Clinical Features

The spectrum of articular disease in hemophilic patients has been the subject of numerous comprehensive reviews ⁶^–¹⁰ and includes acute hemarthrosis, subacute or chronic arthritis, and end-stage hemophilic arthropathy. The usual distribution of joint involvement is shown in Figure 119-1. Involvement of the small joints of the hands and feet also may occur, although infrequently.

Figure 119-1 Distribution of acute hemarthrosis based on a study of 139 patients with hemophilia. Clinical and radiologic features of chronic arthritis in hemophilia.

(Adapted from Steven MM, Yogarojah S, Madhok R, et al: Haemophilic arthritis, QJM 58:181, 1986.)

Acute Hemarthrosis

Nearly all patients with severe hemophilia A or B (<1% activity of the deficient factor) and half of patients with moderate disease activity experience hemarthrosis. Acute hemarthroses generally first occur when a child begins to walk, and they continue, usually cyclically, into adulthood, when the frequency diminishes. Patients frequently have premonitory symptoms, such as stiffness or warmth in the affected joint, followed by intense pain, which may be due in part to rapid joint capsule distention.

Pain is accompanied by objective clinical findings of warmth, a tense effusion, tenderness, limitation of motion, and a joint that is often held in a flexed position. Joint pain responds rapidly to replacement of the deficient clotting factor. If hemostasis is achieved early after onset of hemarthrosis, full joint function may be regained within 12 to 24 hours. If the hemorrhage is more advanced, however, blood is resorbed slowly over 5 to 7 days, and full joint function is regained within 10 to 14 days.

Subacute or Chronic Arthritis

Recurrent hemarthroses, particularly in patients with severe factor deficiency, may lead to a self-perpetuating condition in which joint abnormalities persist in intervals between bleeding episodes. The involved joint is chronically swollen, although painless and only slightly warm. Chronic synovitis, including prominent synovial proliferation with or without effusion, may be present. Mild limitation of motion may be noted, often with a flexion deformity. Factor replacement does not modify these findings.

End-Stage Hemophilic Arthropathy

Long-standing end-stage hemophilic arthropathy has features in common with degenerative joint disease and advanced rheumatoid arthritis. The joint appears enlarged and “knobby,” owing to osteophytic bone overgrowth. Synovial thickening and effusion are not prominent, however. Range of motion is severely restricted, and fibrous ankylosis is common. Subluxation, joint laxity, and malalignment are frequently present. Hemarthroses decrease in frequency, however.

Septic Arthritis

Until the early 1980s, septic arthritis rarely occurred in hemophilic patients. With widespread occurrence of human immunodeficiency virus (HIV) infection as a result of contaminated factor concentrates, the incidence of this complication has increased significantly.^11,¹² Septic arthritis is seen more often in adult than in pediatric hemophilic patients and is most commonly monoarticular, usually involving the knee. In contrast to spontaneous hemarthrosis, septic arthritis is significantly associated with a temperature greater than 38° C within 12 hours of presentation and articular pain that does not improve with replacement therapy.¹¹ Peripheral leukocyte count may not be elevated, particularly in HIV-positive patients.¹³ A predisposing factor other than hemophilic arthropathy is often identifiable, including previous arthrocentesis or arthroplasty, intravenous drug use, and an infected indwelling venous access catheter. Staphylococcus aureus is the most frequently identified organism even in HIV-infected patients, followed by Streptococcus pneumoniae.¹³

Muscle and Soft Tissue Hemorrhage

Bleeding into muscles and soft tissue is common in hemophilic patients and may be more insidious than hemarthrosis because of the lack of premonitory symptoms. Bleeding into the iliopsoas and gastrocnemius muscles and the forearm results in well-described syndromes with which the rheumatologist should be familiar. Iliopsoas hemorrhage produces acute groin pain with marked pain on hip extension and a hip flexion contracture. Rotation is preserved, in contrast to intra-articular hemorrhage. If untreated, the expanding soft tissue mass may compress the femoral nerve, causing signs and symptoms of femoral neuropathy.^6,¹⁴ Bleeding into the gastrocnemius muscle can cause an equinus deformity from heel cord contracture.⁶ Finally, hemorrhage into closed compartments can cause acute muscle necrosis and nerve compression.¹⁵ Of particular importance is bleeding into the volar compartment of the forearm, which can cause flexion deformities of the wrist and fingers. If a compartment syndrome is suspected, compartment pressures should be measured to confirm the diagnosis.

