The Practical Management

of Haemophilia

M. Winter SUMMA R Y. Haemophilia is a rare and complex disorder and its successful management will depend upon the establishment of a network of ‘comprehensive care’ including the services of haematologists, orthopaedic surgeons, rheumatologists, dental surgeons, physiotherapists, specialised nurses and counsellors. One of the major lessons to be learned from the HIV epidemic in haemophilia is that it is critical to strive to obtain the safest and purest forms of blood products for these patients. The advent of clinically available recombinant factor VIII is expected soon; in the meantime there is a move towards treating all patients with high purity products.

The Practical Management of Haemophilia Haemophilia is a rare disorder, affecting only one in every 8000 males. The medical management of haemophilia has always presented an unusual challenge in that it is a coagulation disorder (and therefore usually managed by haematologists) whose most prominent clinical manifestation is arthropathy-a form of pathology more familiar to rheumatologists and orthopaedic surgeons. Both the rarity and complexity of the disorder make it logical to argue that all patients with haemophilia should be treated, or at least reviewed regularly, in specialised centres. It cannot be expected that centres treating only a handful of patients will be able to muster either the expertise or the finance to establish the network of care-haematological, orthopaedic, immunological, psychosocial-that modern haemophilia care demands. The experience of the HIV epidemic over the past 10 years tells us that significant mismanagement of patients is less likely to occur when treatment is at least being supervised by a centre that specialises in haemophilia care. There is no reason why patients M. Winter, East Kent Hospital, St Peters Road, Blood Reviews (1992) 6, 174-181 Q 1992 Longman Group UK Ltd

Haemophilia Centre, Thanet District Margate, Kent CT9 4AN, UK.

should not receive acute treatment at a local haemophilia treatment unit, but all those who receive blood products should be reviewed regularly at a centre that is able to offer the full range of services enshrined in the concept of ‘comprehensive care’.

Clinical Aspects of Haemophilia Patterns of Bleeding The frequency of bleeding in haemophilia varies widely. Nevertheless, most severely affected patients will experience between 30-50 bleeding episodes each year. It is not altogether clear as to why patients with unrecordable levels of factor VIII do not bleed more frequently. Curiously, many patients report an increase in the number of bleeds during the autumn. Bleeding often occurs around episodes of infection. A characteristic pattern is for the patient to remain free of problems for a few weeks and then suffer several bleeds into one or two joints over a short period of time. Some patients report a form of ‘aura’ at the earliest onset of a bleed. This is not quite the same as the aura of epilepsy, but is rather an innate feeling that bleeding has started, even though objective signs of a bleed are not yet apparent.

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Joint Bleeding The knees and elbows are the joints most likely to be affected, followed in order by the ankles, shoulders and hips. It is thought that the increased frequency of bleeding into the hinge joints of the knee and elbow is the result of several factors: they contain a relatively larger amount of synovium, known to be the initial site of bleeding the supporting musculature is less stable than for the socket type joints such as the shoulder and hip they are less able to withstand rotatory and angulatory stresses.l Muscle Bleeding Bleeding into deep seated muscles is a particularly serious event and should be treated aggressively with high doses of factor VIII. Generally speaking, bleeding tends to be more common in flexors rather than extensors; particularly likely to be affected are the iliopsoas, quadriceps and gastrocnemius. Bleeding into the iliopsoas may be readily mistaken for a bleed into the hip joint; sometimes the only telltale sign as to the true diagnosis is an area of dysaesthesiae over the anterior aspect of the thigh. Bleeding into other sites Until recently, cerebral haemorrhage was the commonest cause of death in haemophilia. Any unexplained headache should therefore be considered presumptively as a possible bleed and treated. Episodes of intra-oral bleeding should also be taken seriously, particularly in young children where obstruction at the back of the throat by a friable blood clot can obstruct the airway. Haematuria is a symptom experienced by most severely affected patients at some time or other and does not require further investigation in the first instance. Antifibrinolytic agents are strictly contraindicated in this situation, as they can promote episodes of thrombosis within the renal vasculature. Pathological Aspects of Bleeding

