1 Musculoskeletal disorders in the haemophilias JOHN

ROBERT

YORK

THE H A E M O P H I L I A S AND RELATED DISEASES

Although haemophilia has a low prevalence in most communities variably recorded as up to 10:100000 (Rizza and Spooner, 1983) this uncommon disorder is of increasing importance because of its most frequent complication, musculoskeletal haemorrhage (Houghton, 1982). Not only does intra-articular haemorrhage particularly if repeated result in a devastating deforming arthritis, but the pathogenesis of the associated synovitis may ultimately shine light on mechanisms of joint damage in other forms of inflammatory arthritis notably rheumatoid arthritis (RA) (Steven, 1984). Haemophilia is inherited as a sex-linked recessive trait. It occurs in two forms, classical haemophilia A (factor VIII deficiency) and haemophilia B or Christmas disease (factor IX deficiency) so named after the first British patient in whom it was described (Biggs et al, 1952). Haemophilia B has a slightly reduced frequency of chronic joint disease at equivalent factor levels compared with haemophilia A the reason being unknown (Steven et al, 1986). As haemophitia A is nine times as prevalent in the population as haemophilia B (Chorba and Evatt, 1987) it is by far the most common cause of haemophilic arthropathy. Von Willebrand's disease (von Willebrand, 1926) is a closely related autosomal dominant disorder with an abnormality of factor VIII-related antigen as well as platelet function. Joint bleeding is less frequent than in the haemophilias due to higher levels of coagulant activity. The risk of joint bleeding in all these conditions in general parallels the level of the deficiency, remains constant in the individual and breeds true in families. Deficiencies in several other clotting factors for example factor XI (haemophilia C), factor XII (Hageman factor) and other single clotting factors have been described but are exceedingly rare. Factor VIII antibodies resulting in acquired haemophilia have been reported in otherwise normal individuals (Green et al, 1980) and in patients with underlying diseases most frequently RA (Herbst et al, 1981). BLOOD COAGULATION The bleeding disorder in haemophilia is due either to factor VIIIc or IXc BailliOre's Clinical Rheurnatology--

Vol. 5, No. 2, August1991 ISBN0-7020-1536-9

197 Copyright9 1991,byBailli6reTindall All rights of reproductionin any formreserved

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I.R. YORK INTRINSIC PATH Surface contact

x, &l i-I xl &l l

EXTRINSIC PATH & Ca**

PO,0o,,,0Jl[J

Tissue Thromboplastin VII Ca +*

COMMON PATHWAY

]

] Activated

factor

THROMBIN

l

I ---~ FIBRIN

Figure 1. The blood coagulation (clotting) cascade. deficiency which interferes with the intrinsic pathway of coagulation (Figure 1). The factor VIIIc molecule specified on the X chromosome circulates non-covalently bound to the high-molecular-weight factor VIII-related antigen of which von Willebrand factor is a component. Factor IX circulates on a single-chain glycoprotein and both factors IXc and IX Ag can be measured. Both factors VIIIc and IXc are involved in the mid-phase of coagulation in activation of factor X and are synthesized in the liver (Webster et al, 1971; Lewis et al, 1985).

GENETICS A single gene disorder such as haemophilia A or B may result from a gene deletion; or a point mutation resulting in the synthesis of an inactive molecule. Attempts to detect such molecules have produced conflicting results. A reasonable interpretation of the findings is that the functional defect in mild to moderate haemophilia is due to the presence of a defective molecule, which is absent in the vast majority of severe haemophiliacs (Madhok, 1989). The sex-linked recessive mode of inheritance of haemophilia results in all the sons of a haemophilic father being normal as they receive his normal Y chromosome whereas his daughters who all receive his abnormal X chromosome are obligatory disease carriers. Where a female carrier marries a normal man, 50% of their sons may be haemophiliacs and 50% of daughters carriers. In the very rare situation where a haemophilic man marries a female carrier there is a 1 in 4 chance of the birth of a homozygous haemophilic female. The first report of such a case resulting from a consanguinous marriage was published by Sir Frederick Treves (1"886). Some

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female carriers have significantly lowered levels of factor VIII or IX and may suffer from excessive bleeding after surgical procedures, or menorrhagia, but joint haemorrhage is uncommon. Haemophilia has one of the highest rates of spontaneous mutation recorded in any of the inherited diseases (Arnold and Hilgartner, 1977) with spontaneous rates of up to 25% despite meticulous family studies to detect any previous haemophiliacs or carriers (Ramgren et al, 1962). Phenotypic carrier screening is available in many centres, but apart from obligatory carriers, it is not possible to determine with absolute certainty whether or not a particular woman is a carrier and provides only a probability of carrier status. Genotypic identification is now possible using two recently developed techniques. Normal polymorphic deoxyribonucleic acid (DNA) variations within or close to a particular gene can act as markers for a normal gene. They are detected using specific DNA probes and Southern blotting techniques after restriction enzyme digestion. Direct gene defect detection, more advanced in the identification of haemophilia B and previously a very tedious procedure has been made practicable by DNA amplification using the polymerase chain reaction (Graham, 1990). Fetoscopy and fetal blood and chorionic villus sampling are available in several highly specialized centres throughout the world enabling prenatal detection and providing the option of termination. However, these advances have not solved the ethical dilemma for parents and the young female relatives of a haemophiliac and genetic counselling should preferably be undertaken with young people in their late teens and early 20s and at all stages of any developing relationships. HISTORY

The name haemophilia (Greek: love of blood) is attributed to the German physician Sch6nlein but was first recorded by his pupil Hopf in a dissertation at Wurzburgh in 1828 (Forbes, 1972). The earliest references to a bleeding disorder affecting males and transmitted by females occurred in Jewish religious literature in the fifth century AD (Rosner, 1969). The circumcision of a woman's third son was forbidden if her two older sons had died of haemorrhage after circumcision on the authority of Juda the Patriarch in the second century AD. Circumcision was also forbidden for the son of a woman if the sons of three of her sisters had died of haemorrhage (Seligsohn, 1973). Maimodes extended this in the twelfth century to the sons of a woman's second marriage if the sons of the first marriage had died of haemorrhage; in all an interesting example of preventive medicine occurring long before haemophilia came to the attention of physicians. The first medical author to record hereditary haemorrhagic disease was Khalif Ibn Abbas, commonly known as Albucasis (Legg, 1872). He was a Moorish surgeon who lived in the eleventh century and documented the deaths of men and boys in a certain Spanish village from uncontrollable haemorrhage after trivial wounds and bleeding.