A large intramuscular hemorrhage uncommonly results in the formation of a simple muscle cyst, which clinically appears to be an encapsulated soft tissue area of swelling overlying muscle. Cyst formation in this setting is confined by the muscular fascial plane and most likely results from inadequate resorption of blood and clot. Subperiosteal or intraosseous hemorrhage, in contrast, may lead to a pseudotumor, a rare skeletal complication of hemophilia. Hemophilic pseudotumors are of two types: the adult type, which occurs proximally, usually in the pelvis or femur; and the childhood type, which occurs distal to the elbows or knees and carries a better prognosis.^16,¹⁷

Conservative early management of muscle cysts and childhood-type pseudotumors is indicated, including immobilization and factor replacement. In adult-type pseudotumors, which usually are refractory to conservative therapy, and in progressive childhood pseudotumors, surgical removal is indicated ¹⁶ to prevent serious complications, such as spontaneous rupture, fistula formation, neurologic or vascular entrapment, and fracture of adjacent bone. Aspiration of a pseudotumor or cyst is contraindicated.

Diagnostic Imaging

Radiographs

The earliest radiographic changes in hemophilic arthropathy are confined to the soft tissue and reflect acute hemarthrosis. The joint capsule is distended with displacement of fat pads, and an increased hazy density caused by intra-articular blood is noted. Hemarthrosis before epiphyseal plate closure may result in epiphyseal overgrowth and irregularity. Occasionally, premature epiphyseal closure is seen.

With progression of chronic proliferative synovitis, irreversible radiologic changes appear.¹⁸ These changes reflect the inflammatory and degenerative nature of chronic hemophilic arthropathy (Table 119-1 and Figure 119-2A). Certain changes unique to hemophilic arthropathy occur as well (see Table 119-1 and Figure 119-2B). Radiographic findings in hemophilic arthropathy have been recently reviewed.^18a

Table 119-1 Radiologic Manifestations of Chronic Hemophilic Arthropathy

Characteristic	Also Seen in
Periarticular soft tissue swelling	RA
Periarticular demineralization	RA
Marginal erosions	RA
Subchondral irregularity and cyst formation	RA, OA
Decreased joint space	OA
Osteophyte formation	OA*
Chondrocalcinosis	CPPD
Specific Femoral intercondylar notch widening Squaring of distal patellar margin (lateral view) Proximal radial enlargement (see Figure 119-2B) Talar flattening ± ankle ankylosis ^†

CPPD, calcium pyrophosphate deposition disease; OA, osteoarthritis; RA, rheumatoid arthritis.

^* From Jensen PS, Putnam CE: Chondrocalcinosis and hemophilia, Clin Radiol 28:401, 1977.

^† From Schreiber RR: Musculoskeletal system: radiologic findings. In Brinkhous KM, Hemker HC, editors: Handbook of hemophilia I, New York, 1975, Elsevier.

Figure 119-2 Radiographic changes of hemophilic arthropathy. A, Early arthritis of the knee, showing soft tissue swelling, widening of the femoral condyles and tibial plateau, irregularity of the distal femoral epiphysis, and a few subchondral bone cysts. B, More advanced arthritis involving the elbow, showing almost complete loss of joint space and extensive subchondral cyst formation. Widening of the proximal radius is characteristic of hemophilic arthropathy.

