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Hematologic Disorders
Hemophilia
Hemophilia, a genetically determined disorder, is characterized by abnormal blood coagulation as a result of a functional deficiency of factor VIII or IX. Since biblical times, the crippling deformities of the musculoskeletal system and death resulting from uncontrolled hemorrhage have been well depicted in the pages of history.
The term hemophilia, coined by Hopff in 1828, means “blood loving.” Wright is credited with being the first to demonstrate the prolonged clotting time in the disorder. Patek and Taylor isolated the deficient substance, terming it antihemophilic globulin.
Modern management of hemophilia has reduced the morbidity of the disease remarkably. The development of human immunodeficiency virus (HIV) infection in those receiving blood products was a major setback near the end of the 20th century. Better treatment of HIV infection and safer methods of blood product screening and factor preparation have dramatically reduced the incidence of this unfortunate disease complex. Currently, factors VIII and IX are produced with recombinant DNA methods, which avoids the hazards of bloodborne disease. During the HIV era, the mortality rate of patients with hemophilia was determined to be two to three times higher than that of the general male population, largely because of the consequences of viral infections. Interestingly, studies have continued to show that the mortality rate of patients with hemophilia who were not infected with HIV continue to exceed the mortality rate of the general population by a factor of 2.6. ,
Incidence
The incidence of hemophilia is estimated to be 1/10,000 male births in the United States and 0.8/10,000 male births in England. , The national prevalence has been estimated to be 13,320 cases of hemophilia A and 3640 cases of hemophilia B, with a US birth prevalence of both A and B of 1/5032 live male births.
Classification and Inheritance
Hemophilia may be classified as hemophilia A, hemophilia B, or von Willebrand disease. Hemophilia A and B are further classified as mild, moderate, or severe, based on the functional plasma factor levels ( Table 39.1 ). Patients with severe hemophilia may have spontaneous hemarthroses, intramuscular bleeding, and visceral bleeding, even in the absence of trauma.
Table 39.1
Classification of Severity of Hemophilia A and B.
| Severity | Factor Level (Percentage of Normal) |
|---|---|
| Mild | >50 |
| Moderate | 25–50 |
| Moderately severe | 1–24 |
| Severe | <1 |
Hemophilia A
Hemophilia A, or classic hemophilia, results from a congenital deficiency in factor VIII (also known as antihemophilic factor or antihemophilic globulin). This type accounts for approximately 80% of cases and is caused by a mutation of the factor VIII gene on the X chromosome. Studies have identified at least 58 different mutations that result in a deficiency in normally functioning factor VIII protein.
Hemophilia A occurs in boys and is transmitted by asymptomatic female carriers. A girl could be affected if her mother were a carrier and her father a hemophiliac; however, this is very rare.
Hemophilia B
Hemophilia B, or Christmas disease, is caused by a deficiency in factor IX (plasma thromboplastin component, or Christmas factor). Its clinical manifestations are similar to those of classic hemophilia. The hereditary transmission also is by an X-linked recessive gene. As with hemophilia A, many mutations of the gene responsible for factor IX production have been identified. , Hemophilia B accounts for approximately 15% of cases of hemophilia.
von Willebrand Disease
In this bleeding disorder, factor VIII deficiency and platelet functional abnormality are present. The disorder is inherited as an autosomal dominant trait and occurs in both genders. The bleeding disorder is relatively mild.
Factor VIII, a glycoprotein with a molecular weight of 2000 kDa, is composed of subunits, each with a molecular weight of approximately 200 kDa. All these subunits contain carbohydrates and are held together by disulfide bonds. , The precoagulant, sex-linked, hemophilic defect is located on the lighter protein portion of the glycoprotein, whereas the autosomal dominant von Willebrand defect is related to the heavier carbohydrate moiety of the molecule.
