Imaging brings precision to hemophilia diagnosis

May 11, 2005

The term hemophilia encompasses a range of bleeding disorders caused by clotting factor deficiencies. The most common, hemophilia A, or classical hemophilia, is due to factor VIII deficiency and accounts for 80% to 85% of cases. Hemophilia B, otherwise known as Christmas disease, is due to factor IX deficiency and is seen in 14% of cases. Both are X-linked recessive disorders. The remaining cases of hemophilia are due to various other inherited clotting factor deficiencies or to auto-antibodies to clotting factors.

The term hemophilia encompasses a range of bleeding disorders caused by clotting factor deficiencies. The most common, hemophilia A, or classical hemophilia, is due to factor VIII deficiency and accounts for 80% to 85% of cases. Hemophilia B, otherwise known as Christmas disease, is due to factor IX deficiency and is seen in 14% of cases. Both are X-linked recessive disorders. The remaining cases of hemophilia are due to various other inherited clotting factor deficiencies or to auto-antibodies to clotting factors.

Hemophilia affects approximately one in 5000 males worldwide, regardless of geographic location. About one-third present in the neonatal period with bleeding complications, such as prolonged bleeding from the umbilical cord, bleeding after circumcision, or, most serious, intracranial hemorrhage. Bleeding in infants is less common but may occur during teething. Once the child becomes mobile, musculoskeletal, particularly articular, bleeding dominates the clinical picture.

The severity of hemophilia is classified according to the severity of injury that will cause hemorrhage. This system correlates well with laboratory measurements of the deficient factor's activity. Hence, these levels are used as surrogate markers of clinical severity (Table 1).

Intravenous clotting factor replacement is the mainstay of hemophilia treatment. These agents were traditionally made from plasma-derived concentrates, but recombinant factor VIII is now available widely in developed countries. Recombinant products are not dependent on blood donation for production and are virtually free of risk of blood-borne infection, which has been a major problem in the use of plasma-derived products. Recombinant products may also reduce the incidence of antifactor antibody formation. For these reasons, recombinant products are now viewed as the treatment of choice for severe hemophilia.

Treatment strategies can be broadly divided into on-demand therapy and prophylactic therapy. The former involves administering the factor only in the event of bleeding episodes or as a preventive measure prior to surgery or dental work, for example. The latter requires repeated factor transfusions on a regular basis. Treatment choice is determined in part by the availability and expense of factor replacement, although prophylactic therapy is now the norm in many countries for patients with severe hemophilia.

JOINT BLEEDING

Recurrent intra-articular bleeding resulting in arthropathy is the leading cause of morbidity in hemophilia, affecting up to 90% of patients with severe disease.1 Hemarthroses begin during the first two decades of life. They trigger a series of events that often result in recurrent bleeding in the affected joint and progressive joint damage. Hemophilic arthropathy tends to affect a small number of target joints, which are generally established by the age of 20. Large, mobile joints are most commonly affected, particularly the knee, ankle, and elbow.

Hemophilic arthropathy is often described as resembling severe degenerative joint disease in terms of radiologic and pathologic presentation. While this is true of advanced hemophilic joint disease, the earlier pathophysiologic processes have features similar to inflammatory arthropathies.

Hemorrhage, which may occur spontaneously or after trauma, begins in the synovium before extending into the joint space itself. Blood excites an inflammatory response in the synovium, resulting in synovial hypertrophy and joint hyperemia. These responses make further bleeding more likely. Hyperemia in the unfused skeleton results in epiphyseal overgrowth and osteoporosis. Widening of the knee and elbow intercondylar notches, which also occurs in younger patients, probably reflects the combined effects of synovial hypertrophy with epiphyseal overgrowth.

The end result of the pathologic processes is cartilage destruction. This has been attributed to a direct damaging effect of blood, erosive synovial hypertrophy, and chronically raised intra-articular pressure. Cartilage fissures occur early in the process. A hallmark of hemophilic arthropathy is the development of large subchondral cysts, which have been attributed to both synovial intrusion through fissures in the joint surface and primary intra-osseous hemorrhage.2-4

Plain radiography has traditionally been the primary imaging tool for evaluation of hemophilic joint disease. Radiographs adequately demonstrate advanced bone changes such as osteoporosis, epiphyseal overgrowth, large cysts, and joint space narrowing (Figure 1). They have poor sensitivity, however, for the earlier soft-tissue changes that occur before irreversible cartilage damage sets in.

MR imaging has emerged as a more sensitive means of imaging the hemophiliac joint, particularly when visualizing soft-tissue changes. Joint effusions are common findings at all stages of joint disease that can be detected accurately on MRI. Although blood products may sometimes be demonstrated within effusions, it is more usual to see simple effusions. Recurrent hemorrhage causes hemosiderin to accumulate within hypertrophied synovium. Synovial hypertrophy is readily demonstrated on MRI, particularly when gradient-recalled echo techniques are used, accentuating the magnetic susceptibility effects of hemosiderin (Figure 2A). Gradient-recalled echo sequences are also useful when demonstrating cartilage loss.

