhage (Table 26.1-2).
The weightbearing joints are the most
common sites of hemophilic arthropathy, with the frequency of
involvement being, in decreasing order, the knee, elbow, shoulder,
ankle, wrist, and hip. The vertebral column is rarely involved.
Clinical findings depend on the severity of hemorrhage and whether the hemarthrosis is acute, subacute, or chronic (Table 26.1-3).
Other musculoskeletal problems in hemophilia include:
- □ Pseudotumor (slowly progressive
  hemorrhage that increases in size within a confined space, causing
  pressure necrosis and erosion of the surrounding tissues)
- □ Neuropraxias (femoral, peroneal, sciatic, median, and ulnar)
- □ Ectopic ossifications
- □ Fractures
- □ Ischemic contractures or compartment syndrome
After history and physical examination, laboratory tests should be ordered (Table 26.1-4).
If these screening procedures suggest a bleeding tendency, factor
assays must be carried out to establish not only the specific
deficiency but also its degree.
Most patients with hemophilia present to
an orthopaedist with a known diagnosis. Clinical manifestations of
hemophilia A and B are similar and depend on the blood levels of factor
VIII or IX (Table 26.1-5).

TABLE 26.1-2 DIFFERENTIATING BLEEDING FROM SYNOVITIS

Bleeding	Synovitis
Acute onset	Slow onset
Painful	Minimal pain
Warm and tender	Warm and nontender
Marked limitation of motion	Good range of motion
Responds rapidly to factor replacement	Does not respond rapidly to factor replacement (responds to prednisone)

Radiologic Features

Features of radiographs in knee hemarthrosis (Fig. 26.1-1):

Distended capsule
Synovitis
Cartilage thinning
Widening and erosion of intercondylar notch
Enlargement of ossification centers (especially distal end of femur)
Widening of distal femoral epiphysis
Squaring of inferior pole of patella
Flattening of distal femoral condyles
Hemophiliac pseudotumor
Epiphyseal overgrowth with leg length discrepancy
Osteopenia

P.296

TABLE 26.1-3 CLINICAL STAGES OF HEMARTHROSIS

Stages of Hemarthrosis	Characteristic Findings	Response of Factor Replacement Therapy
Acute	Pain and swelling with distention of the joint capsule are the principal findings. Local tenderness and increased heat are present. The joint will assume the position of minimal discomfort, which is also the position of minimal intraarticular pressure (e.g., knee joint is held in flexion).	Rapid
Subacute	Develops after several episodes of bleeding into the joint. Pain is minimal. Joint motion is moderately restricted.	Slow
Chronic	Develops after 6 months of involvement. Progressive destruction of the joint takes place, with the end stage being a fibrotic, stiff, totally destroyed joint	No

TABLE 26.1-4 ROUTINE LABORATORY TESTS FOR PATIENTS WITH COAGULOPATHY

Tests	Objectives
Platelet count combined with inspection of the blood smear Ivy bleeding time	To assess platelet function, defective in hemophilia A and B
Plasma prothrombin time (PT)	To assess the extrinsic and common pathways of coagulation (I, II, V, VII, X)
Plasma partial thromboplastin time (PPT)	To assess the intrinsic and common pathways of coagulation (II, V, VIII, IX, X, XI, XII). Defective in hemophilia A and B

TABLE 26.1-5 CLINICAL MANIFESTATIONS OF HEMOPHILIA ACCORDING TO BLOOD LEVELS OF FACTORS VIII AND IX

Degree	Level of Hemostasis (% of Normal Blood Level)	Clinical Findings
Normal	>50	None
Mild	25-50	Excessive bleeding occurs only after major trauma or during surgery
Moderate	5-25	Severe and uncontrolled bleeding occurs only after minor injury or during an operative surgery
Moderately severe	1-5	Major hemorrhages occurring after minor injury or unrecognized mild trauma
Very severe	<1	Repeated spontaneous hemorrhages into joints and bleeding into deep soft tissues

The radiologic evaluation classification recommended by
the orthopaedic advisory committee of the World Federation of
Hemophilia is shown Table 26.1-6. It includes functional status. An additional radiographic classification useful for bony changes is shown in Table 26.1-7.

