AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Background

Hemophilia is the oldest known bleeding disorder. This condition first came to public attention when the disease appeared in the offspring of Queen Victoria of England.¹ Presumably, hemophilia occurred in Queen Victoria's children because of a mutation in one of the queen's X chromosomes. Then, close intermarriages between European royalty caused the disease to spread from the English royal families to the German, Spanish, and Russian royal families in the 19th and 20th centuries. At the time, the mechanism for the bleeding was not known. However, in 1868, the physician Volkmann defined the role of hemorrhage in the pathogenesis of the articular findings in hemophilia.²

• Hemophilia was common in the royal families of Europe because of close intermarriage, beginning with the offspring of Queen Victoria.
• The last Czar of Russia, Nikolas II, had one son, the heir to the throne, Alexis, who had hemophilia.¹ Alexis was a constant source of concern for the royal parents such that worry over his poor health may have contributed to deterioration of the state of the country and the overthrow of the monarchy at the time of the Bolshevik revolution. Prince Alexis, along with his parents and siblings, was later executed at the time of the revolution.

Patient Education

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Hemophilia.

Related eMedicine topics:
Hemophilia, Type A
Hemophilia, Type B
Hemophilia C
Hemophilia, Acquired

Related Medscape topics:
Hard-to-Control Bleeding Disorders
Hepatitis C Seems Milder in Patients With Hemophilia

Pathophysiology

The deficiency or absence of either of 2 clotting elements—factor VIII or factor IX—leads to the clinical condition described as hemophilia A or hemophilia B, respectively. Hemophilia B was formerly known as Christmas disease and is not described in this article; in this condition, life-threatening bleeding into the head or the abdomen may occur at any age.

People with one of these bleeding disorders are prone to have recurrent episodes of hemorrhage into the joints. Acute bleeding increases the pressure in the synovial cavity and bone marrow, which leads to severe pain and possibly osteonecrosis or a pseudotumoral mass. Intra-articular bleeding produces a direct chemical effect on the synovium, cartilage, and bone. Over time, the blood becomes deposited in the form of hemosiderin in these tissues. Recurrent hyperemia of the joint in the growing child causes juxta-articular osteoporosis and overgrowth of the epiphysis.

Roosendaal and Lafeber studied the pathogenesis of the joint changes in both experimental and clinical cases of hemophilia.³ The authors found that the articular cartilage is sensitive to the presence of blood and that damage may occur to the cartilage independent of the synovial changes caused by bleeding. However, practically speaking, the imaging changes that appear first are effusion and synovial proliferation. Damage to the bone and articular cartilage appears later.

Frequency

United States

An estimated 20,000 persons have hemophilia A, which accounts for 75% of all cases of hemophilia in the US (see eMedicine topic Hemophilia, Overview). Women are rarely affected; however, homozygous disease has been reported in females, as well as in patients with Turner (XO) syndrome (see Images 1-2).

International

Hemophilia affects all races and has been reported in all parts of the world. The World Federation of Hemophilia and philanthropic groups have attempted to aid families with this condition who live in developing countries. Current descendents of the royal families in England and Spain appear to be free of either the disease or the female-carrier state.

Mortality/Morbidity

The severity of hemophilia varies.

• Beginning in the early 1980s and continuing to the present, acquired immunodeficiency syndrome (AIDS) has been a significant complication of hemophilia. The use of plasma-derived factor replacement from pooled plasma sources led to 50% of hemophiliacs developing AIDS in the 1980s (see eMedicine topic Hemophilia, Overview). Once the risk of transfusion-related human immunodeficiency virus (HIV) transmission was recognized, the prevalence of new cases of AIDS in hemophiliac patients decreased to nearly zero.

  Screening for HIV products in blood is effective, but there is still concern that other agents, such as hepatitis A, parvovirus, and the prions that cause Creutzfeldt-Jakob disease, can be transmitted through blood transfusions. In developed countries, recombinant factor VIII is produced synthetically without blood products; this development has allayed fears of some types of disease transmission by eliminating the need for human plasma transfusions.

• See also Clinical Details.

Race

No racial predilection exists for hemophilia.

Sex

Hemophilia is a disease almost exclusively of males because the defective gene is found on the X chromosome.