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Bulloch and Fildes (1912) attributed the earliest European report of a family with definite haemophilia to Consbruck (1793). In 1803, Dr John Otto a young physician in Philadelphia published details of a Plymouth, New Hampshire, family with a bleeding disorder clearly due to haemophilia (Otto, 1803). In England the first report of haemophilia was published by Blagden (1817) who described a boy suffering from recurrent bleeding problems finally succumbing after a dental extraction despite carotid artery ligation. Interestingly, the first Scottish report by Davis (1826) noted the presence of swollen joints and severe rheumatic pains in one of the affected male members of a haemophilic family. Sporadic case reports of uncontrollable bleeding, some of which would have been due to haemophilia continued to appear and several authors published reviews of the condition confirming the pattern of inheritance (Nasse, 1820; Grandidier, 1855). Lane (1840) was the first to report the successful use of a blood transfusion in a haemophiliac bleeding postoperatively but this therapy was apparently not used again until the twentieth century. Joint and soft tissue involvement were noted in subsequent reports, Dubois (1838) suggesting without proof that joint swelling was due to intra-articular blood, this speculation being confirmed by Poncet (1871) in a report of the pathology found in a boy who died of haemorrhage after a swollen knee joint was incised. Legg (1872) in his monograph on haemophilia described the major clinical features of haemophilic arthropathy and the frequency of knee and elbow involvement. Forty years later Bulloch and Fildes (1912) published a comprehensive review and bibliography clearly defining the role of the healthy carrier and male expression of the disease. The occurrence of an apparent spontaneous mutation affecting Queen Victoria of England and the transmission of haemophilia from her affecting the Royal families of Prussia, Russia and Spain during the late nineteenth and twentieth centuries added a fresh incentive to research into the disease. This chance event also played a significant part in the socio-political developments of the era, especially in Russia as the young tsarevich, Queen Victoria's great-grandson was a severe haemophilic. The events leading up to the Russian Revolution and the fall of the tsars were undoubtedly influenced by parental despair and contemporary therapeutic impotence. The basic coagulation defect in the haemophilias was progressively defined following Wright's (1898) demonstration that the clotting time of haemophilic blood was prolonged. Antihaemophilic globulin (later termed factor VIII) was isolated by Patek and Taylor in 1937 and factor IX identified in 1952 (Aggeler et al, 1952; Biggs et al, 1952). With the advent of factor VIII and IX concentrates in 1966, elective surgery was undertaken much more commonly, especially for bone and joint disease. Jordan (1958) in his monograph on haemophilic arthritis advocated treatment with splinting and other conservative orthopaedic techniques but since then extensive series of surgically treated orthopaedic problems have been published, from the UK and USA including joint replacement procedures (Duthie et al, 1972; Post and Telfer, 1975; Luck and Kasper, 1989).

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The acquired immune deficiency syndrome (AIDS) epidemic tempered the increased enthusiasm for surgical treatment but with the relative safety of currently available blood products momentum is being regained. Over the last decade, monumental advances in molecular biology and the development of gene probe techniques have resulted in the isolation and cloning of the factor VIII gene and more recently for factor IX (Chorba and Evatt, 1987). This has resulted in the production of synthetic factors VIIIc and IXc and also allowed more accurate mapping of the underlying genetic defects in the haemophilias. HAEMOPHILIC ARTHROPATHY The acute haemarthrosis The initiating event in haemophilic arthropathy is joint haemorrhage, frequently occurring spontaneously or in response to minor trauma. The occasional occurrence of established haemophilic arthropathy in a joint not previously the site of a recognized acute bleeding episode indicates that subclinical haemorrhage limited to the synovium can occur. However, intra-articular haemorrhage is usually clearly apparent with prodromal stiffness then acute pain, warmth and swelling. Untreated, the pain can be agonizing due to the increased intra-articular pressure which eventually terminates the bleeding and also to the irritating effect of blood within the joint. The pain and swelling, accompanied by bruising gradually resolve over several weeks. The age of onset and frequency of acute haemarthroses depend mainly on the severity of the factor deficiency (Figure 2). The site of joint bleeding and subsequent joint disease is determined by many factors such as weight-bearing (the knee is the most commonly involved joint) and initial episodes often coincide with the child beginning to walk. It is of relevance that synovium is deficient in tissue thromboplastin

HAEMOPHILIA

SEVERITY FACTOR LEVEL ( % NORMAL) 1

SEVERE (50% of cases)

1-5

MODERATELY SEVERE

5-20

MODERATE

FREQUENCY OF HAEMOARTHROSES JOINT INVOLVED KNEE ELBOW ANKLE SHOULDER HIP OTHER

20-60 MILD

Figure 2. Severityand frequencyof joint involvement.

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(Astrup and Sjolin, 1958) contributing to the predilection to joint haemorrhage. The type of joint is also important (stable ball and socket versus hinge type) as is the level of physical activity and any altered joint alignment due to progressive disease. It is in general more common on the dominant side and where neurological damage has occurred it may spare the paralysed side.

Subacute arthropathy The onset of the second or subacute stage of the disease usually becomes apparent after repeated haemarthroses, one or several target joints often emerging in which bleeding is frequent. Clinically these joints exhibit a 'boggy synovitis' with persistent synovial thickening, moderate joint effusion and usually less severe pain unless there has been recent haemorrhage. Muscle wasting occurs early on and minor ligamentous laxity is common but crepitus is surprisingly rare and the range of joint motion generally well preserved. Muscle weakness and joint laxity predispose the joint to further mechanical stresses and this together with the friable nature of the vascular synovium leads to further haemorrhage thus creating a vicious cycle of events. Whilst prompt and adequate treatment has greatly reduced the incidence there is unfortunately as yet no convincing documented evidence that it can prevent this stage and consequent chronic joint disease. Our experience in Sydney has,indicated that in some instances progressive damage has occurred despite intensive home-based therapy or prophylactic factor replacement therapy. An extensive prospective orthopaedic outcomes study relating factor VIII usage to orthopaedic outcomes has been in progress now for five years and may result in the development of optimal therapeutic regimens (Aledort, 1990).

Chronic arthropathy After a variable period, usually measured in years but on occasions more rapidly, the soft tissue swelling slowly resolves, the effusions resorb and bony thickening, deformity, loss of movement and coarse crepitus supervene. At this stage pain may become less prominent although this is by no means inevitable, and pain and post-exercise stiffness may be severe in weight-bearing joints. Rarely spontaneous fibrosis or bony ankylosis may occur, more commonly seen in the ankle and between the patella and femur. This stage of chronic arthropathy often coincides with the achievement of adulthood. There has been considerable speculation as to whether this resolution of the inflammatory changes indicates a reduced tendency to bleed or a more sedate lifestyle (Guenther et al, 1980).