Evaluation of the clinical stage of hemophilic arthritis
has improved with the use of ultrasound and magnetic resonance imaging
(MRI), which can provide early, detailed information about the
synovium, cartilage, and the joint spaces.

Hemosiderin deposits can be seen on MRI (Fig. 26.1-2), as can subchondral and intraosseous cysts or hemorrhage (Figs. 26.1-3 and 26.1-4).
- □ The limitation of MRI is that the cost may be prohibitive when serial exams are necessary.
Ultrasound has been shown to be a sensitive and reproducible technique to assess synovial proliferation in a variety of joints.
The activity of disease, in terms of acute synovitis, may further be assessed with power Doppler ultrasound.

P.297

Figure 26.1-1 Anteroposterior (A) and lateral (B)
knee plain radiographs of a 10-year-old boy with hemophilia: loss of
joint cartilage space, marked enlargement of the epiphysis, and
extensive joint destruction (stage V according to Arnold and Hilgartner
radiographic classification).

TABLE 26.1-6 ROENTGENOGRAPHIC CLASSIFICATION OF HEMOPHILIC ARTHROPATHY

Radiologic Change		Score
Osteoporosis
	Absent	0
	Present	1
Enlarged epiphysis
	Absent	0
	Present	1
Irregular subchondral surface
	Absent	0
	Present	1
Narrowing of joint space
	Absent	0
	Present, joint space >1 mm	1
	Present, joint space <1 mm	2
Subchondral cyst formation
	Absent	0
	Present	1
Erosions at joint margins		0
	Absent	1
	1 cyst	2
	>1 cyst
Gross incongruence of articulating bone ends (angulation or displacement between articulating bone ends)
	Absent	0
	Slight	1
	Pronounced	2
Joint deformity		0
	Absent	1
	Slight	2
	Pronounced
Possible total		0 to 13
Adapted from Petterson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop 1980;149:153-156.

P.298

TABLE 26.1-7 RADIOGRAPHIC CLASSIFICATION OF HEMOPHILIC ARTHROPATHY

Stage	Description
0	Normal joint
I	No skeletal abnormalities; soft tissue swelling present
II	Osteoporosis and overgrowth of epiphysis; no erosions; no narrowing of cartilage space
III	Early subchondral bone cysts; squaring of the patella; intercondylar notch of distal femur or humerus widened; cartilage remains preserved
IV	Findings of stage III more advanced; cartilage space narrowed
V	Fibrous joint contracture; loss of joint cartilage space; marked enlargement of the epiphysis and substantial disorganization of the joint (extensive joint destruction)
Adapted from Arnold WD, Hilgartner MW. Hemophilic arthropathy. J Bone Joint Surg (Am) 1977;59:287-290.

TREATMENT

Treatment of hemophilia is generally overseen by a
hematologist, with input from a variety of other medical professionals
including orthopaedists, physical therapists, vocational therapists,
nurses, dentists, social workers, psychiatrists, and genetic
counselors. There are several factors that affect the choice of type of
therapy (Table 26.1-8).

Figure 26.1-2
Right elbow magnetic resonance image of a 6-year-old boy with
hemophilia. Synovial hypertrophy and large hemosiderin deposit are seen.

Medical Treatment

The most common approach to medical management in North
America involves early intervention for bleeding episodes with
increased factor given at the onset of discomfort and, if possible,
even prior to the observation of joint swelling. This approach is often
referred to as an on-demand treatment. It involves the use of home
infusion of factor VIII without the need to be seen initially at a
hospital or a clinic. Factor levels of 30 to 50 IU/dL are optimal in
controlling an acute hemorrhage.

Prophylactic factor replacement (to maintain plasma
factor levels greater than 1%) prevents hemophilic arthropathy better
than on-demand therapy (Table 26.1-9).