• The 2 sex-linked disorders (ie, hemophilia A and hemophilia B) become clinically apparent in males, and females are generally asymptomatic carriers.
• Hemophilia is so rare in females that another cause of unexplained or problematic bleeding should be considered before this condition. For example, a traumatic effusion or pigmented villonodular hyperplasia is more likely than hemophilia as an etiology for a bleeding disorder in a female.

Age

• Bleeding into target joints (the joints that are most commonly affected with repetitive bleeding in an individual patient) starts before the age of 2 years and persists into adolescence.
• In some patients, bleeding continues into adulthood, even affecting new target joints after the age of 30 years; however, this occurrence is unusual.
• The late sequelae of joint hemorrhage appear in adolescence or adulthood as a joint deformity, contracture, and/or degenerative arthritis.

Anatomy

Imaging tests such as plain radiography or magnetic resonance imaging (MRI) are helpful in defining the degree of joint destruction. The stages of altered anatomy are defined by classification systems that have been developed for plain radiographs and MRI.^{4, 5, 6} The pathologic-anatomic appearance progresses from joint hemorrhage to joint effusion; synovial hyperplasia; hemosiderin deposition in the synovium, cartilage, and bone; osteoporosis; erosion of subchondral bone; bone cysts; articular cartilage destruction; overgrowth of the epiphysis; joint contracture; and degenerative arthritis.

Clinical Details

Approximately 50% of patients with hemophilia develop permanent joint deformities. Pseudotumors can develop in the bone marrow, cortical bone, and soft tissues.

About 70% of patients who have hemophilia are affected with the severe form of the disease and have less than 1% of the normal clotting factor.⁷ Bleeding in these patients occurs spontaneously or after minor trauma. In milder cases of hemophilia, a major bleeding event occurs only after significant trauma or major surgery.

One common presentation is the development of uncontrollable hemorrhage after routine postnatal circumcision in affected male infants. In addition to bleeding into the joints, spontaneous or posttraumatic bleeding may occur in the gastrointestinal or genitourinary tract. Subdural or intracerebral bleeding may be life threatening. Retroperitoneal bleeding may be occult and result in a significant decrease in the patient's hematocrit level.

Hemarthrosis occurs in 75-90% of patients with hemophilia. Young children and adolescents are more likely to bleed into joints than adults are; this may be because adults are better able to protect their joints from trauma. Bleeding occurs in predictable patterns, affecting some joints more than others. The most common target joints are the knee, ankle, and elbow.

The disease tends to be asymmetric in its involvement. Approximately 50% of patients with hemophilia develop permanent changes in the joint. These chronic changes include thick synovial deposition, richly laden with hemosiderin. The synovial masses erode the juxta-articular cartilage and the subchondral bone (see Image 3). Invasion into the bone substance produces intraosseous cyst formation. Bleeding into the bone may rarely produce large, vacuolated spaces that are referred to as intraosseous pseudotumors. Similar blood masses may occur in the cortex and the soft tissues (see Image 7).

Knee involvement

The knee is the classic target joint. Involvement of this joint is most commonly described in the literature and is the basis for the findings described in the Arnold-Hilgartner classification (see the Table below).

The chronic joint effusions in hemophilia may be denser than other effusions because of the presence of iron. Juxta-articular osteoporosis develops, especially in children, secondary to the hyperemic state. The irregular appearance of the subchondral surface is secondary to either blood that directly destroys bone or to synovial intrusion.

Deeper invasion of the synovium and joint fluid leads to multiple subchondral cysts. Chronic hyperemia causes overgrowth of the epiphysis and widening of the intercondylar notch in the growing child. Squaring of the inferior pole of the patella (seen in 20-30% of patients with hemophilia) is another form of overgrowth. A similar effect of overgrowth may be seen in children with juvenile rheumatoid arthritis (JRA). A fixed flexion deformity and painful limitation of motion are late findings on physical examination.

Table. Arnold-Hilgartner classification⁶

Ankle involvement

Findings similar to those in the knee also develop in the ankle. With increased screening for joint abnormalities as part of an aggressive treatment regimen for patients with hemophilia, investigators have found that the ankle is more commonly involved as a target joint than the knee. The overgrowth pattern in the ankle leads to a condition called talar tilt, which is a tibiotalar slanting that is due to relative undergrowth of the lateral side of the tibial epiphysis and that leads to a pronated foot position. MRI shows the extension of ankle effusion-synovitis into the subtalar joint (see Image 8).