The development of an acute bleed into a joint induces an acute inflammatory response and the ensuing synovial injury results in the release of enzymes which tend to degrade the underlying articular cartilage. If untreated, this can be followed by a sequence of events including osteoporosis, destruction of subchondral bone, bone cysts and osteophyte formation. The synovium itself hypertrophies in response to recurrent bleeding and macroscopically resembles fronds of seaweed; these are especially fragile and tend to bleed easily. It is inevitable that joint bleeding will damage and destabilise a joint, in turn making more episodes of bleeding likely, particularly as there may have been

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atrophy of the surrounding musculature. One of the principle aims of therapy therefore is to prevent the development of this cycle of increasing pathological damage. Treatment of Bleeding

The advent of coagulation factor concentrates in 1973 represented a revolution in haemophilia care. The ability to restore levels of factor VIII and IX to the normal range at times of an acute bleed was soon shown to radically improve the quality of life of patients with haemophilia.’ The advent of home therapy programmes3 was a logical further development and it was possible to demonstrate that the prompt administration of coagulation factor concentrates reduced the likelihood of subsequent arthropathy. Furthermore, patients with haemophilia could be afforded the opportunity of establishing a degree of control over their disability, and to become more independent. As the half life of factor VIII is of the order of only 8 h, the traditional method of treatment has been to reserve infusions of concentrates to those occasions when the patient is bleeding acutely‘demand’ therapy. The circulating level of factor VIII that is required to establish haemostasis will depend upon both the site and gravity of the bleed, with levels well in excess of 50 iu/dl being particularly desirable for serious bleeds and perioperatively. The required dose of factor VIII can then be estimated from the formula: 1 unit factor VIII/kg body weight increases the circulating factor VIII level by 2 iu/dl (1 iu/dl for factor IX) Once reconstituted, the concentrate is administered as an intravenous bolus, given over a few minutes. For patients undergoing surgical procedures, where satisfactory levels of factor VIII are particularly critical, it may be preferable to use a continuous infusion.4 Using demand therapy, the annual factor VIII requirement will inevitably vary widely, but for severely affected patients will be in excess of 50000 units. There is a growing belief amongst clinicians treating haemophilia that we should now be looking towards greater use of prophylaxis, particularly for children and young adults where the opportunity of preserving normal joint function is a realistic goal and offers tangible rewards. Although the cost of prophylaxis might appear to be high, it is anticipated that the prevention of chronic joint damage by prophylaxis in these young patients may in fact prove to be cost effective, although this will need to be confirmed by long-term studies. In any case, there is a clear analogy to be drawn with other deficiency states such as diabetes mellitus. Although we cannot yet hope to realise the ultimate goal of normalising circulating factor VIII levels in haemophiliacs, it is logical to try and prevent episodes

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of bleeding rather than waiting for them to develop. The prophylactic administration of 20-25 units/kg, given thrice weekly, may lead to only a small increase in circulating factor VIII levels but in effect converts the severely affected patient into a mild one, and makes spontaneous episodes of bleeding relatively unlikely. Prophylaxis should at least be strongly considered for all severely affected children until the age of 18 and also for those patients who experience recurrent episodes of bleeding into a ‘target’ joint, Factor VIII and Purity

There is considerable controversy as to the type of blood product that patients with haemophilia should be receiving. In essence we have now reached a situation where all currently available forms of factor VIII and IX are perceived as being free of known viral contaminants. Instead, attention is now turning towards the question of concentrate purity, particularly as it is realised that products of so-called intermediate purity contain in reality less than 1% factor VIII and are comprised mainly of proteins such as fibrinogen, fibronectin, immunoglobulins and beta-Z microglobulin. These considerations are particularly relevant in view of the protein load that regularly treated patients receive-most batches of concentrate are derived from at least 20000 donors and it has been estimated that over a period of 10 years severely affected patients are likely to be exposed to the blood (and therefore the viruses) of half a million donors. It is therefore no great surprise that regularly treated patients are immunosuppressed, independently of HIV.5 A number of specific immunological abnormalities have been reported: reduced levels of CD4 cells6 functional CD4 defects’ impaired interleukin-2 production* impaired expression of interleukin-2 receptors9 defects in monocytic functionlO depressed natural killer cell activity.” It remains uncertain as to whether these abnormalities are the result of either viral contamination or protein impurities but whatever the cause they are not observed in patients treated with high purity products. Intermediate purity concentrates display significant amounts of proteolytic activity in vitro” and regularly treated patients have markedly raised levels of alpha-2-macroglobulin, a major proteinase inhibitor I3 these levels return towards normal when the paiients are then treated with exclusively high purity material. l4 Are these in vitro observations of any clinical relevance and does it really matter if patients continue to receive intermediate purity products, even if they have been shown to be immunosuppressive? Two studies are especially worthy of comment: In the Edinburgh cohort study 18/33 patients who