P.299

It has been useful in preventing the spontaneous bleeding typically
seen in patients with severe disease. The amount of product necessary
to achieve a nonbleeding state with few breakthrough bleeding episodes
varies from patient to patient. The age of onset at which a patient may
begin to experience hemarthrosis also varies, but is usually before the
age of 4 years. Decreased hemophilic joint destruction and arthropathy
have been demonstrated in patients who have started prophylaxis at 2 to
3 years of age. In certain situations, factor VIII levels should be
increased for prophylaxis (Table 26.1-10).

Figure 26.1-3 Left ankle sagittal magnetic resonance image of a 6-year-old boy with hemophilia. Subchondral bone cyst is seen.

Figure 26.1-4 Eight-year-old boy with factor VIII deficiency. (A and B) Anteroposterior plain x-rays of the shoulder show cyst formation in the humeral head. (C and D) Coronal magnetic resonance images reveal marked synovial hyperplasia and hemosiderin deposits, called a blooming appearance.

TABLE 26.1-8 FACTORS THAT AFFECT THE CHOICE OF THERAPY FOR HEMOPHILIC ARTHROPATHY

Factor	Effects
Age	3-6 mo of conservative care is indicated at any age
Inhibitor status	Chemical synovectomy, which involves only an injection and not a surgical approach, is the procedure of choice
Associated medical factors	In cases in which HIV or hepatitis are advanced, radiosynovectomy is procedure of choice
Joint status	With advanced arthritis changes, results of synovectomy are less successful
Multiple joint involvement	Indication for chemical or radiation synovectomy because several joints can be treated at same time
Economic/geographic	Not all treatment modalities are available at hemophilia treatment centers throughout the world
Other	Expertise of treating physician
HIV, human immunodeficiency virus.

TABLE 26.1-9 PROPHYLACTIC TREATMENT OF HEMOPHILIC ARTHROPATHY

Model	Definition
Primary prophylaxis	Regular continuous treatment started before age of 2 yr or after first joint bleed
Secondary prophylaxis	A. Regular continuous (long-term) treatment, started at the age of >2 yr or after 2 or more joint bleeds
	B. Periodic (short-term) treatment, due to frequent bleeds

P.300

Because of the risk of human immunodeficiency virus
(HIV) transmission and hepatitis in human factor VIII replacement,
recombinant products are preferred and are available for factors VII,
VIII, and IX. The dosage required to replace a factor deficiency
depends on the patient’s weight and plasma volume. The hematologist
makes the calculation and is in charge of administering the factor. The
orthopaedic surgeon, however, should be aware of the fact that 20 to 30
minutes after administration of the antihemophilic factor, the plasma
level will rise.

Pain Management

Analgesics such as aspirin, that are known to inhibit
platelet aggregation and prolong the bleeding time, should be avoided
in patients with hemophilia. Patients should be warned against the use
of any medication containing an aspirin compound, guaiacolate, or
antihistamine. Proxyphene, paracetamol, meperidine, codeine
amitriptyline, or methadone may be used. Narcotic analgesics are used
with care because in such a chronic disease, addiction can easily
become a problem.

TABLE 26.1-10 SITUATIONS IN WHICH FACTOR VIII LEVELS SHOULD BE INCREASED

Situation	Percentage of Normal Level
Physical therapy	20
Treatment of hematoma	30
Acute hemarthrosis	>50
Soft tissue surgery	>50
Skeletal surgery	100 (preoperatively); >50 (postoperative 10 days)

Physical Therapy

Early physical therapy helps to prevent complications
and yields the best results. Adequately prescribed and correctly
supervised physiotherapy very rarely requires concurrent replacement
therapy, except after surgery. Every patient generally requires
individual exercise programs.

Orthosis

Any orthosis must be lightweight and should have a
cushioned lining. Care should be taken to avoid muscle atrophy. There
are four distinct functions for orthoses used in hemophiliac
arthropathy:

Protection and stabilization of an unstable joint
Nocturnal use, in the immediate postoperative period or to complete casting
Prevention of some joint contractures, in particular flexion deformity
Braces, splints, and walking bandaging are useful to enhance joint stability without limiting movement.