Elbow involvement

A radiopaque effusion is more easily seen on radiographs in the elbow than in the knee or ankle (see Image 11). The trochlear notch may be widened. Enlargement of the radial head and limited elbow motion are present in advanced cases.

Hip involvement

The hip is not commonly a target joint, but because of the way the blood supply reaches the femoral head, osteonecrosis may occur after intra-articular bleeding does. Osteonecrosis may also occur in the shoulder or ankle (see Image 12). Severe osteoporosis and spontaneous hip dislocation may develop. This distribution in the hips, shoulders, and ankles is probably related to the way the vascular supply enters the joint capsule and nourishes the underlying epiphysis.

Wrist involvement

Wrist-joint deformity may occur from synovitis, but clinical wrist involvement is more common in JRA than in hemophilia.

Shoulder involvement

As in the hip joint, osteonecrosis may occur in the shoulder joint (see Image 14).

Preferred Examination

Plain radiographic classification systems for describing the clinical progression of arthropathy were developed in the 1970s. However, radiographs may lead to the underestimation of soft-tissue changes that precede bone destruction. Treatment of patients with hemophilia at an early age may prevent progression to the later, destructive changes seen on radiographs.

MRI has played a major role in defining such destructive soft-tissue changes and has led to early, aggressive treatment of affected patients with factor prophylaxis or replacement.⁴ Overall, the best imaging modality is MRI because this technique combines excellent spatial resolution with the ability to detect soft-tissue bleeding at an early stage. In a given case, all of the other mentioned imaging modalities may play a role, but the first choice is MRI.

Ultrasonography offers an appealing alternative for assessing the joint fluid and synovial proliferation. This technique has been used more extensively in Canada and Europe than in the United States.⁸

Limitations of Techniques

As mentioned above (see Preferred Examination), plain radiographs cannot clearly depict soft-tissue changes. In early hemophilic disease, radiographs may not be needed at all. MRI is the best technique for detecting soft-tissue changes, but it is expensive, and 10% of patients are too claustrophobic to undergo the examination. In addition, some patients' implanted devices, such as pacemakers, preclude MRI evaluation. MRI may not be warranted when the radiographic findings already show advanced disease.

DIFFERENTIALS

Section 3 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Other Problems to Be Considered

• Trauma, scurvy, myeloproliferative disease, and anticoagulant overdose may cause acute hemarthrosis.
• Over time, JRA causes joint deformities in a pattern that is similar to that of hemophilia.
• Pigmented villonodular synovitis (PVNS) produces hemosiderin deposition in the synovium similar to that of hemophilia.
• Synovial hemangiomas may look like hemorrhagic synovitis.²

RADIOGRAPH

Section 4 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

In 1977, Arnold and Hilgartner published a classification scheme for staging hemophilic arthropathy that has been widely used.⁶ The radiographic progression of disease is divided into 5 stages (see the Table in Clinical Details, and see Images 15-16).

Degree of Confidence

The early changes of effusion and synovitis in hemophilic arthropathy are poorly seen on radiographs.

False Positives/Negatives

Early soft-tissue abnormalities are not well depicted on radiographs. Radiographic findings of other diseases may mimic hemophilia in a given joint.

CT SCAN

Section 5 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

Masses that develop in a patient with hemophilia can be evaluated by computed tomography (CT) scanning, which is good for defining pseudotumors, whether they occur in soft tissues, in cortical bone, or in the medullary cavity. Soft-tissue hemorrhage that causes neurovascular compromise can also be evaluated with this modality. In particular, pathology in bone, such as an osseous pseudotumor, is well seen with CT scanning.

Degree of Confidence

Soft-tissue changes are better seen with MRI than with CT.

MRI

Section 6 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

Soft-tissue changes are depicted well on MRI, including joint effusion, hemarthrosis, synovitis, and hemosiderin deposition.

Degree of Confidence

MRI offers excellent soft-tissue contrast resolution and spatial resolution. Special techniques have been developed and are undergoing development to improve the visualization of articular cartilage.