PATHOPHYSIOLOGY The pathophysiology of hacmophilic joint disease is incompletely understood although clinically recognizable intra-articular bleeding is almost

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invariably the initiating event9 Repeated intra-articular injections of blood into both canine (Convery et al, i976) and rabbit (Madhok et al, 1988) joints produced synovial changes resembling those seen in haemophilia, including lining cell hyperplasia and hypertrophy, macrophage infiltration and haemosiderin deposits9 The changes seen in spontaneous canine haemophilia more closely resemble human disease with softening, pitting and erosion of the joint cartilage and the development of subchondral cysts (Swanton, 1959)9 In early studies of the pathology of haemophilic joints it was noted that there were features in the synovium resembling RA; and in the cartilage and adjacent bone resembling osteoarthritis. Konig (1892) described the synovial changes as follows, as recorded by Steven (1984): the great number of brownish synovial tufts was particularly noticeable the somewhat thickened synovialis was found, as if covered by moss. In water the strange brown, soft tufts standing close together, gave the impression of a Medusa h e a d . . , the entire synovialis.., became red-brown . . . . 9

On light microscopy the synovial changes are reminiscent of RA but the villi are thinner and more filamentous. There is thickening of the lining cell layer and mononuclear cell infiltration of the stroma and 'angiomatoid' proliferation of the capillaries. The inflammatory cell infiltrate is largely perivascutar but with less tendency to form lymphoid aggregations. The thickened lining cell layer contains brownish granules of haemosiderin which are also present within the stroma and stain prominently for iron. Ultrastructural studies using electron microscopy have demonstrated red cell phagocytosis by synovial cells in rabbits and humans. Siderosomes and free electron dense deposits are visible in the cytoplasm of synovial cells with hyperplasia of intermediate and type B cells and signs of increased metabolic activity (Roy and Ghadially, 1967). Stein and Duthie (1981) examined tissue removed from haemophilic joints at surgery and showed chondrocyte necrosis, more marked in the deeper layers of cartilage in association with iron deposition. In both haemophilic and rheumatoid arthritis, iron is mainly deposited as ferritin and Blake et al (1981) have hypothesized that its presence in RA may be of importance in both causing and maintaining the chronic inflammation. The amount of ferritin present in synovial fluid has also been shown to correlate with other measures of disease activity in RA (Blake and Bacon, 1981)9 The generation of toxic products of oxygen in the synovium such as superoxide anion and hydroxyl radicles by reduction-oxidation reactions involving iron is capable of destroying cell membranes by lipid peroxidation and could be a common mechanism in both conditions. Further investigation of the cellular pathology in haemophilic synovium may thus contribute to our understanding of the pathology in RA. The actual site of iron deposition differs in the two conditions being mainly subsynovial in RA but synovial, subsynovial and within chondrocytes in haemophilia. This observation may simply reflect the source and quantity of phagocytosed red cells arising from the synovial cavity in haemophilia but from intrasynovial vessels in RA. As haemophilic arthritis may

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rarely follow bleeding apparently limited to the synovium the geographic differences in iron deposition may not be significant. Similarities between the two diseases are also apparent in the production of inflammatory chemical mediators by the synovium. Mainardi et al (1978) demonstrated production of latent collagenase and other proteolytic enzymes in tissue cultures obtained from surgical specimens of haemophilic synovium and Steven (1984) showed levels of cathepsin D comparable to those in the most active cases of RA. Prostaglandins have also been implicated in the inflammatory process (Robinson and Granda, 1974). It is apparent that the presence of intra-articular and intra-synovial blood results in synovial inflammation with high levels of proteolytic enzymes and that these changes are likely to be of importance in both haemophilic and rheumatoid synovitis. Elevated lymphokine levels such as interleukins (IL) 6 and 1 in both blood and synovial fluid have been demonstrated in R A and may play a part in the inflammation of haemophilic arthritis. Other possible contributing processes that have been advanced include: autoimmune-induced inflammation either due to antibodies against red cell membranes (Arnold and Hilgartner, 1977) or immune complexes raised in response to infused blood products (Hilgartner, 1982). Increased fibrinolysis due to substances produced in the hypertrophic haemophilic synovium (Storti et al, 1971) may cause continued bleeding as well as having a direct damaging effect on articular cartilage (Lack and Rogers, 1958). The effects of anticoagulant antibodies demonstrated in small quantities in the synovium from both rheumatoid and haemophilic joints could conceivably contribute to both disease processes (Rainsford et al, 1982). Konig went on to describe changes in the joint cartilage (Konig, 1892; Steven, 1984): 9 it has lost its white colour and its shine; it is discoloured red-brown or grey-brown. In odd places the cartilage has a fibrous mass which shows a tendency to form connective tissue . . . . However the truly characteristic changes consist in the strangely sharp edged defects, advancing as on a land map, small and big, deep in the joint and on the surface, with gnawing defects to the cartilage, in various spots of the joint but mostly at the same places where the fibrous deposits are found.

Cyst formation is a prominent feature due to either intraosseous haemorrhage or 'geode' formation through minor defects in the articular cartilage and subsequent collapse of these defects adds to the joint damage. The progressively severe erosive changes in the cartilage secondary to synovial inflammation and dense fibrous pannus formation finally result in joint disorganization and loss of function, aptly described by J. Vernon Luck Snr as arthrofibrosis (Luck and Kasper, 1989). IMAGING X-ray and ultrasound

The characteristic radiological changes in haemophilic arthropathy are

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listed below. Many are not specific and occur in other arthropathies, especially those of childhood and most notably in juvenile chronic arthritis. Early 9 peri-articular soft tissue swelling 9 peri-articular demineralization 9 increased radiodensity of thickened synovium* Intermediate 9 Harris (growth arrest) lines 9 epiphyseal widening and/or premature fusion 9 widening of femoral and humeral intercondylar notches* 9 squaring of inferior border of patella--lateral view 9 proximal radial head enlargement* 9 ankle deformities--tibiotalar slant --flattening of talus Late 9 cartilage irregularity and narrowing, central and marginal erosions 9 incongruity of joint surfaces 9 sub-articular sclerosis and osteophyte formation 9 sub-articular bone cysts 9 subluxations, joint disorganization 9 bony ankylosis (* considered to be specific for haemophilic arthroplasty) Changes in the femoral head similar to those seen in Perthe's disease are occasionally seen (Middlemiss, 1960) presumably due to ischaemic necrosis resulting from intracapsular or intraosseous haemorrhage and similar changes may occur in the talus. Chondrocalcinosis has been described in several cases of haemophilic arthritis (Jensen and Putman, 1977; Leonello et al, 1981) introducing intriguing complexities into the aetiopathology of the arthropathy, on the one hand in its relationship to iron metabolism and haemochromatotic arthropathy and on the other to the reported destructive potential of intra-articular calcium pyrophosphate dihydrate crystals in certain circumstances (Richards and Hamilton, 1974; McCarty, 1976). Several classifications have been proposed to grade the degree of X-ray change (Arnold and Hilgartner, 1977; Pettersson et al, 1980; Ahlberg et al, 1981; Steven et al, 1986). Most seek to define a stage at which the changes within the joint are still potentially reversible to the extent of preserving reasonable to good joint function. In some instances a score taking into account both radiological and clinical findings has been assigned by which to assess and compare severity. Computerized tomography is useful in the detection of bleeding in and around the hip joint where recognition is vital in young children and in the definition of pseudotumours. Ultrasonic examination is of value in assessing muscle haematomata and cysts. Joint scanning Radionuclide joint scanning using technecium (Te-99m) polyphosphate is a