Surgical Treatment

Surgical procedures useful in the management of
hemophilic arthropathy are generally divided into two groups:
procedures such as synovectomy that are done to control repetitive
joint bleeding episodes and the more conventional orthopaedic
procedures designed to correct or reconstruct joint deformities.

Surgery in hemophiliacs should be carried out with
careful technique using tourniquet control when feasible and securely
ligating all vessels insofar as possible. Cautery is a less
satisfactory method of hemostasis in hemophiliacs. Before the wound is
closed, the tourniquet must be released and bleeding surgically
controlled. Appropriate perioperative factor replacement is imperative.

Aspiration

The need for routine joint aspiration has been debated.
Some experts recommend aspiration only for an extremely tense
hemarthrosis and avoid aspiration in ordinary cases, citing the risk of
introducing infection, the discomfort to the patient, and the
possibility that aspiration will incite more bleeding of the joint.
Aspiration of the joint should be performed under strict aseptic
conditions.

P.301

Synovectomy

The objective of synovectomy is to prevent progression
of hemophilic arthropathy. The general consensus of opinion is that
synovectomy relieves pain, decreases swelling, and diminishes the
number of bleeding episodes per year (Box 26.1-1). Synovectomy is ineffective and contraindicated patients with radiographic stage IV or V hemophilic arthropathy.

Traditional open synovectomy is often complicated by
loss of range of motion of the affected joint. Arthroscopic synovectomy
is most useful when performed before severe degenerative changes have
developed. Contraindication for arthroscopy of hemophilic patients is
inhibitory antibodies to factor replacement. As complete a synovectomy
as possible should be performed. After surgical synovectomy the knee
should be immobilized in a Jones bandage for 3 days and active movement
encouraged. Postoperative factor replacement supervised by a
hematologist is required. Weidel has shown with a 10- to 15-year
follow-up that the procedure was effective in stopping the bleeding
episodes, and by maintaining the range of motion, joint deterioration
continued to progress at a slower rate.

Radiosynovectomy consists of destruction of synovial
tissue by intraarticular injection of a radioactive agent (yttrium-90,
gold-198, phosphorus-32, and rhenium-186). It requires only one
session, but has a higher cost (Box 26.1-2). A
possible concern is that the damaging effects of the radioactivity are
not strictly limited to the synovium but may also affect the articular
chondrocytes. In addition, there is a theoretic concern of future
oncogenesis (Fig. 26.1-5).

Chemical synovectomy has been performed with rifampicin,
D-penicillamine, and osmic acid. Rifampicin is commonly used with
successful results for chemical synovectomy in developing countries
where there is a lack of radioactive materials. However, it is quite
painful during injection and must be injected weekly, with the number
of injections ranging from 5 (in ankles and elbows) to 10 (in knees).
Osmic acid is another agent for using chemical synovectomy, but its
results are no better than those of rifampicin.

Arthroplasty

The ultimate procedure for hemophilic arthropathy is
total joint replacement. Disabling pain with advanced destruction of
articular cartilage is the prime indication for surgery. It has been
done routinely for knees, hips, and shoulders and sporadically for
elbows and ankles. The problems of arthroplasty in hemophiliacs are
considerable and include difficulties with lack of bone stock,
deformities of the joint, muscle contractures, adhesions, and soft
tissue contractures. The most common cause of failure is infection. It
is difficult to salvage prostheses complicated by infection. However,
the life expectancy of hemophilic patients is lower than that of the
general population of patients treated with total knee arthroplasty,
and the improvement in the quality of life after knee arthroplasty for
hemophilic arthropathy may outweigh the risk of failure.

Total hip replacement is indicated in stage IV or stage
V hemophiliac arthropathy when pain is persistent with severe
disability not relieved by conservative measures. The most common
problem is aseptic loosening of cemented components, probably because
of microhemorrhages at the bone-cement surface. Studies suggest that
arthroplasty, particularly of the hip and knee, can be a valuable
option in the management of severe hemophilic arthropathy although
complications are commonly described and the surgery is technically
demanding.

