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Haemophilia B is an inherited bleeding disorder associated with a deficiency of coagulation factor IX. The hallmark of the severe phenotype is recurrent and spontaneous bleeding into joints which can lead to joint deformity and arthritis at an early age. Recombinant factor IX is now increasingly regarded as the treatment of choice because it is free of the risk of transmission of human pathogens. All patients in the UK now receive this product exclusively. Conventional treatment now consists of the administration of concentrate on a prophylactic basis to prevent bleeds and hence minimise disability in the long-term. Trials of gene therapy are also underway but these are in the very early stages and will not be a realistic option for at least another twenty years.
Haemophilia B is an inherited bleeding disorder associated with a deficiency of coagulation factor IX. The bleeding tendency is proportional to the degree of deficiency. The hallmark of the severe phenotype is recurrent and spontaneous bleeding into joints which can lead to crippling joint deformity and arthritis at an early age in the absence of effective treatment. The condition is inherited as an X-linked disorder although there is no family history in approximately one third of cases and this represents a new mutation. In the absence of effective treatment, the prognosis is poor but the development of blood products in the last few decades has transformed the outlook and patients can now live essentially normal lives. Recombinant factor IX is now increasingly regarded as the treatment of choice because it is free of the risk of transmission of such pathogens as hepatitis, HIV and prions. All patients in the UK now receive this product exclusively. The use of recombinant factor IX is not associated with an increased incidence of inhibitor development. Although the plasma-half life of recombinant factor IX is similar to that of conventional plasma-derived product, reduced in vivo recovery has been observed. Desmopressin and cryoprecipitate are of no value in the treatment of haemophilia B. Conventional treatment now consists of the administration of concentrate on a prophylactic basis to prevent bleeds and hence minimise disability in the long-term. Looking to the future, it is likely that modified molecules with enhanced properties such as increased half-life will be developed. A transgenic factor IX molecule derived from pigs is also in the early stages of development. Trials of gene therapy are also underway but these are in the very early stages and will not be a realistic option for at least another twenty years.
Haemophilia is a congenital disorder of coagulation and affects approximately 1 in 10,000 of the male population in all ethnic groups. Haemophilia A is due to a deficiency of factor VIII in the circulating blood, and haemophilia B (also known as Christmas disease) is a clinically identical disorder caused by factor IX deficiency. The prevalence of haemophilia B is about a fifth that of haemophilia A. A specific factor assay is required to confirm the diagnosis. The clinical severity (phenotype) is critically determined by the level of circulating factor VIII (or IX) in the blood, and severe haemophilia is defined by a clotting factor level of <1 iu/dl (1). A national database of patients with bleeding disorders was set up in the UK in 1968 (2). There are currently 5560 patients in the country registered with haemophilia A and 1188 with haemophilia B (of whom and 2201 and 444 have severe haemophilia A and B respectively). The hallmark of severe haemophilia is recurrent and spontaneous haemarthrosis (3). Typically, hinge joints such as the knees, elbows and ankles are affected but bleeds may also occur in the wrist or shoulders. Recurrent bleeds into a joint lead to synovitis and joint damage resulting in crippling arthritis. Bleeding into muscles is also a feature of haemophilia, but this is usually a consequence of direct injury, albeit often minor. Bleeding from the gastrointestinal tract (melaena) and bleeding into the urinary tract (haematuria) may also occur. There is also a significant risk of intracranial haemorrhage in severe haemophilia which was a significant cause of mortality in the past when treatment was not so readily available. Higher levels of factor VIII (or IX) above 5 iu/dl are associated with a milder form of the disease, with no spontaneous joint bleeds but a definite risk of bleeding after even relatively minor injury or surgery.
Treatment of bleeding episodes involves the intravenous injection of coagulation factor concentrates; the total dose and frequency of treatment will also be determined by the severity and site of bleeding. The great majority of joint bleeds will resolve with a single infusion of material, if the bleed is recognised early and treated promptly. There is an increasing move to prophylactic therapy, in which the patient gives himself injections of coagulation factor concentrate once or twice a week to prevent bleeds rather than just treating on demand when bleeds occur. Patients on prophylactic therapy experience few or even no spontaneous bleeds, and thus progressive joint damage and arthritis can be avoided. The quality of life of patients on prophylaxis may be greatly enhanced, allowing them to lead much more independent lives (4). Approximately 30% of patients with severe haemophilia A can be expected to develop inhibitory antibodies to factor VIII at some stage (5). Inhibitor development in haemophilia B is, by contrast, very rare and encountered in 1-6% of patients. The development of such antibodies poses considerable problems in treatment as these immunoglobulins (IgG) are capable of rapidly inactivating infused factor VIII.