received an HIV contaminated batch of factor VIII seroconverted. The likelihood of seroconversion was related to the degree of previous treatment in that every patient with a lifetime exposure of more than 30 bottles seroconverted.” During an outbreak of tuberculosis on a paediatric ward, children with haemophilia were infected at a similar rate to immunosuppressed children receiving chemotherapy. l6 Furthermore, are these findings of special relevance to those patients who are already immunosuppressed through infection with HIV? For instance, HIV replication is known to be stimulated by antigens, lymphokines and tumour necrosis factor” and thus might conceivably be stimulated by those impurities or antigens present in intermediate purity concentrates. In other words, might the development of AIDS be accelerated by the continued use of a less pure product? Two important studies have now reported on this issue, following the protocol produced by The International Society of Thrombosis and Haemostasis. la Mannucciig studied a group of 33 asymptomatic HIV antibody positive patients who were randomised to receive a product of either intermediate or high purity, the latter being prepared by ion exchange chromatography. After 2 years of study, there was no significant difference in the rate of decline of CD4 counts between the two groups. In contrast, a similarly designed study that involved treatment with high purity factor VIII purified by monoclonal antibody technology has shown different results. In contrast to the control group, who continued to receive intermediate purity products and whose CD4 counts continued to decline, patients who were converted to monoclonal factor VIII showed no significant change in CD4 cell counts over the 96 weeks of follow-up.2o Taken together with the results of a meta-analysis2’ it can now be recommended that HIV positive patients with measurable CD4 counts should receive high purity products. It should be noted that these benefits have only been demonstrated thus far for concentrates produced by monoclonal antibody technology. Most recently, the UK Regional Haemophilia Centre Directors have formally recommended that all patients with haemophilia should be treated with high purity concentrates. 22 As these products are at least 50% more expensive these recommendations are likely to have far reaching consequences and for financial reasons it may be necessary to introduce these changes gradually, starting with HIV positive patients who have CD4 counts in excess of 100. These considerations are probably less relevant for those patients who are already profoundly immunosuppressed, with CD4 levels below 100. High purity products will also be of benefit to the small number of patients who experience allergic reactions with intermediate purity concentrates.

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The fractionation of monoclonal factor VIII involves two viral inactivation steps-purification with monoclonal antibody followed by either pasteurisation or solvent detergent treatment-and thus these products may prove to be not only purer but also safer than intermediate purity products. As they also dissolve readily in a small volume of diluent. monoclonal concentrates are particularly suitable for young children with haemophilia. Monoclonally purified products may contain trace amounts of mouse antibody in the final preparation. However, only a small number of patients have developed any immunological response and this is not thought to be of any clinical significance. Concern has also been expressed about a possible increase in the incidence of inhibitor formation in patients treated with these products. However, it is now generally accepted that previous estimates of 668% for antibody development in haemophilia were based on retrospective data and were unrealistic. A recent prospective study23 showed that inhibitors developed in 15/63 (24%) of patients with haemophilia A. Compared with these latest figures, there remains no evidence for an increase in inhibitor formation in patients receiving monoclonally purified products.24

Recombinant

Factor VIII

Genetically engineered factor VIII has been in clinical trial since I989 and has been demonstrated to achieve satisfactory clinical haemostasis, both in the control of serious episodes of haemophiliac bleeding and as prophylaxis during major surgical procedures.25 To date, there is no evidence that recombinant factor VIII contains any immunological determinants that are not present in human plasma.26 As for the monoclonal products, particularly close attention is being paid to the incidence of inhibitor development-Lusher2’ reported that 7/37 previously untreated patients developed this complication with recombinant factor VIII. However, these antibodies were of low titre and continued treatment with factor VIII was possible.