Arthrodesis

Arthrodesis is a salvage procedure for hip and knee
joints in which arthroplasty has failed or become infected. Arthrodesis
of the ankle, subtalar, and midtarsal joints in the foot, elbow, or
shoulder may be indicated when these joints are destroyed.

Fractures

Fractures usually heal in the normal time. Whenever
possible, fractures are treated by closed reduction and immobilization
in a cast. External fixators should be avoided. Open reduction and
internal fixation are carried out when closed methods are not
appropriate.

Hemophilic Pseudotumors

Symptomatic pseudotumors should be excised if they are
accessible. Prior to surgical intervention, angiography, computed
tomography, and nuclear MRI should be performed to provide accurate
anatomic detail of adjacent vessels. Rarely, radiotherapy may be
considered in surgically inaccessible sites.

P.302

Figure 26.1-5 Right elbow lateral plain radiograph (A) and coronal magnetic resonance image (B) of an 8-year-old boy with hemophilia A and recurrent bleeding approximately eight times a year despite factor treatment. (C) Right elbow P-32 radioisotope synovectomy was performed.

Neuropraxia

Neuropraxia is treated by factor replacement therapy. Occasionally, decompression of the entrapped nerve may be required.

SUGGESTED READING

Arnold WD, Hilgartner MW. Hemophilic arthropathy. J Bone Joint Surg (Am) 1977;59:287-290.

Battistella LR. Maintenance of musculoskeletal function in people with hemophilia. Haemophilia 1998;4 2:26-32.

Beeton K, Rodriguez-Merchan EC, Altree J. Total joint arthroplasty in hemophilia. Haemophilia 2000;6:474-481.

Eickhoff HH, Koch W, Raderschadt G, et al. Arthroscopy for chronic hemophilic synovitis of the knee. Clin Orthop 1997;343:58-62.

Fernandez-Palazzi
F, Rivas S, Viso R, et al. Synovectomy with rifampicine in hemophiliac
haemarthrosis. Haemophilia 2000;6:562-565.

Gilbert MS, Radomisli TE. Therapeutic options in the management of hemophilic synovitis. Clin Orthop 1997;343:88-92.

Greene
WB, Wilson FC. The management of musculoskeletal problems in
hemophilia. Part II (Pathophysiologic and roentgenographic changes in
hemophilic arthropathy). AAOS Instr Course Lect 1983;32:217-233.

Hermann
G, Gilbert MS, Abdelwahab IF. Hemophilia: evaluation of musculoskeletal
involvement with CT, sonography, and MR imaging. AJR Am J Roentgenol
1992;158:119-123.

Hilgartner MW. Current treatment of hemophilic arthropathy. Curr Opin Pediatr 2002;14:46-49.

Norian JM, Ries MD, Karp S, et al. Total knee arthroplasty in hemophilic arthropathy. J Bone Joint Surg (Am) 2002;84:1138-1141.

Petterson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop 1980;149:153-156.

Rodriguez-Merchan
EC, Wiedel JD. General principles and indications of synoviorthesis
(medical synovectomy) in haemophilia. Haemophilia 2001;7(Suppl 2):6-10.

Saphiro
F. Hematologic disorders. In: Pediatric orthopaedic deformities—basic
science, diagnosis, and treatment. San Diego: Academic Press,
2001:909-933.

Siegel
HJ, Luck JV Jr, Siegel ME, et al. Phosphate-32 colloid radiosynovectomy
in hemophilia: outcome of 125 procedures. Clin Orthop 2001;392:409-417.

Wiedel JD. Arthroscopic synovectomy of the knee in hemophilia: 10- to 15-year follow-up. Clin Orthop 1996;328:46-53.

