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Hemophilia-associated arthritis
Key Points
Hemophilia
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Hemophilia is an X-linked inherited bleeding disorder caused by a deficiency of factor VIII (hemophilia A) or IX (hemophilia B).
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Bleeding occurs either spontaneously or with minor trauma. Recurrent hemarthroses can lead to progressive arthritis, particularly affecting the ankles, knees, and elbows.
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Treatment involves adequate factor replacement. Prophylactic treatment from a young age is beneficial in preventing hemorrhage and preserving joint function.
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Chemical or radioactive synoviorthesis is effective treatment of recurrent bleeding and synovitis. Joint replacement or fusion is beneficial for the treatment of chronic, severe arthritis.
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Viral transmission of bloodborne viruses is virtually eliminated with the use of recombinant factor.
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Inhibitor development occurs in about 30% of patients with hemophilia A and 5% of patients with hemophilia B and is associated with worse joint outcomes and quality of life.
Von Willebrand Disease
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von Willebrand disease is the most common of the inherited bleeding disorders.
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It is caused by a deficiency in von Willebrand factor and characterized by mucocutaneous bleeding.
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Severe forms are associated with hemarthroses and arthritis similar to patients with hemophilia.
Hemophilia
History
The term hemophilia (Greek: “love of blood”) is attributed to Schönlein in 1818, although his pupil Hopf first referred to it in a dissertation. The disease was well recognized and documented by Jewish religious writers in the 5th century ad because of the hazards of circumcision in hemophilic infants. Albucasis, who documented the deaths of men and boys in a certain Spanish village from uncontrollable hemorrhage after trivial wounds and bleeding, recorded the first published medical recognition of the disorder some 500 years later.
Joint disease secondary to chronic intraarticular bleeding was increasingly noted from the early 19th century onward. Elucidation of the underlying coagulation defect and the advent of effective clotting factor replacement during the 20th century revolutionized the management of hemophilia in general and allowed the potential prevention of joint disease and surgical correction of established deformity. Early therapeutic optimism with human-derived blood products was tempered by the high incidence of bloodborne virus infection in patients treated with blood products, particularly in the 1980s. The next major therapeutic breakthrough was the development of recombinant factors that remove the risk of infection, but they remain expensive and do not eliminate the need for frequent infusions. More recent therapeutic advances are detailed later in the chapter.
Epidemiology
Hemophilia A has an incidence of 1 in 5000 and hemophilia B an incidence of 1 in 30,000 male births. The distribution of both is generally uniform throughout the world, and there are no obvious associations with human leukocyte antigens. Because they are both inherited as X-linked recessive disorders, they are seen almost exclusively in men. Symptomatic hemophilia may occur in carrier (heterozygote) females as a result of nonrandom lyonization or in 50% of female offspring born to affected fathers and carrier mothers.
Classification
Primary hemophilia refers to an inherited deficiency of any of the coagulation factors involved in hemostasis. The most well-known are deficiencies in factors VIII (hemophilia A) and IX (hemophilia B).
In secondary hemophilia, factor deficiencies are caused by decreased synthesis, increased clearance, or destruction of clotting factors. The most common mechanism is antibodies (inhibitors) directed against factor VIII, although antibodies can develop to other factors, such as IX, X, or von Willebrand factor (vWF). In 50% of cases, no underlying pathologic process is identified. Autoantibodies can develop postpartum or be associated with a range of diseases, most commonly autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders. They also associate with skin diseases, lymphoproliferative disorders, other malignancies, and drugs. The clinical features are similar to those of inherited hemophilias.
Etiology
Bleeding in hemophilia is caused by failure of secondary hemostasis. Formation of the platelet plug (primary hemostasis) is normal, but stabilization of the plug by fibrin is abnormal because of inadequate thrombin generation. An overview of the coagulation cascade relevant to hemophilia and von Willebrand disease (vWD) is provided in Fig. 210.1 .
Hemophilia A and hemophilia B are both inherited as X-linked recessive traits. The factor VIII (F8) gene is situated on the long arm of the X chromosome and is made up of 26 exons spanning 186 kb. It is a large gene and constitutes around 0.1% of the X chromosome. The factor IX (F9) gene is also situated on the long arm of the X chromosome, made up of eight exons spanning 33.5 kb. Genetic analysis is recommended in all patients to establish the causative mutation. The most common mutations in the F8 gene are inversions of intron 22 (the “flip-tip” mutation found in approximately 40%–45% of patients with severe hemophilia A) and intron 1 (found in 1%–6% of patients with hemophilia A). More than 2000 other unique molecular defects in F8 have been described. Similarly, molecular characterization of the F9 gene has revealed over 1000 unique variants so far. Next-generation sequencing is providing enhanced opportunities to characterize molecular defects, particularly in patients whose molecular defect has yet to be determined (as occurs in approximately 2%–17% of patients with hemophilia A).