Although haemophilia was recognised by 1850 as a well-defined clinical entity with a clear pattern of X-linked inheritance, the aetiology remained elusive for many years. The term antihemophilic globulin (AHG) was first used in 1937 to describe a concentrated globulin derived from normal plasma which reduced the coagulation time of haemophilic blood. With the development of Cohn fractionation it was subsequently shown that the active factor was present in fractions I and III of normal plasma, but not in similar fractions of haemophilic plasma. The development of a new test, the thromboplastin generation test, was an important advance as it allowed a more detailed analysis and localisation of clotting defects. By using either the absorbed plasma, or the serum, or the platelet component from the patient and completing the system with the two remaining components from normal blood, it was possible to ascribe the cause a clotting defect to one or more of these components. As anticipated, the results of the thromboplastin generation test in classical haemophilia were indicative of a defect in the plasma component.
A further complication arose when it also soon became apparent that haemophilia was not a homogenous disorder in terms of the clotting defect (6). Alfredo Pavlovsky (1907-1984) in Buenos Aires reported that "occasionally (in vitro) the blood of some of the hemophilic patients with a greatly prolonged clotting timeâ€¦when added to other haemophilic blood possessed a coagulant action nearly as effective as normal blood". We now know that this was due to the normal level of factor VIII in the plasma of patients with haemophilia B correcting the defect in patients with the much commoner form, haemophilia A.
Christmas factor (later to be labelled factor IX) was the first coagulation protein to be named after a patient, a precedent established by Biggs (1912-2001) and Macfarlane (1907-1987) in Oxford in 1952. In December of that year they published the clinical and laboratory findings in seven cases of what appeared to be classical haemophilia, but in whom the thromboplastin generation test indicated a defect in the serum component (7). The authors named the disease after their first patient, Stephen Christmas. The Christmas edition of the British Medical Journal (BMJ) typically publishes light-hearted and even frivolous papers. The timing of the publication was perfect and the BMJ agreed to accept the paper at very short notice but the response to this important publication was not all entirely positive. Some thought it was a student's prank or that the story had been made up. The distinguished serologist Alexander Wiener also wrote to the journal and urged the adoption of the alternative name of haemophilia B. However, the term "Christmas disease" still remains in widespread use in the English-speaking world.
Molecular basis of haemophilia B:
The gene for factor IX was cloned in 1982 and is considerably smaller than that of factor VIII. The factor IX gene is also located on the long arm of the X chromosome at band Xq27, and is encoded by a stretch of DNA approximately 34kb long which contains eight exons. The basic structure of the gene is similar in organisation to those of protein C and coagulation factors VII and X, and it is likely that they all originated in the distant past from a common ancestral gene by duplication. Factor IX is a polypeptide of 415 amino acids, and is made up of a glutamic acid-rich sequence (Gla domain) and two epidermal growth factor (EGF)-like domains separated from the serine protease domain by an activation region. The 12 glutamic acid residues in the Gla domain undergo post-translational g-carboxylation which is necessary for binding of calcium, and exon 2 encodes a recognition site for the carboxylase. Exon 1 encodes the signal peptide necessary for transport into the endoplasmic reticulum. Exon 6 encodes the activation peptide that is cleaved off during the activation of factor IX by either factor XI or a complex of tissue factor and factor VII. Exons 7 and 8 encode the catalytic regions of factor IX, which are responsible for subsequent activation of factor X in the coagulation cascade.
Point mutations account for the vast majority of cases of haemophilia B, and over 500 have been described from families from around the world (8). The factor IX mutation database is available online (www.kcl.ac.uk/ip/petergreen/hemBdatabase.html).The great majority involve single base changes which have been identified in all domains of the protein. The unusually high frequency of mutations at CG dinucleotide sites in haemophilia B probably reflects the high number of CG dinucleotides at critical sites in the factor IX gene. Gene deletions account for only approximately 3% of all cases of haemophilia B. No equivalent of the factor VIII gene inversion has been encountered in haemophilia B. Determination of the underlying mutation in each case also facilitates the identification of female carriers in the family, and allows the option of antennal diagnosis. Female carriers may themselves have modest reductions in the factor IX level and this should be checked prior to surgery or there invasive procedures.