False Positives/Negatives

Effusion and synovitis may develop from causes other than hemophilia, such as trauma or infection. In patients with PVNS, hemosiderin deposition may look exactly like that which is caused by hemophilia in a given joint. JRA can cause knee deformity in a way that is similar to that in hemophilia, and bleeding may cause ectopic ossification in the soft tissues that looks like posttraumatic myositis ossificans.

Masses are especially common in the pelvis. Starker described these masses as pseudotumors in 1918; they are seen in 2% of patients with hemophilia.²

The 3 forms of pseudotumor are intraosseous, subperiosteal (or cortical), and soft tissue. The intraosseous form is most common in the femur, pelvic bones, tibia, and hand bones; the lesions can be variably sized. The pseudotumor is usually well demarcated, but it may also be bubbly and destructive. The lesion may simulate malignancy such as that from Ewing sarcoma, metastasis, or infection because of the pseudotumor's aggressive appearance. The subperiosteal type leads to cortical atrophy, subperiosteal new-bone formation, and soft-tissue extension. This is seen most commonly in the fibula. The soft-tissue form of the mass is surrounded by a fibrous capsule and may cause deformity of the adjacent bone.

Regarding other findings, calcification in hemosiderin may simulate other calcified masses on MRIs. Chondrocalcinosis occurs more commonly in calcium pyrophosphate deposition disease or primary hyperparathyroidism than in hemophilia. Septic arthritis can develop in a child with hemophilia; this may be a problem in early diagnosis. Contracture of soft tissues around joints may cause impingement on blood vessels or nerves.

ULTRASOUND

Section 7 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

Soft tissues are seen well with ultrasonography. A mass that is suspected of being a joint effusion or a soft-tissue pseudotumor can be demonstrated quickly with this modality.

Degree of Confidence

If the acoustic window is adequate, the finding of a sonolucent mass on ultrasonography is highly suggestive of fluid. Mixed signal intensity is likely due to a soft-tissue mass, such as a hematoma.

False Positives/Negatives

• The inability to place the ultrasound transducer over the area of interest precludes scanning.
• Bone blocks the sound waves and limits the ability to see subchondral cysts and erosions.
• Cartilage cannot be adequately differentiated from bone.

NUCLEAR MEDICINE

Section 8 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

Bone scans are highly sensitive for detecting areas of increased osteoblastic activity; the scans are useful for surveying the entire skeleton for disease. Follow-up bone scans can be used to determine the effectiveness of a patient's treatment. Radioisotopes, such as phosphorus-32 (³²P), can be injected therapeutically into a joint to decrease the amount of bleeding/effusion.⁹

Degree of Confidence

Bone scans combine high sensitivity with low specificity. Therefore, a negative bone scan should exclude acute joint hemorrhage or synovitis.

False Positives/Negatives

The lack of specificity of bone scans makes it difficult to determine the exact cause of a positive bone scan. The findings are more helpful in the acute phase of the disease than at other times.

ANGIOGRAPHY

Section 9 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Findings

Before the development of MRI, there was a place for angiography, especially in the evaluation of pseudotumors. Currently, angiography is not used in the evaluation of musculoskeletal complications of hemophilia.

INTERVENTION

Section 10 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Aggressive treatment of hemophilia with factor VIII or factor IX replacement, sometimes on a prophylactic basis, is the current standard of care for this condition. Early factor replacement may prevent the later joint destruction that is so commonly seen in patients with hemophilia, and studies remain ongoing. Educating patients about the use of ports for intravenous infusion makes home care prophylaxis possible. Recombinant clotting factors have also been used to treat affected patients,⁷ but these factor-replacement treatments are expensive. An ongoing concern is the development of patient antibodies to the factor replacement; this occurs in about 20% of cases.⁷ Plasma-free factor derivatives have eliminated the AIDS risk in transfusions.

MRI is used to detect early hemophilic disease and to help direct the appropriate therapy.

Radioactive injections into joints (radiosynoviorthesis) can control hemorrhage. This treatment was initially used in cases of JRA. Subsequently, radiosynoviorthesis was shown to be effective in reducing bleeding and effusion in selected cases of hemophilic arthropathy.