P.303

26.2 SICKLE CELL ANEMIA

Susan A. Scherl

Sickle cell diseases are a group of hereditary
hemoglobinopathies, which cause chronic hemolytic anemia,
immunosuppression, and pain and organ damage secondary to vascular
occlusion. Variants include sickle cell anemia (SCA), hemoglobin SC
disease, and hemoglobin S β-thalassemia. SCA is the most common form,
and can present with numerous musculoskeletal manifestations and
complications. The diagnosis and management of the musculoskeletal
problems associated with SCA can pose a considerable challenge to the
orthopaedist.

PATHOGENESIS

Etiology

Sickle cell disorders occur as the result of an
inherited genetic mutation that codes for the substitution of normal
adult hemoglobin (HbA) with sickle hemoglobin (HbS), or less commonly,
with another variety of abnormal hemoglobin. Normal HbA consists of two
α-polypeptide chains and two β-polypeptide chains. In HbS, a mutation
on chromosome 11 substitutes valine for glutamine in the sixth amino
acid position of the β-globin chain. Children who are homozygous for
the mutation have SCA; heterozygotes have sickle cell trait (SCT).

Epidemiology

About 8% of African Americans (approximately 2 million
people) have SCT, and approximately 1 in 400 has SCA. In regions where
malaria is endemic, the incidence of SCT can be as high as 40%, since
heterozygotes have slightly increased resistance to malaria.
Individuals of a variety of other ethnicities (Mediterranean, Asian,
Hispanic, and Middle Eastern) may also inherit the trait or disease.
The total number of persons in the United States with a clinically
manifest variant of sickle cell disease is about 72,000.

TABLE 26.2-1 CLASSIFICATION OF SICKLE CELL ANEMIA

Syndrome	Abbreviation	Hemoglobin (Hb) Make-Up	Clinical Manifestation
Sickle cell anemia	SCA	Homozygous: HbSS	Severe
Sickle cell trait	SCT	Heterozygous: HbSA	None
Sickle cell C	SCC	Heterozygous: HbSC	Milder than SCA
β⁰-Thalassemia	Sβ⁰	No HbA, HbS with ↓β-globin chains	Similar to SCA
β⁺-Thalassemia	Sβ⁺	Some HbA, HbS with ↓β-globin chains	Similar to SCC
Sickle cell D and E		Heterozygous: HbSD and HbSC	Similar to SCC

Pathophysiology

Low oxygen tension causes hemoglobin S to polymerize,
which changes it from a liquid to a gel. The orientation of the
hemoglobin S molecules into longitudinal fibers, combined with their
decreased plasticity due to increased viscosity, is what causes the
characteristic sickling of the erythrocytes. The presence of other
forms of hemoglobin mitigates the severity of the sickling. That is why
heterozygotes, whom have a significant proportion of HbA, are
clinically asymptomatic, except under conditions of severe hypoxia.
Similarly, sickle cell disease does not clinically manifest itself in
children under the age of 1 year, since fetal hemoglobin (HbF), which
persists until that time, is protective. Even other abnormal
hemoglobins, such as those with the thalassemia mutation, which
decreases the amount of β-globulin produced, generally are less
severely affected than HbSS homozygotes.

Other conditions that increase the rate of HbS
polymerization include dehydration, increased temperature, and falling
pH. Though sickling is reversible, repeated episodes cause cell
membrane damage that leads to permanently sickled cells. These cells
are hemolyzed intravascularly or in the spleen. The average life span
of a red blood cell in a patient with SCA is only 10 to 30 days (120
days is normal). The relative inelasticity of the sickled cells (and
even nonsickled cells with increased amounts of polymerized HbS) causes
increased blood viscosity, and decreased blood flow rate; this
contributes to occlusion and infarction of the microvasculature.

Classification

See Table 26.2-1 for the classification of Sickle cell disorders.

P.304

DIAGNOSIS

The gold standard diagnostic test for sickle cell
disease is a hemoglobin electrophoresis. The different disease variants
have characteristic electrophoresis patterns. A 5-minute solubility
test, called a Sickledex, can be used in initial screening, or in an
emergency setting, but if it is positive, an electrophoresis needs to
be done to differentiate between a carrier and disease state. The
Sickledex also has a relatively high false-negative rate.