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sensitive technique to detect the presence of joint involvement in haemophilia and may be of value in the assessment of treatment outcomes (Steven et al, 1985a). It is clearly of value in detecting the disease in previously demonstrated normal joints but the non-specific increased uptake seen in joints with secondary degenerative changes makes the assessment of progression of disease in an affected joint with this modality difficult. In vivo blood pool scanning with 99mTe pertechnetate labelled red cells following pretreatment with stannous polyphosphate has been advanced as a sensitive method to detect recurrent joint bleeding and differentiate the resultant pain from that due to chronic arthritis (Green et al, 1981). As this important and frequently encountered dilemma has bearing on the quantity and cost of annual factor replacement requirement in an individual, the differentiation has considerable relevance. However, the logistics of the procedure and the consequent delay in therapy make it an impractical technique other than in a research setting, although the facilities are available in most haemophilia treatment centres. The increasing popularity of home-based therapy in long-term treatment also discourages its use. Magnetic resonance imaging Magnetic resonance imaging (MRI) has introduced an exciting new dimension into the non-invasive examination of the joint. It is considered by many to be superior to arthroscopy where surgical intervention is not required as it demonstrates the anatomy of areas of the joint not normally accessible to the arthroscope. LABORATORY INVESTIGATIONS No consistent abnormalities in the standard laboratory investigations performed in arthritic disease have been demonstrated in haemophilic arthritis. In a large series of 139 cases of haemophilia (Steven et al, 1986) mild anaemia was noted in 19% but in only 4 was the haemoglobin below 11 g/dl in each case following recent haemorrhage. Ten patients had an elevated ESR (greater than 22 mm/h) but in only four was it above 40 mm/h, all in relation to recent haemarthroses. Rheumatoid factors in any titre were found in 17% of patients but only 4 had significant titres (> 1:32), 2 of whom were considered to have rheumatoid arthritis in addition to their haemophilia. Non-significant titres of rheumatoid factor and non-specific elevation of the ESR were more prevalent with increasing age but there were no other clinical correlations. No other particular autoantibody associations were apparent, although minor abnormalities of immunoglobulin levels were noted. In a significant minority of cases lowered complement levels suggested complement consumption. HLA status Steven (1984) also performed a detailed family study to determine the possible effects of HLA type on the development of haemophilic arthro-

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pathy and showed that haemophilic arthritis was present in sons with different paternal and maternal genotypes providing no evidence for a strong HLA association with the joint disease. In a study in Sydney (York et al, 1982) complete HLA typing was performed on 43 haemophilic patients with chronic arthropathy and 10 without significant arthropathy. No significant HLA associations were apparent in the group with joint disease and in particular there was no increase in the HLA DR4 antigen. However, the control group without arthritis was small and it is possible that some protective association with HLA type was not detected. TREATMENT The aim of treatment in haemophilia is to correct the defect in the intrinsic coagulation pathway and thus to allow normal haemostasis to occur. The first principle is to obtain prompt control of bleeding, in this context musculoskeletal haemorrhage and thereby to provide relief of symptoms, prevention of progression of disease and the maintenance of joint function. The second principle is to educate the haemophiliac and his family about the disease. While AIDS has introduced totally unforeseen and devastating new dimensions into comprehensive haemophilia care the principles remain the same.

Team management These principles are best implemented in a haemophilia treatment centre providing expert medical haematological care and laboratory support and an associated integrated team of people from other medical disciplines and allied health professions. The key person in most centres is the haemophilia nursing sister who is ideally the first point of contact for patients. Inevitable delays in most general emergency departments make them a less satisfactory alternative primary contact and a lack of staff experienced in haemophilia care may result in suboptimal management. Other medical specialties represented in the team should include orthopaedic and general surgery, rheumatology, rehabilitation and immunology. However, all branches of medical and dental care will be required at some time at the centre. Physiotherapists play an important role in the management of musculoskeletal problems at all stages of the disease but especially in the post-operative care after orthopaedic procedures such as joint replacement. Counselling is a vital part of the centres' activity and is often a shared responsibility between nursing and medical staff, social workers and liaison psychiatrists. Recently there has been an ever-increasing need for intensive counselling for AIDS sufferers and their families. Both the local haemophilia associations and the World Federation of Haemophilia are involved in education, research and treatment evaluation. The latter body has an important coordinating function as well as setting up training programmes in less well developed countries and organizing international workshops and conferences. These general principles can then be

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applied to the management of haemophilic arthritis at each of its described stages although there is in practice considerable overlap between them. Acute haemarthrosis

The recognition of the subtle prodromal symptoms of bleeding either by the patient or in the young child by his parents is very important so that treatment can be instituted at once. The acute haemarthrosis requires prompt and adequate replacement therapy to raise levels of the appropriate factor to about 30 i.u./dl (30%) in most instances stopping further bleeding. Further treatment may be required before physiotherapy for several days. In most developed countries heat-treated lyophilized factor VIII or IX concentrates are available and can be re-constituted with sterile water and infused. Simple formulae utilize body weight as the multiplication factor where it is assumed that each i.u. of factor VIII or IX infused per kilogram body weight raises plasma factor VIII or IX levels by 2 i.u./dl or 2%. More accurate prediction of the amount of factor VIII or IX required can be calculated from the estimated blood volume, available in published tables and in more critical situations, such as during surgery and the immediate post-operative period, this accuracy is essential (Table 1). Recent published observations suggest that surface area is also critical in dose calculations. Table 1. Replacementprotocols.