A study of serial radiographs of symptomatic joints in hemophilic patients suggests that serial scoring with conventionally accepted techniques may be a cost-effective alternative to magnetic resonance imaging (MRI) in predicting progressive synovial hypertrophy.¹⁹

Other Imaging Methods

MRI is now routinely used to stage hemophilic arthritis accurately to determine optimal treatment and to follow response to therapy.²⁰ A scoring system based on MRI has been proposed.²¹ MRI has been demonstrated to be superior to conventional radiography and computed tomography in the detection of erosions and cysts, bone marrow edema and hemorrhage, and synovial hypertrophy and torn ligaments (the latter in patients whose radiographs showed widened intercondylar notches).²² As preventive measures improve, it will continue to be important to use the most advanced techniques, including MRI, both to stage hemophilic arthropathy and to assess the benefits of new therapies such as prophylactic infusion.²³ Additionally, MRI and ultrasonography are useful in the detection and quantitation of soft tissue bleeding, cysts, and pseudotumors.^24,²⁵

Pathologic Features and Pathogenesis

Pathologic studies of human hemophilic arthropathy have been limited to synovial specimens obtained at surgery ^26,²⁷ or at postmortem examination and reflect changes of advanced disease only. Studies of experimentally produced hemarthrosis in animals,^28,²⁹ post-traumatic hemarthrosis in nonhemophilic humans,³⁰ and canine and murine models of hemophilia A³¹^–³³ have provided an understanding of the earliest changes induced by acute hemarthrosis and their evolution to chronic arthritis.

As reviewed more recently,³⁴ the process most likely includes catabolic activation of synovial cells by exposure to blood components with subsequent cartilage destruction and a direct destructive effect of intra-articular blood on cartilage. A single synovial hemorrhage induces serial changes in the synovial membrane, including early focal villous synovial proliferation and subsynovial diapedesis of erythrocytes, followed by the appearance of perivascular inflammatory cells, patchy subsynovial fibrosis, and intracellular iron accumulation in synovial cells and subsynovial macrophages. With repeated hemarthroses, the synovium becomes grossly hypertrophied and hyperpigmented, with eventual organization into a pannus that invades and erodes marginal cartilage. On histologic examination, villous hypertrophy and subsynovial fibrosis progress, but inflammatory cells are scarce (Figure 119-3).²⁷ Seventy-five percent of synoviocytes contain siderosomes (electron-dense, iron-filled deposits within lysosomes), in contrast to 10% in normal synovium and 25% in rheumatoid synovium.³⁵ Iron deposits are associated with the production of proinflammatory cytokines and synovial inhibition of the formation of human cartilage matrix. Although the inflammatory synovial changes are mild, the synovial production of proinflammatory mediators, including interleukin-1 and interleukin-6 and tumor necrosis factor, approaches that of rheumatoid synovium.³⁴ The articular cartilage is grossly and microscopically abnormal in the setting of recurrent hemarthrosis.²⁸ Areas of cartilaginous fissuring and rarefaction expose sclerotic bone. The remaining cartilage is thin and unevenly distributed, often freely protruding into the joint cavity. Bone erosions appear at weight-bearing surfaces. Loss of matrix glycosaminoglycan occurs and is also seen in degenerative arthritis.^27,³⁶

Figure 119-3 Proliferative synovitis of hemophilia. Villous hypertrophy of the synovium with pigment deposition in superficial cells. The reaction is mainly synovial cell hyperplasia. Infiltrating inflammatory cells are scarce. (Hematoxylin and eosin, ×2500.)

Current studies suggest that recurrent hemarthrosis induces joint destruction in hemophilic arthropathy through direct and indirect effects of iron on the synovium ^35,³⁷ and cartilage,^36,³⁸ by the degradative effect of proliferative synovium,³⁹ and through an alteration in cartilage biochemical composition similar to that seen in degenerative arthritis. A relationship between hemarthrosis-induced overexpression of oncogenes (e.g., c-myc and mdm-2) and the dysregulated, tumor-like proliferation of hemophilic synovium has been noted.⁴⁰^–⁴² Angiogenesis induced by growth factors such as vascular-derived endothelial growth factor may be important in inducing and sustaining a synovial proliferative response to hemarthrosis.⁴²