Knowledge of the causative gene mutation has increased the accuracy of carrier detection and prenatal diagnosis within families and has made genetic counseling more accurate. Fetal gender can now be determined by the detection of free fetal DNA after 9 weeks’ gestation in maternal blood, an important early step when screening for X-linked disorders. An alternative to conventional prenatal diagnosis is preimplantation genetic diagnosis, which provides couples with a known transmissible genetic disease the possibility to start a pregnancy with the knowledge that their child will be unaffected.
Von Willebrand Disease
von Willebrand disease (VWD) is the most common of the inherited bleeding disorders and occurs in approximately 1% of the population. Many of these individuals do not come to clinical attention because they fall towards the mild end of the disease spectrum. VWD is caused by a deficiency in VWF, which has an important role in both primary hemostasis and formation of the fibrin plug. VWF binds to both platelets and the endothelium at sites of injury and forms an important bridge to aid in platelet clotting. It is also bound to factor VIII as a carrier protein. In the absence of VWF, factor VIII has a markedly reduced half-life.
In type 1 VWD, there is a partial deficiency of VWF, in type 2 a functional VWF deficiency and in type 3, the most severe phenotype, virtually a complete absence of VWF. The inheritance is variable depending upon subtype. More severe forms of VWD can result in recurrent joint hemorrhages, and between 2% and 30% of patients develop arthritis indistinguishable from patients with hemophilia. The general treatment approach is similar to hemophilic arthritis.
Hemophilic Arthritis
Clinical Features
Mild, moderate, and severe forms of the hemophilias are defined by plasma coagulation factor levels corresponding to <40%, <5%, and <1% of normal, respectively. Hemophilic arthritis is the most important cause of morbidity in patients with severe hemophilia. Bleeding into muscle occurs at about one tenth of the frequency of joint hemorrhages.
Some female carriers of the hemophilia genes have relatively low factor levels and may have problems during menstruation and with hemostasis during surgery and dental extractions, but bleeding into joints rarely occurs.
Acute hemarthrosis
Acute hemarthrosis is the initiating event in hemophilic arthritis and occurs spontaneously or in response to minor trauma with severe or moderate disease. Patients often describe a tingling sensation and tightness in the joint preceding the clinical signs of hemarthrosis. The joint then rapidly loses range of motion and becomes acutely painful, warm, and swollen. Rising intraarticular pressure eventually terminates the bleeding, and resolution of symptoms occurs slowly, accompanied by bruising. Milder bleeding episodes may manifest less dramatically and be limited to the subsynovium or go unrecognized.
The age at first bleeding episode and the subsequent frequency of acute hemarthroses depend mainly on the extent of the factor deficiency. Levels of 5% of normal or less are almost invariably associated with recurrent hemarthroses, although established arthritis may occur even with levels up to 20%. Weight-bearing joints on the dominant side are more commonly affected, coincident with the child beginning to walk. The joints traditionally affected in decreasing order of frequency are those of the knees, elbows, and ankles. However, prophylactic factor replacement has induced a changing pattern of joint involvement, with the ankle surpassing the knee as the most common site of bleeding. Avascular necrosis of the femoral head as a result of hemorrhage into the hip joint may also occur, with the clinical and radiologic features resembling those of Perthes disease.
Differential diagnosis of acute hemarthroses
Occasionally, musculoskeletal hemorrhage is the first indication of the underlying condition, which if not recognized, can result in major morbidity or mortality. In this event, the differential diagnosis includes other causes of hemarthrosis, such as intraarticular fractures, other bleeding diatheses such as platelet deficiencies or anticoagulant therapy, blood dyscrasias, villonodular synovitis, acute inflammatory arthritides, and joint neoplasms.
Subacute arthritis
Subacute arthritis can follow repeated hemarthroses occurring in one or several joints—the “target joint.” A target joint is defined as a joint in which three or more spontaneous bleeding episodes have occurred within a consecutive 6-month period. A persistent boggy synovitis with synovial thickening, chronic joint effusion, and variable levels of pain, in the absence of recent hemorrhage, is seen. Muscle weakness and joint laxity contribute to further bleeding from the hyperemic, thickened synovium, which results in continuing damage. The hyaline articular cartilage is progressively eroded by the inflammation associated with iron deposition. Ultimately, deep pits filled with friable blood clot occur in the cartilage, along with a surviving plateau of less damaged articular cartilage. Subarticular cyst formation is common, and cartilage collapse may result in large bony defects.
Chronic arthritis
The end result of repeated acute episodes of bleeding, after several months to years, is a disorganized joint exhibiting bony thickening, deformity, loss of movement, and coarse crepitus as a result of the loss of articular cartilage and sclerosis of subchondral bone. Joint contracture secondary to fibrosis or ankylosis is common. Soft tissue swelling and effusions are rare at this stage, and pain is fluctuating and variable but at times can be severe.
Non–Joint-Related Disorders
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