Surgical total joint replacement is a valuable treatment for end-stage hemophilic disease. Soft-tissue pseudocysts may be drained percutaneously (with adequate factor replacement during the procedure); imaging may aid in needle placement for this procedure.

Gene therapy offers an appealing alternative for preventing transmission of this inherited disease, and research is under way for gene therapy as a means of eliminating the hemophilia genes.

Medical/Legal Pitfalls

• AIDS was a devastating complication of transfusion treatment in the 1980s. Once the causal association between tainted transfusions and HIV was recognized, the prevalence of transfusion-related AIDS diminished drastically.
• Surgical replacement of joints can lead to postoperative complications.
• Radionuclide synovectomy has a good record for low complication rates; however, there remains concern that the radiation exposure in young children could lead to radiation necrosis or tumor induction.

Special Concerns

• Many affected families recognize hemophilia as a condition that recurs regularly in their offspring, either as active disease or in the carrier state.
• • Making certain that such families have access to adequate medical care is a key public health concern.
  • Genetic counseling may be useful.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

Media file 1:  Knee radiograph in a 37-year-old man with hemophilia. This image shows moderate factor IX hemophilia. The bony excrescence on the lateral side of the femur is a hemophilic pseudotumor.
	View Full Size Image
Media type:  X-RAY

Media file 2:  Radiograph of the lower extremity of the 3-year-old daughter of the patient in Image 1. This image shows mild factor IX hemophilia with talar tilt. The girl not only inherited 1 diseased X chromosome from her father but also has Turner (XO) syndrome. The child's only X chromosome had the hemophilia gene.
	View Full Size Image
Media type:  X-RAY

Media file 3:  Magnetic resonance image from a patient with hemophilia. This image shows dark, synovial masses that erode the cartilage and produce subchondral cysts (arrows).
	View Full Size Image
Media type:  MRI

Media file 4:  Anteroposterior radiograph from a patient with hemophilia. This image demonstrates hemarthrosis with hemosiderin deposition. Note the irregularity of the articular surfaces and the presence of subchondral sclerosis with cysts. Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  X-RAY

Media file 5:  Lateral radiograph from the same patient as in Image 4. This image shows a large hemarthrosis that is distending the suprapatellar recess. Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  X-RAY

Media file 6:  Axial gradient-echo magnetic resonance image from a patient with hemophilia. This image demonstrates hemosiderin deposition in the synovium as hypointense material that outlines the joint capsule. Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  MRI

Media file 7:  Radiograph in a patient with hemophilia. This image depicts a pseudotumor that is deforming the cortex of the femur (arrow). Other ossified masses in the soft tissues (arrowheads) are probably soft-tissue pseudotumors.
	View Full Size Image
Media type:  X-RAY

Media file 8:  Sagittal magnetic resonance image of the ankle joint in a patient with hemophilia. This image shows extension of abnormal joint fluid from the ankle joint into the subtalar joint. Note the dark hemosiderin posterior to the subtalar fluid (arrow).
	View Full Size Image
Media type:  MRI

Media file 9:  Computed tomography scan of the pelvis in a patient with hemophilia. This image demonstrates a giant pseudotumor (a large expansile lytic lesion that involves the right iliac bone and extends into the sacrum, with inhomogeneous internal attenuation). Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  CT

Media file 10:  Axial T2-weighted magnetic resonance image of the pelvis. This image demonstrates a large pseudotumor of the pelvis with sacral extension. Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  CT

Media file 11:  Lateral elbow radiograph in a patient with hemophilia. This image shows an opaque joint effusion due to the presence of iron in the synovium (arrows).
	View Full Size Image
Media type:  X-RAY

Media file 12:  Radiograph of the ankle in a 20-year-old patient with hemophilia. This image shows the development of osteonecrosis (arrow) in the talar dome.
	View Full Size Image
Media type:  X-RAY

Media file 13:  Sagittal T2-weighted magnetic resonance image of the lower extremity in a patient with hemophilia. This image demonstrates hemosiderin-laden synovium with low signal intensity that outlines the capsule of the tibiotalar joint. Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  MRI