Factor IX Deficiency The management of Christmas disease (factor IX deficiency) is similar to that of classical haemophilia, with the exception that factor IX concentrates have the ability to cause episodes of venous thrombosis28 and also disseminated intravascular coagulation,29 particularly in relation to surgery. These side-effects are thought to be due to the presence of activated vitamin K dependent coagulation factors. Because of the significant risk of thrombosis, and even though heparin is added to the concentrates during their preparation, it is prudent to administer additional heparin, at a dose of 100 units for every 500 units of factor IX concentrate infused.

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The likelihood of a thrombotic complication is significantly reduced by the use of highly pure factor IX concentrates.30 The arguments in favour of exclusive therapy with high purity products are therefore even stronger for patients with factor IX deficiency than for those with factor VIII deficiency.

von Willebrands Disease The bleeding tendency in von Willebrands disease is generally milder than that in haemophilia. Joint bleeding is extremely uncommon and most episodes of bleeding are mucocutaneous in nature. Most intermediate purity factor VIII concentrates contain only small amounts of high molecular weight von Willebrand factor, known to be important for mediating haemostasis in these patients. Exposure to blood products can in any case usually be avoided by the use of DDAVP.” Administered at a dose of 0.3 ug/ kg, a 2-4 fold increase in factor VIII activities is usually observed, following release from endothelial cells. DDAVP is also the treatment of choice for patients with mild haemophilia. The drug is administered by slow intravenous infusion and tends to cause facial flushing, due to release of endothelial prostacyclin. In elderly patients, attention will also need to be paid to the possibility of fluid overload. A few elderly patients have also been reported as experiencing episodes of thrombosis.32 There are a number of specific von Willebrand factor concentrates available for those patients who will not respond to DDAVP.33 In view of this, cryoprecipitate should now be considered as being obsolete.

Complications

of Treatment

Why inhibitors develop is still incompletely understood. It is logical to expect that such patients may prove to have gene deletions; in reality this appears to apply for patients with factor IX deficiency but to only a small percentage of patients with factor VIII deficiency. Although the increased incidence in brother pairs is suggestive of a genetic influence there is at best only a weak correlation with HLA type. It has been suggested that some inhibitors may develop as a result of failure of natural anti-idiotype (i:e:antianti factor VIII) mechanisms. Most inhibitors are of restricted immunological subtype, commonly IgGl or IgG4, with kappa light chains; they are reactive against specific epitopes on the factor VIII surface. The management of patients with inhibitors is complex and there is much to be said for finding a form of treatment that is both clinically effective for the individual patient and familiar to those administering the treatment. This objective can often only be achieved in a wholly empirical manner and it is for

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instance not uncommon to find that one patient obtains a good clinical response to FEIBA or Autoplex whilst another responds better to porcine factor VIII. The choice of treatment will depend upon a number of factors including the inhibitor titre, whether the inhibitor is of the high or low responding type, and on the nature and severity of the bleeding episode. As a general rule, it is preferable to try and raise the factor VIII level directly, by the use of either porcine or human factor VIII. So-called bypass therapies, involving the use of activated factor IX concentrates such as FEIBA or Autoplex, are successful in 50-60% of bleeds34 and have a definite place in clinical management. They are associated rarely with episodes of thrombosis.35 The observation that haemophiliac inhibitors react less strongly with animal factor VIII36 led to the development of porcine factor VIII.37 The likelihood of response to this form of therapy can be assessed in vitro by performing an inhibitor titre against porcine factor VIII; some patients will prove to have a cross-reacting antibody that will preclude treatment. Home therapy has been well tolerated3’ and even reported to induce immune tolerance. Other therapies for patients with inhibitors that are either in clinical use or development include: plasma exchange extra-corporeal immunodepletion recombinant factor VIIa39 phospholipid/factor X complexes4’ recombinant tissue factor.41 Infections