Indication for treatment Haemarthrosis Haematoma Surgery Prophylaxis

Factor VIII or IX elevation (units/100ml) 30 30 100 50 30

Frequency/ day 1 1 3 2 1 3/week

Durationof therapy (days) 1-2 1-2 2-3 3-4 2-3 indefinitely

As haemarthroses most commonly occur in severe and moderately severe haemophiliacs, other forms of treatment such as arginine vasopressin (DDAVP) are not considered appropriate in this context. The comparatively high incidence of chronic joint disease in moderate haemophiliacs reported recently in a large study (Steven et al, 1986) suggests that joint bleeding in moderate haemophilia should be treated energetically with factor concentrates. As treatment is now very often instituted by the patient or his family at home there is less opportunity for joint aspiration, the knee being the most accessible joint for this procedure. In view of the previously described pathophysiology it would seem prudent on theoretical grounds to remove blood from the joint wherever possible but the benefit of very prompt home treatment at the first sign of bleeding outweighs the advantages gained from aspiration. If the joint remains tense and painful or if there is any suggestion of intra-articular sepsis then aspiration should be performed with appropriate factor replacement cover. If considered necessary, evacuation of intra-articular blood clot may on

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occasions be difficult as since the advent of home therapy many patients have received considerable amounts of factor replacement before presentation. It can usually be successfully performed in the knee with the use of a wide-bore needle or polythene cannula. Failing that, arthroscopic irrigation of the joint may rarely be necessary but does allow inspection of the joint and local control of any isolated bleeding point. Ice packs should be applied to the joint which should be immobilized for 24-48h and then mobilized commencing with isometric exercises, each physiotherapy session being preceded by factor replacement for the first few days. Ultrasonic therapy is widely believed to break up blood clot and hasten resorption, although there is no documented evidence to support this contention. As muscle wasting occurs rapidly, considerable encouragement to persist with the appropriate exercises is vital and requires the assistance of parents, school teachers and friends. Kisker and Burke (1970) reported that short courses of oral corticosteroid therapy conferred some advantage in the treatment of the acute haemarthrosis but these claims have not been confirmed and their use is not advocated owing to the potential hazards of repeated use.

Subacute arthropathy The onset of the subacute stage indicates the beginning of progressive inflammatory and degenerative changes in the joint. The aim of treatment is to minimize or prevent further acute bleeding episodes and thus allow the inflammatory changes to settle down before significant joint damage occurs. Prompt therapeutic factor replacement at the first signs of intra-articular bleeding is essential and if acute haemarthroses are frequent in one or several joints, then prophylactic replacement should be considered to maintain levels of about 10% consistently. Intensive physiotherapy is vital to maintain muscle bulk and minimize further damage and requires considerable cooperation from the patient and his family. Hydrotherapy is beneficial if available and carefully planned and supervised exercise programmes remain a vital component of management. Careful questioning may reveal certain activities that are contributing to the frequency of bleeding into a particular joint and these should be avoided. Sometimes bleeding apparently occurs during sleep and suitable light resting splints may be helpful. Where ankle bleeding is a problem the use of sorbothane insoles and footwear with extended uppers or occasionally a light polythene splint are beneficial. Non-steroidal anti-inflammatory drugs are of limited benefit at this stage and simple analgesics such as paracetamol and other non-aspirin containing preparations are often equally effective. The second-line anti-rheumatic drug D-penicillamine has been reported to produce limited benefit in the short term in three haemophilic patients (Corrigan et al, 1985). However, its well-recognized capacity to produce thrombocytopenia necessitates meticulous monitoring. In a limited trial comparing the use of intra-articular corticosteroid injection, a short course of oral corticosteroid and a combination of both in patients with subacute arthropathy, no long-term benefit

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could be demonstrated but some improvement was noted for 4-6 weeks (York et al, 1979).

Synovectomy Surgical synovectomy was popularized by Storti and his associates for recurrent bleeding on the premise that the hypertrophied synovium produced a fibrinolytic agent which aggravated bleeding and directly damaged articular cartilage (Storti et al, 1971). The procedure has been shown to reduce the frequency of bleeding and may retard progression by the removal of pannus. It is ideally done before significant cartilage erosion has occurred (Houghton, 1982; Luck and Kasper, 1989). Thickened synovium may be removed from the knee by either open or arthroscopic synovectomy but open synovectomy has a high incidence of post-operative stiffness. Arthroscopic synovectomy has the advantages of a shorter hospital stay, smaller factor replacement requirements and ease of post-operative joint mobilization but is associated with an increased frequency of post-operative bleeding (Luck and Kasper, 1989). Open synovectomy of the elbow often combined with trimming or excision of the radial head if indicated has been undertaken. Synovectomy of the ankle and shoulder is rarely if ever performed.

Synoviothesis Chemical or radioactive synoviothesis has been used to shrink thickened synovium. Osmium tetroxide ('osmic acid') has been used in rheumatoid arthritis including the juvenile forms for many years (Berglof, 1964) and more recently in haemophilic arthritis (Menkes et al, 1975). In a limited trial in nine patients with haemophilic arthritis in the knee, intra-articular 'osmic acid' reduced both the frequency of bleeding episodes and pain in five of the nine without detriment to the underlying articular cartilage as assessed subsequently by arthroscopic examination (York et al, 1985). Much controversy has surrounded the use of intra-articular radiocolloids, mainly in the knee in haemophilic arthritis to produce a radiation synovectomy. The [3 emitter yttrium-90 has a comparatively short half-life and post-injection immobilization has been shown to reduce regional lymph node irradiation. In this regard it is certainly superior to the previously used radioactive gold but many physicians regard it as contraindicated in the young age group of the haemophiliacs being treated. However, in patients positive for human immunodeficiency virus-1 (HIV-1) the short-term benefits of the procedure may justify the risks. The more recently developed agent dysprosium-165 ferric hydroxide macroaggregates (Sledge et al, 1986) may prove safer because of its even shorter half-life and consequent radiation reduction. McLaren et al (1988) working at the Australian Nuclear Science and Technology Organisation has produced a larger dysprosium particle (dysprosiumhydroxide macroaggregates) for which greater joint retention is claimed and clinical trials in R A are currently being performed. Radioactive synoviothesis is technically

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easier in the knee and shoulder but can be perform6d on the elbow and ankle although accurate placement within the joint cavity is more difficult. Local Xbirradiation of involved joints may reduce the frequency of bleeding but potential damage to adjacent unfused epiphyses limits its usefulness. It is occasionally of value in the shoulder joint if repeated haemorrhage and pain cannot be controlled by other measures.