Clinical Features
Hemorrhage
Uncontrolled hemorrhage and repeated episodes of bleeding are the hallmarks of hemophilia. The severity of the disease varies from patient to patient but is constant in any one patient. Clinical manifestations of hemophilia A and B are similar and depend on the blood levels of factor VIII or IX. The level of hemostasis is normal when the blood level of either factor is at least 50% of normal. When the functional plasma level of the factor is 25% to 50% of normal, the hemophilia is mild, and excessive bleeding occurs only after major trauma or during surgery. When the plasma level of the factor is 5% to 25% of normal, the hemophilia is moderate with severe, uncontrolled bleeding occurring after minor injury or during an operative procedure. When the plasma level of the factor is 1% to 5% of normal, the hemophilia is moderately severe, with major hemorrhage occurring after minor injury or unrecognized mild trauma. When the plasma levels of factor VIII or IX are below 1% of normal, the hemophilia is considered very severe. These patients experience repeated spontaneous hemorrhages into joints and bleeding into deep soft tissues.
Abnormal bleeding may occur in any area of the body. Joints are the most frequent sites of repeated hemorrhage, followed by muscles and soft tissues. In the patient with severe hemophilia, abnormal bleeding may manifest in the neonatal period or early infancy though ecchymosis and soft tissue bleeding are typically minor, resorb relatively readily, and are rarely detected by the parents. Bleeding is usually first detected when an infant begins to crawl or is standing and falling. Physicians initially evaluating such children must have a high index of suspicion for hemophilia to prevent serious consequences or invasive treatment, such as aspiration of the joints.
Hemophilic Arthropathy
Intraarticular hemorrhage is a central clinical hallmark of hemophilia. A single hemarthrosis may precipitate low-grade synovitis, which predisposes the involved joint to recurrent hemarthrosis and a cycle of chronic synovitis, inflammatory arthritis, and progressive arthropathy.
Site of Involvement
Weight-bearing 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. Any joint, however, may be the site of pathologic change.
Pathophysiology
The pathophysiologic process was initially described by Konig in the late 19th century. An initial stage of synovial reaction to the bleeding into the joint occurs first, followed by a later stage of cartilage degeneration and joint destruction. After injury, the synovial vessels rupture and the blood accumulates in the joint. Bleeding continues until the intraarticular hydrostatic pressure exceeds arterial and capillary pressure in the synovium, resulting in tamponade of the synovial vessels and causing ischemia of the synovium and subchondral bone.
With repeated hemorrhage, hyperplasia and fibrosis of the synovium occur, and a vicious circle of bleeding-synovitis-bleeding ensues. Pannus formation by the proliferating synovial tissue erodes the hyaline cartilage peripherally, and compression of its opposing cartilaginous surfaces results in degeneration of articular cartilage centrally. Articular cartilage is also degraded by the action of proteolytic enzymes—lysosomal proteases, acid phosphatase, and cathepsin D. Data from animal studies have suggested that articular cartilage may be more susceptible to blood-induced damage at younger rather than at older ages. Prostaglandin levels are also elevated in hemophilic arthropathy. An inflammatory process invades and destroys cartilage. Loss of joint motion and contractures from the capsular synovial fibrosis follow. Local ischemia causes formation of subchondral bone cysts.
Repeated hemarthrosis causes marked dilation of the capsular and epiphyseal vessels. The resultant hyperemia and increased circulation result in enlargement of the epiphysis and potentially increased length of the limb. Stimulation of growth may be asymmetric, resulting in valgus or varus deformity. Alternatively, shortening of the limb may be produced by early closure of the physis. Osteoporosis and muscle atrophy are common.
Clinical Findings
Clinical findings depend on the severity of hemorrhage and whether the hemarthrosis is acute, subacute, or chronic. In acute hemarthrosis, pain and swelling with distention of the joint capsule are the principal findings. A history of injury may not be elicited. With cessation of bleeding, the intensity of the pain decreases. The joint will assume the position of minimal discomfort, which is also the position of minimal intraarticular pressure. The hip joint, for example, is held in flexion, abduction, and external rotation. Extension, wide abduction, and medial rotation of the hip are limited and painful because they increase intraarticular hydrostatic pressure. The knee joint is held in flexion, with range of motion markedly restricted by protective spasm, pain, and the hemarthrosis. Local tenderness and increased heat are present. The overlying skin becomes tense and shiny. The intense pain of acute hemarthrosis subsides rapidly after the administration of factor VIII or IX.
Subacute hemarthrosis develops after several episodes of bleeding into the joint. Pain is minimal. The synovium is thickened and boggy. Joint motion is moderately restricted. Subacute hemarthrosis does not respond rapidly to the administration of clotting factor.