Hepatitis Hepatitis B. Despite donor selection and screening, and subsequent purification, episodes of Hepatitis B transmission still occur occasionally.42 It is thus especially important that all patients who are likely to be exposed to blood products should be vaccinated. Satisfactory levels of immunity should be assessed regularly in all patients, and booster vaccinations may be required, particularly in HIV positive patients and in those over the age of 40. Hepatitis C. Shortly after the introduction of coagulation factor concentrates it became apparent that the majority of regularly treated patients developed abnormalities of liver function. As classical markers of active hepatitis B infection were absent it was assumed that infection was the result of a different hepatitis virus known as ‘non A, non B’. Subsequently, it was realised that the chances of being infected after a single treatment with coagulation factor concentrate were close to 1OO%.43 The pervading view that these observed abnormalities of liver function were of doubtful clinical significance was radically altered by the study of Hay.44 At liver biopsy, at least 25% of patients proved to have either chronic active hepatitis or cirrhosis. Fur-

thermore, repeat biopsy revealed that these histological changes could be progressive. The hepatitis C virus, eventually isolated by Choo,45 is an RNA virus related to the flaviviruses. The currently available assay is based upon the presence of antibody to a non-structural protein known as C-100. As expected, application of this test reveals that over 80% of regularly treated haemophiliacs are positive46 and that there is an association with histologically proven liver disease.47 There is only a weak relationship between C-100 positivity and infectivity; more specific information can now be obtained by detecting HCV sequences using a nested PCR technique.48 The implications of hepatitis C infection in patients with haemophilia are still emerging. The observation of occasional episodes of sexual transmission49 makes it prudent to advise that all patients who have been exposed to blood products should be offered testing, advised of the result and, together with their partners, be given counselling and advice about the possible implications. Treatment of Hepatitis. Inteferon therapy should now be considered for selected patients with hepatitis B and C, as the carrier state for both these virus infections is associated with deficient alpha-interferon production by lymphocytes. Hoofnagle” has suggested that those most likely to benefit have high levels of aminotransferases and a lack of complications such as HIV or renal impairment. A course of 3 million units, given three times per week, may be recommended initially. The side-effects of therapy are not inconsiderable and include an influenza-like syndrome, fatigue, depression and myalgia. Bontempo 51 has demonstrated that liver transplantation is possible in severe haemophilia. Although a formidable and expensive undertaking, it may need to be considered as increasing numbers of young patients develop end-stage liver disease. A fortunate side-effect of the procedure is that the patient is cured of his haemophilia. Parvovirus There have been reports of transmission of parvovirus by factor IX concentrates.52 This agent is resistant to not only heat treatment but also to solvent detergents. Infection has been associated with a syndrome of aplastic anaemia, arthropathy and erythema infectiosum. HIV The constellation of medical, social and psychological problems that have resulted from HIV infection in patients with haemophilia are too complex to be discussed in full here; they have been reviewed elsewhere.53 Suffice it to say that the management of both the patient’s haemophilia and HIV cannot be

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separated, the two.

for there is a dynamic

relationship

between

The Impact of HIV on Haemophilia. An increase in the incidence of septic arthritis in HIV positive patients has been observed. 54 There is a clinical impression that orthopaedic procedures are less successful in HIV positive patients, particularly in relation to an increased incidence of local infection. Most centres have noted an increased demand for coagulation factor concentrates. As patients fall ill, they are likely to require diagnostic and therapeutic procedures that are invasive and that will need to be covered by blood products. Patients may experience an increased incidence of joint bleeding if they develop HIV associated thrombocytopenia. The Impact of Haemophilia on HIV. The clinical features of HIV infection are different in haemophilia. Kaposi’s sarcoma is extremely rare. A particular tendency towards non-Hodgkin’s lymphoma is becoming apparent. The possible influence of the continued use of intermediate purity concentrates, as discussed above. The emotional and psychological problems that result from HIV infection in haemophilia are likely to be even more complex than in non-haemophiliacs. Inevitably, many patients feel a deep sense of anger that they have been infected through medically prescribed treatment. Many patients are still very young-in our centre, the average age at seroconversion was 18. Many families will have more than one infected member. It is especially important that counselling should encompass the whole family, not forgetting the particular situation of the mother. who not only passed on the haemophilia gene but may also have injected the contaminated batch of factor VIII as part of a home treatment programme. Finally, as we are already aware of a number of viruses that have found their way into blood products we should work on the assumption that there are likely to be as yet undescribed viruses that may be present, either now or in the future, and to therefore do all that we can to ensure that patients always receive the best treatment that is currently available.