Chronic arthropathy Once the process of joint damage has become established there is an almost inevitable progression to chronic arthropathy, arbitrarily defined as being present after 6 months of persistent joint inflammation. Non-steroidal antiinflammatory drugs are often partially effective in relieving pain and stiffness. Ibuprofen has been demonstrated to be effective (Steven et al, 1985b) although having transient effects on platelet function. At the Sydney Centre we have used sulindac because of the convenience of twice daily dosage; while its prolonged action and the long half-life of its major metabolites may be a disadvantage it has proved effective. Although functional platelet abnormalities have been demonstrated after its use they have rarely been associated with significant increased bleeding. Analgesics such as paracetamol or D-propoxyphene are often required in addition. The use of weaker narcotic drugs such as codeine is generally discouraged but many patients do take these agents and a significant number resort to more potent and potentially addictive substances such as dextromoramide (Palfium). At present with the dual problems of HIV-1 infection and delays in obtaining surgery one can only share the very real dilemma faced by many patients with severe persisting pain, and sympathetic support from the centre team is essential. Non-pharmacological measures such as the usual physical modalities of heat and cold, relaxation therapy and transcutaneous nerve stimulation may be beneficial. Pain relief may be potentiated by the use of tricyclic antidepressant drugs, although coincident hepatic disease may reduce their safety. The use of walking sticks, polythene splints and calipers and wheelchairs may be necessary and will often enable the haemophiliac to maintain a reasonable degree of independent mobility. Special appliances such as the extension desubluxation hinge cast (Boone, 1976) or the reverse dynamic sling technique (Houghton, 1982) may be valuable in correcting knee deformities.

Surgery Surgery is frequently the only available option for increasing numbers of haemophiliacs who are now avoiding or surviving the previous lethal complications of the disease. In the past, procedures were limited to osteotomy and joint re-alignment, tendon release and repositioning or arthrodesis, all of which still have a place in management. Joint arthroplasties using either soft tissue or silastic interpositioned material or where only one surface of the joint was replaced, have in general proved unsatisfactory. The development of highly successful total joint prostheses for many

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joints has been of great benefit to haemophiliacs. The knee and less frequently the hip are most commonly replaced although rarely ankle, elbow and shoulder arthroplasties have been undertaken (Luck and Kasper, 1989). Long-term results of hip replacement have been generally good (Houghton, 1982) although a recent large series reported a high revision rate (Luck and Kasper, 1989). Knee replacement in haemophiliacs has also proved to be a very satisfactory procedure (Small et al, 1983). Post-operative results with regard to range of motion which would be considered suboptimal in other forms of arthritis are often regarded by the recipient as highly satisfactory because of the pain relief and preserved independent mobility. The hazards of post-operative haematomata, early and late infection and loosening or mechanical failure of the prosthesis are more worrying in this context than in other arthritides, especially in HIV-1 antibody positive patients. Surgery can be undertaken in most instances in this latter group provided the CD4 T-cell count is greater than 200 x 10.6/1 if the man is in otherwise good condition despite the limited life expectancy but there is an inevitable increased risk of sepsis. This has to be viewed in perspective with the considerable benefit in terms of pain relief and mobility. Similarly, the likelihood of late prosthetic failure or loosening becomes more theoretical. The fear that the stress of surgery and large amounts of clotting factor replacement might accelerate the progression of AIDS has not been realized (Hopkins et al, 1988). There are many individual surgical preferences regarding the type of prosthesis, the use of cemented or non-cemented components, and whether or not the patella should be resurfaced. As the patello-femoral joint is frequently severely involved and if not resurfaced the source of persisting pain post-operatively many surgeons elect to deal initially with all three compartments of the joint (Luck and Kasper, 1989). However, as the patella is generally deeply eroded and thinned, the patellar component is the most likely part of the prosthetic joint to fail due to inadequate bonding between bone and prosthesis (Tyer, personal communication). It is absolutely critical that any surgery in a haemophiliac be performed in a centre where haematological laboratory support and the supply of factor replacement is assured. Joint replacement and other forms of orthopaedic surgery in haemophiliacs should only be undertaken in hospitals where there is a highly experienced orthopaedic surgical staff familiar with the particular problems associated with the disease and supported by the haemophilia centre team. Factor replacement regimens should result in levels of 100% for surgery and 80-90% or above for the first 3-4 days post-operatively slowly reducing to minimal levels of 50-60% by day 6-10. Elective surgery is generally contraindicated in the presence of coagulation factor inhibitors particularly in so-called high responders who develop an anamnestic response on exposure to the coagulation factor with a marked rise in potency of their inhibitor antibody. Surgery in factor IX deficiency is more hazardous than in haemophilia A because of the incidence of post-operative thrombo-embolic disease and the rare occurrence of the disseminated intravascular coagulation syndrome associated with factor IX concentrates.

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Where prosthetic failure or loosening occur in'the knee either with or without joint infection the prosthesis may need to be revised or removed. When removal is necessary, arthrodesis may be difficult to achieve if there is insufficient cancellous bone remaining and on rare occasions the development of an unstable pseudarthrosis, particularly if there are associated discharging and bleeding sinuses, may make amputation the most satisfactory salvage procedure. It is important that all the possible outcomes of such surgery are discussed with the patient before joint replacement is decided upon as most patients are comparatively young men and no centre has any extensive experience of the long-term results of knee replacement in haemophilia. They must be warned that the future outcome is relatively unknown and given the increased life expectancy of haemophiliacs, revision or artbrodesis may be necessary in later life. NON-ARTICULAR COMPLICATIONS Muscle haematomata

In certain situations, bleeding into muscles can be a major problem. Haemorrhage into the ilio-psoas muscle may mimic an intra-articular hip bleed by producing pain and stiffness, limitation of hip movement and joint flexion. If the haematoma is tense, femoral nerve palsy results with consequent weakness and instability of the knee joint and a reduced or absent knee jerk. Prompt treatment with factor replacement is necessary with rest followed by physiotherapy but nerve recovery may be incomplete. Bleeding into other muscle compartments where there is little room for expansion may cause ischaemic muscle necrosis and contracture. This is especially likely to occur in the forearm, leading to Volkmann's ischaemic contracture and in the anterior tibial compartment of the lower leg with similar effects. Again, prompt factor replacement therapy and rest of the affected limb are essential and some authors recommend direct intramuscular pressure measurement and extensive decompressive surgery (Handelsman and Glasser, 1990). This has not been necessary in our experience provided the condition is recognized and therapy administered early. Calf muscle haematomata are more commonly seen and if not adequately treated result in shortening of the tendo-Achilles and ultimately in an equinus deformity of the ankle and foot. Pseudocysts may form in muscle similar to pseudotumours in bone and by their bulk interfere with joint function. Pseudotumours

Pseudotumours in bone are due either to subperiosteal or less commonly intraosseous haemorrhage and since the advent of more effective replacement therapy are rare (Ahlberg, 1975; Gilbert, 1975). Gilbert described two types, a proximal type affecting principally the pelvis and femur and more common in adults and a distal type involving the hands and feet and only occurring in children where the prognosis was better. Involvement of the ilium or femur may rarely affect function in the adjacent hip or