Chronic hemarthrosis develops after 6 months of involvement. Progressive destruction of the joint takes place, with the end stage being a fibrotic, stiff, and totally destroyed joint.
Differential Diagnosis
A difficult diagnostic challenge is the child with hemophilia and a superimposed joint infection. The diagnosis is often delayed because the symptoms are similar to those of acute hemarthrosis. In one series, most but not all children with infection were found to have elevated white blood cell counts. Associated risk factors included infected angioaccess catheters, pneumonia, and generalized sepsis. Affected joints should be treated with antibiotics and repeated aspiration or arthrotomy. ,
Radiographic Findings
Radiographic findings associated with hemarthrosis depend on the stage of the disease, patient age at disease onset, and the joint involved. Magnetic resonance imaging (MRI) is considered the most accurate imaging modality for assessing hemophilic arthropathy and may significantly affect patient management. Initial radiographs of an affected joint disclose soft tissue swelling from distention of the joint capsule. With repeated hemorrhage and resultant chronic synovitis there may be joint effusion, osseous erosion, osteoporosis, enlargement of the epiphysis, subchondral cysts, narrowing of the articular cartilage space, formation of peripheral osteophytes, and other secondary degenerative changes ( Figs. 39.1 and 39.2 ). The final phase of hemophilic arthropathy is fibrous ankylosis ( Fig. 39.3 ).
On the basis of radiographic findings and degree of cartilage destruction, Arnold and Hilgartner classified hemophilic arthropathy into five stages ( Box 39.1 ). A modified version of the Arnold-Hilgartner system has four grades instead of five ( Box 39.2 ). This modified classification eliminates the original stage II (epiphyseal enlargement and juxtaarticular osteoporosis), which is rarely discrete and has no implications for treatment. Osteoporosis frequently accompanies chronic synovitis in patients with stage I arthropathy, and erosions are often present, with epiphyseal enlargement.
Box 39.1
Radiographic Staging of Hemophilic Arthropathy
Adapted from Arnold W, Hilgartner M. Hemophilic arthropathy: current concepts of pathogenesis and management. J Bone Joint Surg Am. 1977;59:287.
Stage I
-
Soft tissue swelling
-
No skeletal abnormality
Stage II
-
Overgrowth and osteoporosis of epiphysis
-
Joint integrity maintained
-
No bone cysts
-
No narrowing of articular cartilage space
Stage III
-
Mild to moderate joint narrowing
-
Subchondral cysts
-
Patellar squaring
-
Widening of intercondylar notch of knee and trochlear notch of elbow
-
Articular cartilage preserved, indicating that disease is still reversible
Stage IV
-
Severe narrowing of joint space, with cartilage destruction
-
Other osseous changes, subchondral cysts, patellar squaring, widening of intercondylar or trochlear notch, very pronounced
Stage V
-
Total loss of joint space with fibrous ankylosis
-
Marked incongruity of the articular structures, with severe irregular hypertrophy of the epiphysis
Box 39.2
Modified Arnold-Hilgartner Arthroplasty Classification
Grade I
-
Soft tissue fullness indicating effusion and synovial thickening
-
Juxtaarticular osteopenia often present
Grade II
-
Widened epiphysis, surface irregularity, and small erosions
-
Normal cartilage interval or joint space
Grade III
-
Narrowing of cartilage interval with extensive surface erosions
-
Juxtaarticular bony cysts may be present
Grade IV
-
Same findings as stage III, but with complete loss of cartilage interval and marked surface irregularity
-
Reactive sclerosis, squaring of the margin of the femoral condyles, and subluxation often present
In a study comparing the ability to detect synovial hypertrophy using plain radiography and MRI, Arnold-Hilgartner staging alone was proven to be predictive of synovial hypertrophy in patients with symptomatic knee and ankle joints, with a sensitivity and specificity of 100% for the detection of synovial hypertrophy within the knee.
Soft Tissue Bleeding
After a direct injury, a large hematoma may accumulate in the subcutaneous tissues. The blood usually is absorbed spontaneously though ulceration occasionally occurs on the forehead, olecranon process, or the prepatellar area. This type of superficial hematoma usually remains fluid and fluctuant for a long time. Superficial soft tissue hemorrhage in the form of ecchymosis is common, especially in a patient with severe hemophilia; it is not of clinical significance.
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