Media file 14:  Radiograph of the shoulder of a 35-year-old man with hemophilia. This image shows advanced degenerative joint disease. The infiltrate in the lung is due to a fungal infection as a complication of the patient's positive HIV.
	View Full Size Image
Media type:  X-RAY

Media file 15:  Radiograph of the leg in a patient with hemophilia. This image depicts stage III joint disease, as determined by the Arnold-Hilgartner classification.
	View Full Size Image
Media type:  X-RAY

Media file 16:  Radiograph of the leg in a patient with hemophilia. This image depicts stage IV joint disease, as determined by the Arnold-Hilgartner classification.
	View Full Size Image
Media type:  X-RAY

Media file 17:  Coronal T2-weighted magnetic resonance image of the knee in a patient with hemophilia. This image demonstrates pseudotumor of the knee, a lytic lesion in the lateral femoral condyle, as well as the characteristic manifestations of hemosiderin deposition in the knee joint and the subchondral cystic changes in the medial femoral condyle. Image courtesy of Javier Beltran, MD.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Multimedia
• References

1. Aronova-Tiuntseva Y, Herreid CF. Hemophilia: "The Royal Disease". National Center for Case Study Teaching in Science. Available at http://ublib.buffalo.edu/libraries/projects/cases/hemo.htm. Accessed August 30, 2007.
2. Resnick D. Diagnosis of Bone and Joint Disorders. 4^th ed. Philadelphia, Pa: WB Saunders Co; 2002.
3. Roosendaal G, Lafeber FP. Blood-induced joint damage in hemophilia. Semin Thromb Hemost. Feb 2003;29(1):37-42. [Medline].
4. Nuss R, Kilcoyne RF. Diagnosis by imaging of haemophilic joints. In: Rodriguez-Merchan EC, ed. The Haemophilic Joints: New Perspectives. Malden, England: Blackwell Publishing; 2003:24-9.
5. Pettersson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop Relat Res. Jun 1980;149:153-9. [Medline].
6. Arnold WD, Hilgartner MW. Hemophilic arthropathy. Current concepts of pathogenesis and management. J Bone Joint Surg Am. Apr 1977;59(3):287-305. [Medline]. [Full Text].
7. National Heart, Lung, and Blood Institute. Hemophilia. NHLBI Diseases and Conditions Index. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/hemophilia/hemophilia_all.html. Accessed August 30, 2007.
8. Bernabeu-Taboada D, Martin-Hervas C. Sonography of haemophilic joints. In: Rodriguez-Merchan EC, ed. The Haemophilic Joints: New Perspectives. Malden, England: Blackwell Publishers; 2003:30-5.
9. Nuss R, Kilcoyne RF, Geraghty S, et al. MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia. May 2000;6(3):162-9. [Medline].
10. Doria AS, Babyn PS, Lundin B, et al, for the Expert MRI Working Group of the International Prophylaxis Study Group. Reliability and construct validity of the compatible MRI scoring system for evaluation of haemophilic knees and ankles of haemophilic children. Haemophilia. Sep 2006;12(5):503-13. [Medline].
11. Jorge Filho D, Battistella LR, Lourenço C. Computerized pedobarography in the characterization of ankle-foot instabilities of haemophilic patients. Haemophilia. Mar 2006;12(2):140-6. [Medline].
12. Kilcoyne RF, Lundin B, Pettersson H. Evolution of the imaging tests in hemophilia with emphasis on radiography and magnetic resonance imaging. Acta Radiol. Apr 2006;47(3):287-96. [Medline].
13. Lundin B, Berntorp E, Pettersson H, et al. Gadolinium contrast agent is of limited value for magnetic resonance imaging assessment of synovial hypertrophy in hemophiliacs. Acta Radiol. Jun 2007;48(5):520-30. [Medline].
14. Pergantou H, Matsinos G, Papadopoulos A, Platokouki H, Aronis S. Comparative study of validity of clinical, x-ray and magnetic resonance imaging scores in evaluation and management of haemophilic arthropathy in children. Haemophilia. May 2006;12(3):241-7. [Medline].
15. Zukotynski K, Jarrin J, Babyn PS, et al. Sonography for assessment of haemophilic arthropathy in children: a systematic protocol. Haemophilia. May 2007;13(3):293-304. [Medline].

Article Last Updated: Mar 21, 2008