Clinical Features

The common clinical manifestations seen in SCA are the
result of vascular occlusion, hemorrhage, infarction, and ischemic
necrosis secondary to increased blood viscosity caused by sickling.
They can be summarized by use of the mnemonic HBSS PAIN CRISIS (problems for which an orthopaedist is frequently consulted are highlighted in italics):

H: hemolysis, hand-foot syndrome (dactylitis)

B: bone marrow hyperplasia

S: stroke (thrombotic or hemorrhagic), subarachnoid bleeding

S: skin ulcers (usually leg)

P: pain crises, priapism, psychosocial problems

A: anemia, aplastic crisis, avascular necrosis (AVN; usually femoral head)

I: infections [central nervous system (CNS), pulmonary, genitourinary, bone, joint]

N: nocturia (urinary frequency)

C: cholelithiasis, cardiomegaly, congestive heart failure, chest syndrome

R: retinopathy, renal failure, renal concentration defects

I: infarction (bone, spleen, CNS, muscle, bowel, renal)

S: sequestration crisis (spleen, liver)

I: increased fetal loss in pregnancy

S: sepsis

Orthopaedic manifestations of SCA can be divided into two groups, based on cause (Box 26.2-1).

Dactylitis

Affects short tubular bones of hands and feet
Age 6 to 12 months (when HbF is replaced by HbS)
Distal extremities become swollen, tender, and painful
Triggered by cold weather
Lasts 1 to 2 weeks
Incidence: 45%
Recurrence: 41%
Rare after 6 years of age (when marrow activity in hands/feet ceases)

Pain Crises

Age between 3 and 4 years
Lasts 3 to 5 days
Localized bone marrow or muscle infarction secondary to sequestration of sickled cells
Commonly: humerus, tibia, femur
Clinically: swelling, decreased range of motion, increased temperature

Osteomyelitis

Clinically: fever, pain, swelling
Polyostotic: 12% to 47%
Erythrocyte sedimentation rate unreliable (usually low) secondary to sickled red blood cells
Staphylococcus aureus and MRSA common, but patients also susceptible to encapsulated organisms secondary to decreased splenic function:
- □ Streptococcus pneumoniae
- □ Haemophilus influenzae
- □ Salmonella
- □ Meningococcus
- □ Klebsiella
Septic and reactive arthritis are less common than osteomyelitis but do occur
Joint fluid in reactive arthritis will show less than 20,000 white blood cells/mm3
Can lead to destruction of the physis, growth arrest, and limb deformity

Stroke

Incidence: 8%
May be hemorrhagic or infarct
Greater than 50% recurrence rate, unless chronic life-time transfusion therapy instituted
May result in spastic hemiplegia requiring orthopaedic management

Pathologic Fractures

May be secondary to bone marrow hyperplasia, osteomyelitis, or disuse osteopenia
Attempt to minimize immobilization during treatment to prevent recurrence

Avascular Necrosis

Femoral head most common, followed by humeral head
Incidence: approximately 10%; bilateral: 54%
Usually diagnosed on plain x-ray, but magnetic resonance imaging may be useful to show extent of head involvement

Radiographic Features

Skull: thickened calvarium: 33% to 50%
Long bones:

P.305
- □ Patchy osteosclerosis
- □ Cortical thinning
- □ Widened intramedullary canal
- □ Areas of infarction
Spine: biconcave vertebrae

Differential Diagnosis

See Table 26.2-2 for the differential diagnosis of sickle cell disease and Table 26.2-3 for diagnosis based on bone and marrow scan results.

TREATMENT

Although most children with SCA are cared for primarily
by a hematologist, the systemic nature of the illness and the clinical
manifestations in various organ systems practically guarantee that most
patients will also be treated by a variety of other subspecialists. The
various acute crises and complications common to the disease often
necessitate presentation in the emergency department as well. Treatment
of patients with SCA can be thought of in three groups: preventive,
problem management, and systemic.