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knee although fractures through a tumour in the femur may seriously compromise hip or knee alignment and movement. Ahlberg and Gilbert both emphasize the danger of aspiration or incision of such pseudotumours because of the likelihood of fistula formation and subsequent infection leading often to death. Radical excision is sometimes necessary and is a formidable and rarely attempted procedure in lesions of the ilium while amputation is usually the only surgical option in complicated femoral pseudotumours. COMPLICATIONS OF TREATMENT WITH BLOOD PRODUCTS Circulatory overload Treatment with infusions of either whole blood or plasma, while effective in correcting haemostasis frequently resulted in circulatory overload especially in children. Cryoprecipitate, the remaining fraction of plasma after freezethawing fresh plasma at 2-4~ was found to be rich in factor VIII and fibrinogen and enabled effective treatment of haemophilia A with the infusion of smaller volumes. The amount of factor VIII in individual packs of cryoprecipitate varied considerably and its storage and transport required controlled refrigeration. It has now been largely replaced by lyophilized factor VIII concentrates with consistent potency and fewer allergic reactions. Lyophilized preparations of factor IX concentrate are also available and these concentrates with greater ease of storage make home treatment possible. Infection The transmission of infection has been a major problem ever since blood products were introduced to treat haemophilia. Despite careful screening of donors, and testing of all donated blood for hepatitis B, high incidences of hepatitis B contamination of blood, and non-A non-B hepatitis in recipients have been reported even in wholly voluntary donor populations (Rickard et al, 1982). In addition the transmission of other viral and bacterial agents, including the recently discovered hepatitis C virus, via whole blood or blood products is well documented. However, no infectious agent has had any effect comparable to that of HIV-1. Its identification in 1984, and the magnitude of the problem of contamination of the world's major blood transfusion services with HIV-1 between 1977 and 1984 has been particularly significant for haemophiliacs. (See Table 2.) Table 2, Viruses transmissible in plasma products. Hepatitis B and delta agent Hepatitis A (rarely) Non-A, non-B hepatitis (including hepatitis C) ? Other hepatitis viruses Serum parvovirus HIV-I and HIV-II

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Heat treatment of the factor concentrates has proved effective in preventing HIV-1 transmission (McDougal et al, 1985; Schimpf, 1989) since 1984 but there is an enormous and tragic legacy of morbidity and mortality amongst haemophiliacs treated with blood products between 1977 and 1984. HIV-1 infection has principally affected patients with severe or moderately severe haemophilia A and B paralleling the amount of factor replacement used during the critical time period. The extent and severity of this complication of treatment has resulted in great anguish in haemophiliacs, their families and their attending physicians often inducing resistance on the part of haemophiliacs to the use of blood products, aggravating the musculoskeletal complications of the disease. More tragically the effects of the high incidence of HIV-1 positivity in severe haemophiliacs and the risk to their spouses and progeny has resulted in great emotional stress. With the increasingly bleak prognosis of HIV-1 positive patients unless effective treatment is developed, the current use of heattreated products and the availability of synthetic factors VIIIc and IXc, the level of HIV-1 positivity in the haemophilic community will return to that of the general population over the next one or two decades. Meanwhile, the disease of AIDS has had a singularly vicious effect on a small and very vulnerable group of people. Non-infective complications

Immunosuppressive effects of blood products The use of blood products in haemophiliacs has been shown to have an immunosuppressive effect in the absence of HIV-1 infection with reduction in CD4 T lymphocyte numbers and CD4/CD8 ratios (Jones et al, 1983; Carr et al, 1984; Wearne et al, 1984). As most of these reports were published before HIV-1 antibody testing was available, it is possible that some of the changes noted were appearing in patients already infected with the virus. However, in a follow-up article to that of Carr et al, Ludlam et al (1985) were able to document the time of HIV-1 seroconversion in some of the previously studied patients following exposure to an infected batch of factor VIII concentrate while others similarly exposed with similar lymphocyte abnormalities did not convert. Madhok (1989) demonstrated impaired cellmediated immunity to several mitogens in HIV-I negative haemophiliacs treated with intermediate purity factor VII and IX concentrates. This effect was absent when pure human factor VIIIc was used.

Immune-mediated reactions All types of immune-mediated reactions to blood products have been well documented and are mostly of a minor nature. SEPTIC ARTHRITIS A more recent problem has been an increase in the incidence of septic arthritis in haemophiliacs. This was previously reported to be less than

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0.15% (Goldsmith et al, 1983) with only 16 recorded cases up until the appearance of HIV-1 infection. It has risen dramatically since then with six reports in the literature over the last four years (Bleasel et al, 1990). At the International Haemophilia Treatment Centre, The Royal Prince Albert Hospital, Sydney, sepsis has occurred in four joints in three patients all HIV-1 positive over the last two years one of whom died during the course of his illness from opportunistic infection. It is often difficult to distinguish between an acute haemarthrosis and a septic joint and aspiration and culture of the synovial fluid is mandatory if there is any suggestion of joint infection. Failure of response to adequate factor replacement with persisting pain and swelling should alert the physician to this possibility, especially in HIV-1 positive patients. Fever and rigors may or may not be present and the white cell count may be normal or low. A dramatic rise in the ESR (greater than 50 mm/h) may also be apparent but can occur in response to intra-articular bleeding although such levels are rarely seen in uncomplicated haemarthroses. The infecting organism is commonly Staphylococcus aureus but both Salmonella and Neisseria meningitidis have been isolated as well as opportunistic organisms. The repeated intravenous cannulations necessary for regular replacement therapy make staphylococcal and other forms of septicaemia a major threat especially in HIV-1 positive patients. A variety of arthritic manifestations other than septic arthritis have been described in HIV positive individuals (Kaye, 1989) but so far these have not been noted in HIV-1 positive haemophiliacs.

THE FUTURE

Treatment may ultimately involve gene insertion therapy whereby suitable cells containing the appropriate portion of a normal X chromosome and capable of secreting the missing coagulation factor are introduced into the haemophiliac. While this sort of genetic engineering is already technically feasible, its application to the human situation is a long way off. The penultimate form of therapy would provide the maintenance of consistently near-normal levels of circulating factors VIIIc or IXc without the risk of introducing any allergenic or infective contaminants or the necessity for intravenous infusions. The commercial production of highpurity synthetic factor VIIIc in adequate amounts and at an acceptable price utilizing recombinant DNA technology in mammalian cell lines is now imminent and similarly factor IXc should soon be available. These products will be free of hepatitis B and C, non-A non-B hepatitis, HIV-1 and other viral agents and are claimed to be non-allergenic but early experience with recombinant factor VIIIc indicates that antigenicity may still be a problem. Experimental non-invasive methods of factor replacement have so far failed to achieve therapeutic efficacy. However, Hemker et al (1980) were able to produce low but measureable levels of factor VIII absorbed via the gut lacteals following its oral administration entrapped in liposomes and other novel approaches should be pursued.