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Serial measurements of joint function are performed and in this way any subtle deterioration in joint function can be identified and corrected. A number of orthopaedic procedures are of proven benefit” and emphasis should be placed on the promotion of active joint function-procedures that involve immobilisation of the joint are unlikely to lead to a satisfactory result. Radiological assessment is advisable, and a grading system has been devised.56 Specific advice and therapy can be given, including physiotherapy, hydrotherapy and ultrasound, with the assistance of a dedicated physiotherapist. Any requirement for anti-inflammatory agents or analgesics can be reviewed. Dental Care Regular dental assessments are best arranged through the haemophilia centre, preferably using a hospital based dental surgeon with expertise in the management of these patients. The involvement of community dental officers is particularly invaluable in helping to educate young patients about dental hygiene. Social welfare/Counselling

All patients with haemophilia should now be able to benefit from comprehensive care. In essence, this is a network of services established in recognition of the fact that management of haemophilia involves more than just treatment of the patient’s episodes of bleeding:

Haemophilia is a lifelong disability and its inevitable companion, even in the most well adjusted of patients, is considerable stress. Setting aside any considerations about HIV, haemophilia itself is associated with an increased likelihood of being unemployed, of being registered disabled and of being unmarried. It is therefore a mistake to assume that only HIV positive patients will benefit from counselling, or indeed from the services of a psychologist. The presence of someone with haemophilia acts to disrupt and disturb the family dynamic. A common observation is that a close bond develops between the affected child and his mother” especially as it is usually she who learns how to administer treatment at home. In this setting it is often the case that the father and the non-affected children can tend to feel rather excluded and even resentful. These pressures may be helped by keeping not only the patient but also the whole family fully informed and by letting the family themselves make all the relevant decisions concerning care. 58 Patients have the right to receive informed advice and help concerning their disability entitlements; these are often unclaimed because the patient is either unaware that the welfare benefit exists or is unable to claim it without assistance.

RheumatologylOrthopaedics

Genetic Counselling

All severely affected patients should be reviewed regularly in combined clinics, held with a rheumatologist or orthopaedic surgeon:

The technology required for genetic counselling is sophisticated and complex and will usually only be available in larger centres. The use of recombinant

Comprehensive

Care

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probes to detect DNA polymorphisms has provided invaluable information concerning three main areas.5g detection of haemophilia carriers ante-natal diagnosis identification of the genetic abnormality that is the cause of the patient’s haemophilia.

The Future

As the prospect of gene therapy emerge@’ we should accept that the management of haemophilia over the past 15 years has involved a litany of missed opportunities. If history is not to repeat itself, we will have to find ways of exerting sufficient political pressure to make sure that there are sufficient funds made available to meet the increasing costs of haemophilia care.