Preventive

Daily supplemental folate, to keep up with red blood cell production demand
Periodic complete blood count check, to catch changes/problems early
Use supplemental iron sparingly; iron overload can become a problem in older patients
Maintain immunizations
Encourage adequate oral hydration
Encourage patients to seek early medical attention when ill
Discourage smoking and alcohol intake
Discourage excessive physical exertion
Avoid extremes of temperature

TABLE 26.2-2 DIFFERENTIAL DIAGNOSIS OF SICKLE CELL ANEMIA

Differentiation to be Made

Similarities

Diagnostic Strategy

Dactylitis vs. osteomyelitis

Pain, fever, ↑WBC count

X-rays: lytic lesion, periosteal reaction

Bone scan unhelpful Perform aspiration of bone

Osteomyelitis vs. infarct

Pain, fever, swelling

X-rays initially normal

Infarct much more common

ESR unreliable

Bone scan alone unhelpful

Sequential bone marrow and bone scans may be helpful

ESR, erythrocyte sedimentation rate; WBC, white blood cell.

TABLE 26.2-3 DIAGNOSIS BASED ON SEQUENTIAL BONE MARROW AND BONE SCANS RESULTS

Results
Bone Marrow Scan Uptake	Bone Scan Uptake	Diagnosis
Decreased	Increased	Acute infarct
Normal	Increased	Osteomyelitis
Normal	Normal	Neither
Decreased	Normal	Old infarct (usually asymptomatic)

Problem Management

Pain

Nonsteroidal antiinflammatory drugs (NSAIDs) for chronic pain

Acute Pain Crisis

Analgesia with NSAIDs/narcotics
Hydration
Bed rest
Identify and correct underlying precipitators (especially infection)
Administration of oxygen, and monitoring, if the patient has documented hypoxemia

Osteomyelitis

Antibiotic coverage for S. aureus and Salmonella
Surgical drainage for chronic
osteomyelitis with sequestrum formation, or for patients who are
systemically septic or not responding to antibiotic therapy

Septic Arthritis

Arthrotomy and drainage, in conjunction with antibiotics

P.306

TABLE 26.2-4 PROBLEM MANAGEMENT IN AVASCULAR NECROSIS

Extent

Treatment

Caveats

Lateral pillar intact

Conservative: Activity modification Physical therapy Protected weightbearing Bracing

May be ineffective

Need to control the underlying sickling as much as possible

Whole head involvement

Younger patient

Core decompression (early)

Redirectional femoral or pelvic osteotomies (late)

Usually stopgap or salvage measures

Older patient

Total joint arthroplasty

↑ Rate of infection

High intraoperative blood loss

↑ Rate of intraoperative femoral fracture

Early aseptic loosening

Avascular Necrosis

See Table 26.2-4 for problem management in AVN.

Systemic

Oral Hydroxyurea

Dose 1 to 35 mg/kg/day (see Table 26.2-5 for pros and cons)

Transfusion Therapy

Simple transfusion to hemoglobin level of 10 g per dL now preferred over exchange transfusions for preoperative optimization.
Use of antigen-matched blood and adequate
hydration/oxygenation helps prevent complications during transfusion
therapy and postoperatively.
Acute transfusions are indicated for life-threatening complications of SCA such as stroke and aplastic anemia.
Chronic transfusion therapy for life is indicated to prevent recurrent strokes.

TABLE 26.2-5 PROS AND CONS OF ORAL HYDROXYUREA THERAPY

Pros		Cons
↓	Pain crises	Can cause bone marrow suppression
↓	Hospital admissions	Long-term risks/benefits not known
↓	Need for transfusion by up to 50%	Not recommended for children

Central Nervous System Ischemia Screening

By use of transcranial Doppler ultrasound or magnetic resonance imaging/magnetic resonance angiography
15% of patients have asymptomatic CNS ischemic injury
Trials ongoing to establish role of transfusion therapy for prevention of CNS ischemic injury