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SUMMARY T h e m a n a g e m e n t of the haemophilias has b e e n i m p r o v e d by the a d v e n t of p o t e n t consistent clotting factor r e p l a c e m e n t therapy. T h e previously lethal m a j o r complications such as intracerebral h a e m o r r h a g e are n o w rare, and the infective complications of t r e a t m e n t , m o s t notably hepatitis and A I D S , are n o w potentially preventable with the n e w synthetic products. T h e r e is also the prospect o f 'cure' by gene insertion therapy. A d v a n c e d a r t h r o p a t h y has b e e n minimized but not p r e v e n t e d by early effective t r e a t m e n t of h a e m a r t h r o s e s , and there is a diminishing legacy of severely affected patients m a n y of w h o m m a y require joint r e p l a c e m e n t surgery. T h e p r e s e n t group of such patients has a high prevalence of H I V - 1 infection and an increased risk of joint sepsis. T h e available avenues of t r e a t m e n t for the subacute stage of the arthrop a t h y have not b e e n particularly effective, emphasizing the n e e d to p r e v e n t recurrent bleeding. T h e d e v e l o p m e n t of a multidisciplinary t e a m - m a n a g e m e n t a p p r o a c h in centres of expertise has b e e n a significant factor in the i m p r o v e d longevity, life satisfaction and preserved mobility n o w available to most h a e m o philiacs.

Acknowledgements This chapter was written during the tenure of a senior research fellowship in the University Department of Medicine, Glasgow Royal Infirmary. I am deeply indebted to Professor Roger Sturrock and Dr Rajan Madhok from the Centre for Rheumatic Diseases, and Dr Gordon Lowe from the Department of Haematology, Glasgow Royal Infirmary for their encouragement and expert advice.

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Ramgren O, Nilsson IM & Blombach M (1962) Haemophilia in Sweden IV. Hereditary investigations. Acta Medica Scandinavica 171: 759-769. Richards AJ & Hamilton EBD (1974) Destructive arthropathy in chondrocalcinosis articularis. Annals of Rheumatic Diseases 33: 196-203. Rickard KA, Batey RG, Dority P et al (1982) Hepatitis and haemophilia therapy in Australia. Lancet 2: 146-148. Rizza CR & Spooner RJD (1983) Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976-80: report on behalf of the directors of haemophilia centres in the United Kingdom. British Medical Journal 286: 929-933. Robinson HJ & Granda JL (1974) Prostaglandins in synovial inflammatory disease. Surgical Forum 25: 476-477. Rosner F (1969) Haemophilia in the Talmud and Rabbinic writings. Annals of Internal Medicine 70: 833-839. Roy S & Ghadially FN (1967) Ultrastructure of synovial membrane in human hemarthrosis. Journal of Bone and Joint Surgery 49A: 1636-1646. Schimpf K, Brackmann HH, Kreuz W e t al (1989) Absence of anti-human immunodeficiency virus types I and 2 seroconversion after the treatment of hemophilia A or von Willebrand's disease with pasteurized factor VIII concentrate. New England Journal of Medicine 321: 1148-1152. Seligsohn U (1973) Haemophilia and other clotting disorders. Israel Journal of Medical Science 9: 1338-1340. Sledge CB, Zuckerman JD, Zalutsky MR et al (1986) Treatment of rheumatoid synovitis of the knee with intra-articular injection of dysprosium-165--ferric hydroxide macro-aggregates. Arthritis and Rheumatism 29: 153-159. Small M, Stevcn MM, Freeman P A e t al (1983) Total knee arthroplasty in haemophilic arthritis. Journal of Bone and Joint Surgery 65-B: 163-165. Stein H & Duthie RB (1981) The pathogenesis of chronic haemophilic arthropathy. Journal of Bone and Joint Surgery 63B: 601-609. Steven MM (1984) Haemophilic arthritis. MD Thesis, University of Aberdeen. Steven MM, Lewis D, Madhok R et al (1985a) Radioisotopic joint scans in haemophilic arthropathy. British Journal of Rheumatology 24: 263-268. Steven MM, Small M, Pinkerton C et al (1985b) Non steroidal anti-inflammatory drugs in haemophilic arthritis--a clinical and laboratory study. Haemostasis 15: 204-209. Steven MM, Yogarajah S, Madhok R et al (1986) Haemophilic arthritis. Quarterly Journal of Medicine 58: 181-197. Storti E, Magrini U & Ascari E (1971) Synovial fibrinolysis and haemophilic haemarthrosis. British Medical Journal 4: 812. Swanton MC (1959) Hemophilic arthropathy in dogs. Laboratory Investigations 8: 1269-1277. Treves F (1886) A case of haemophilia: pedigree through 5 generations. Lancet 2: 533-534. Von Willebrand E A (1926) Hereditare pseudohemofili. Finska Lakarsalls. Hand L 67: 7-12. Wearne A, Joshua DE, Rickard KA et al (1984) Abnormal T cell sub-populations in hemophilic patients receiving factor VIII concentrates from voluntary donors. Australian and New Zealand Journal of Medicine 14: 149-153. Webster WP, Zukoski CF, Hutchin P e t al (1971) Plasma factor VIII synthesis and control as revealed by canine organ transplantation. American Journal of Physiology 220: 11471150. Wright AE (1893) On a method of determining the condition of blood coagulability for clinical and experimental purposes, and on the effect of administration of calcium salts in haemophilia and actual or threatened haemorrhage. British Medical Journal 2: 223-235. York J, Rickard K & MacDonald D (1979) The management of chronic synovitis in haemophilic arthropathy. Abstr. R.A.C.P. Ann. Scient. Meeting. Australian and New Zealand Journal of Medicine 9: 355. York J, Rickard K, McGirr E et al (1982) HLA studies in haemophilic arthropathy. Abstr. Aust. Rheum. Assoc. Ann. Scient. Meeting. Australian and New Zealand Journal of Medicine 12: 578. York J, Rickard K & MacDonald D (1985) Intra-articular osmium tetroxide in haemophilic arthropathy. Abstr. Aust. Rheum. Assoc. Ann. Scient. Meeting 1984. Australian and New Zealand Journal of Medicine 15(supplement 1): 186.

Musculoskeletal disorders in the haemophilias.

The management of the haemophilias has been improved by the advent of potent consistent clotting factor replacement therapy. The previously lethal maj...
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