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15. Ludlam C 1988 Effects of alloantigens on immunity. Seminars in Haematology 25: 3-7 16. Beddall A C, Hill F G H, George R H, Williams M D. Al-Rubei K 1985 Unusually high incidence of tuberculosis amongst boys with haemophilia during an outbreak of the disease in hospital. Journal of Clinical Pathology 38: 11631165 17. Margolick J B, Volkman D J, Folks T M, Fauci A S 1987 Amplification of HTLV-III/LAV infection by antigen induced activation of T cells and direct suppression by virus of lymphocyte blastogenic responses Journal of Immunology 138: 1719-1723 18. Brettler D 1989 Proposed protocol for the evaluation of the effect of high purity factor concentrates on the immune system of haemophilia patients. Thrombosis and Haemostasis 62: 8 1 I 19. Mannucci P M, Gringeri A, De Biasi R, Ciavarella N, Baudo F, Morfini M 1991 Immune status of HIV positive haemophiliacs; a randomised comparison of treatment with a high purity or an intermediate purity factor VIII concentrate. Thrombosis and Haemostasis 65: 824 20. de Biasi R, Rocino A, Miraglia E, Mastrullo L, Qurino A A The impact of a very high purity factor VIII concentrate on the immune system of HIV infected haemophiliacs; a randomised, prospective, two year comparison with an intermediate purity concentrate 1991 Blood 78: 1919-1922 21. Seremetis S, Aledort L, Sacks H 1990 Differential effects on CD4 counts of high or intermediate purity factor VIII concentrates in HIV positive haemophiliacs; a meta-analysis Blood 76: 48 22. UK Regional Haemophilia Centre Directors Committee 1992 Blood Coagulation and Fibrinolysis 3: 2055214 23. Ehrenforth S, Kreuz W, Scharrer I, et al 1992 Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 339: 5944598 24. Lusher J 1990 Lack of inhibitor to monoclonal antibody purified factor VIII concentrates Lancet 336: 1249-1250 25. Schwartz R S, Abilgaard C F, Aledort L 1990 Human recombinant DNA derived antihaemophilic factor (factor VIII) in the treatment of haemophilia New England Journal of Medicine 323: 1800&1806 26. Esmon P C, Kuo H S, Fournel M A 1990 Characterisation of recombinant factor VIII and a recombinant factor VIII deletion mutant using a rabbit immunogeneticity model system Blood 76: 1593-1600 27. Lusher J M, Arkin S, Abilgaard C, Hilgartner M 1991 Observations in previously untreated haemophiliacs receiving recombinant factor VIII Thrombosis and Haemostasis 65: 706 28. Blatt P M, Lundblad R L, Kingdon H S 1974 Thrombogenic materials in prothrombin complex concentrates Annals of Internal Medicine 91: 766 intravascular coagulation 29. Conlan M G 1990 Disseminated and haemorrhage in haemophilia B following elective surgery American Journal of Haematology 35: 203-207 M. Huart J J 1989 30. Burnouf T, Michalski, Goudemand Properties of a highly purified human plasma IX:C therapeutic concentrate prepared by conventional chromatography VOX Sang 57: 225 MI CancianiN T, Rota L, Donovan B S 1979 31. Mannucc;P Resoonse of factor VIIIlvon Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrands disease British Journal of Haematology 43: 283-293 32. Mannucci P M, Lusher J M I989 Desmopressin and thrombosis Lancet ii: 675-676 A, Gordemand A 33. Mazurier C, de Romeuf Parquet-Gernez 1989 In vitro and in vivo characterisation of high purity/ solvent detergent treated factor VIII concentrate: evidence for its therapeutic efficacy in von Willebrands disease European Journal of Haematology 43: 7-14 M, Aledort L, Andes A, Gill J 1990 Efficacy and 34. Hilgartner safety of vapour-heated anti-inhibitor coagulant complex in haemophiliac patients Transfusion 30: 625-630 35. Sullivan D W, Purdy L J, Billingham M, Glader B E 1984 Fatal myocardial infarction following therapy with prothrombin complex concentrates in a young man with haemophilia A Paediatrics 74: 279 36. Bennett B, Ratnoff W D 1973 Immunological relationships L

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hepatitis C viral sequences in blood donations by nested polymerase chain reaction and prediction of infectivity Lancet 335: I419 Tedder R S 1991 Hepatitis C virus; evidence for sexual transmission British Medical Journal 302: 1299- 1302 Hoofnagle J H 1990 Alpha interferon therapy of chronic hepatitis B-current status and recommendations Journal of Hepatology 11: 100 Bontempo F A, Lewis J H, Gorenc T J et al 1987 Liver transplantation in haemophilia A. Blood 69: I721 - 1724 Lyon D J, Chapman C S, Martin C 1989 Symptomatic parvovirus B19 infection and heat treated factor IX concentrates Lancet 335: 105 Winter M 1991 The care and management of children with haemophilia and HIV infection. In: Claxton R, Harrison A (eds) Caring for Children with HIV and AIDS. Edward Arnold pp. 46-60 Ragni M V, Hanley E R 1989 Septic arthritis in haemophiliac patients and infection with human immunodeficiency virus Annals of Internal Medicine IO: 168-169 Smith M A, Savidge G F, Fountain E 1983 Interposition arthroplasty in the management of advanced haemophiliac arthropathy of the elbow Journal of Bone and Joint Surgery 65: 436-440 Petterson H, Ahlberg A, Nilsson I M 1980 A radiological classification of haemophiliac arthropathy Clinical Orthopaedics 149: 153-l 59 Penn P 1983 Coalitions and binding interactions in families with chronic illness Family Sys Medicine 1: 16-25 Levi J, Simon R, Weis H 1986 Family therapy in haemophilia-a chronic disease model Clinical Laboratory Research 16: 125 Kogan S C, Doherty M. Gitschier J 1987 An improved method for prenatal diagnosis of genetic disease by analysis of amplified DNA seauences-aaoulication to haemouhilia A New England Journal of Medicine 317: 985 1 Thompson A R 1991 Status of gene transfer for haemophilia A and B Thrombosis and Haemostasis 66: 119-122