Synovial hypertrophy can also be visualized clearly on gadolinium-enhanced studies (Figure 2B). This technique may be more sensitive to changes that occur early, before the presence of hemosiderin, although the use of contrast is not widespread.5 Subchondral cysts are more accurately demonstrated on MRI than on plain radiographs.3,6 STIR sequences are particularly suited to this application (Figure 2C). The cysts' signal characteristics will depend on whether their contents comprise simple fluid (most typically), synovium, or blood products.

Ultrasound has a limited role in the assessment of chronically affected joints in hemophilia. The modality is valuable when joints are acutely swollen or painful, and it may accurately determine whether an acute hemarthrosis is present. Radionuclide scintigraphy is rarely used, although it can survey the whole skeleton, identifying target joints for further investigation where clinical findings are equivocal.7

Imaging may inform a variety of treatment decisions in hemophilic arthropathy. Detection of early features can help with patient selection for prophylactic factor replacement, especially where this treatment is costly or not widely available. Some institutions may offer therapies in addition to factor replacement, such as synovectomy or intra-articular steroid injection, and imaging can evaluate the appropriateness of such treatments. Joint replacement remains the sole option for the end-stage joint, and imaging can identify those patients for whom other treatments may be futile.

A number of scoring systems have been developed to assess hemophiliac joints on imaging, using results from plain-film and MR examinations. Additive scoring systems, such as the Pettersson plain-film score8 (Table 2) and the European MRI scale,9 derive the final score from the sum of scores for individually rated features. Progressive systems, such as the Arnold-Hilgartner plain-film score10 and the Denver MRI scale (Table 3), produce a score according to the most severe changes present.11

EXTRA-ARTICULAR INVOLVEMENT

Approximately 15% to 30% of hemophilia bleeding episodes occur outside of joints, typically in muscles, the retroperitoneum, and bones. The most common muscular bleeding sites are the quadriceps and iliopsoas muscle groups.

Patients may present with acute pain and restricted movement. Clinical diagnosis is usually straightforward when superficial muscles are involved, and such episodes may be managed at home by the patient with a self-infusion of factor concentrate. Muscle bleeds near joints, however, may be difficult to distinguish from acute hemarthrosis, and ultrasound is useful in distinguishing them. Deep muscle bleeds, as in the psoas, often require imaging confirmation, and both CT and ultrasound are helpful (Figure 3A). Resolution of deep muscle bleeds following treatment should be confirmed on imaging.

Muscle bleeds that go unrecognized or are not treated properly may become chronic and recurrent, resulting in a hemophilic pseudotumor. Modern treatment has made this complication, previously reported to have an annual incidence of 1% to 2%, increasingly rare. MRI should show an encapsulated mass, often with cystic components, demonstrating blood of varying ages.12 Hemophilic pseudotumors may also occur in a primary intra-osseous location. They present typically as expansile, lytic lesions and can simulate giant cell tumors, expansile metastases, and aneurysmal bone cysts (Figure 3B). These too have become rare.

Intracranial hemorrhage accounted for most deaths in hemophiliac patients prior to the emergence of HIV infection. Neonatal intracranial hemorrhage occurs in 1% to 2% of patients, and it may have long-term sequelae. In older patients, intracranial hemorrhage is most likely to be triggered by trauma, although spontaneous hemorrhage can happen in conjunction with any type of hemophilia. The annual incidence of intracranial hemorrhage is estimated to be 2%.13 All types of intracranial hemorrhage are known to occur, with the most common sites being subdural and subarachnoid (Figure 3C).

VIRAL INFECTION

The use of plasma-derived blood products in the 1980s caused the majority of hemophiliacs undergoing treatment to contract HIV, hepatitis B, or hepatitis C infection. HIV-related illnesses produced a 10-fold increase in mortality in the hemophiliac population. Fortunately, mortality from HIV infection has been falling among hemophiliacs for the past seven years, due to the prevention of new infections and the availability of effective treatments. HIV complications in hemophiliacs are similar to those in the nonhemophiliac HIV-positive population (Figure 3D).

Chronic hepatitis C infection is virtually universal among hemophiliac patients treated before 1986, with consequent morbidity and mortality from chronic liver disease. Screening for complications of hepatitis C represents an increasing part of the imaging workload in hemophilia. Ultrasound examination of the liver performed annually or twice a year to screen for hepatocellular carcinoma is a generally accepted practice for this group of patients. Abnormalities detected on ultrasound may require further evaluation with CT or MRI.

Imaging plays a central role in the assessment of the hemophiliac patient. Greater use of the appropriate modality should result in more efficient and timely interventions.

DR. CALDER is a radiology registrar, and DR. HOLLOWAY is a consultant radiologist, both at the Royal Free Hospital, London.

References

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