A few patients with haemophilia B have been described in whom the factor IX level rises significantly after puberty, and this is associated with loss of the bleeding tendency. Several point mutations have been reported in association with this interesting variant, referred to as the haemophilia B Leiden phenotype (9). All are located in the promoter region of the factor IX gene, for example TTGàTAG at -20 and GàA at nucleotide -6. Most of these mutations have been shown to be located in regions which contain binding sequences for liver-enriched transcription factors which are presumably influenced by androgenic steroids.
Selection of products:
The World Federation of Hemophilia (WFH) has published a guide (10) for the assessment of clotting factor concentrates which deals with all types of available products. The UK Haemophilia Centre Doctors' Organization (UKHCDO) has also published relevant guidelines (11). It is beyond the scope of this review to include details of all the available coagulation factor concentrates but the WFH guide also includes a registry of all coagulation factor concentrates. This is updated on annual basis and is also available through the WFH web site (www.wfh.org). The registry includes information on: donors (nationality, whether paid or voluntary); method of obtaining plasma; serological tests on donors; testing of mini-pools for viruses using PCR amplification; location of fractionation facilities; methods of fractionation; methods of viral inactivation/elimination; levels of purification; identity of distributor and manufacturer; intended area of distribution (domestic or export).
In recent years, the relative merits of plasma versus recombinant products have been a major topic of debate (12, 13). The arguments focus primarily on safety with regard to transmission of pathogens which must be of prime concern in the selection of products for the treatment of haemophilia. Recombinant factor IX is now increasingly regarded as the treatment of choice in many countries. All patients in the UK now receive this product exclusively as is the case in the Republic of Ireland and Canada. The recent experience of an acute and world-wide shortage of recombinant factor VIII has certainly served to focus minds on the fact that the number of manufacturing plants is very limited, particularly so in the cases of recombinant factor IX. There is only one brand of recombinant factor IX available (BeneFIX) and this is manufactured in a single plant in the United States. Recombinant factor IX is expressed by Chinese hamster ovary (CHO) cells and purified using for sequential chromatographic steps and a final viral retention nanofiltration step (14). The CHO cells are grown and produced recombinant factor IX in serum-free medium containing only vitamin K, recombinant insulin and amino acids and salts. Following purification, the recombinant factor IX is diafiltered into an albumin-free formulation and lyophilized. However, one important positive consequence of the progressive switch to recombinant products in developed countries is that this will help to secure effective and safe treatment for people in developing countries.
Plasma-derived concentrates are still widely used in many countries and there are at least ten different brands available. There are some common steps involved in the manufacture of coagulation factor concentrates. Plasma proteins such as albumin, coagulation factor concentrates, and immune globulin preparations are manufactured from large pools of human plasma, primarily by the Cohn cold ethanol fractionation method. This method involves the sequential precipitation of specific proteins under varying conditions of ethanol and pH conditions. Factor IX is prepared by anion-exchange chromatography in the presence of heparin, applied to cryoprecipitate-depleted plasma, or the use of immuno-affinity chromatography. The coagulation factor protein is then freeze-dried and lyophilised concentrate bottled under sterile conditions. Nucleic acid testing (NAT) of source plasma is now mandatory for hepatitis C, but is employed for detection of other viruses such as HIV, parvovirus B19 and both hepatitis A and B by an increasing number of manufacturers. At some stage, either as a final step or during the manufacturing process, a specific virucidal step such as heat-treatment and/or solvent/detergent treatment is applied to provide an additional level of safety. The introduction of heat-treatment and solvent/detergent treatment in the mid 1980's effectively eliminated the risk of transmission of HIV and HCV (hepatitis C) through the use of plasma-derived products (15, 16, 17). Although highly effective against a wide range of viruses with a lipid envelope, solvent/detergent treatment with such agents as TNBP and Triton X-100 does not inactivate non-enveloped viruses such as hepatitis A (18, 19). Furthermore, some viruses (such as human parvovirus B19 virus) are relatively resistant to both types of physical process (20, 21). All virus inactivation and removal steps have their limitations. It is recommended that two distinct and effective steps that are complementary be incorporated into the plasma product manufacturing process. Nanofiltration may also be performed in the case of factor IX. This is an efficient method of removing more than 4 to 6 logs of a wide range of viruses and has the added advantage of having no adverse or denaturing effect on plasma proteins (22). It is recommended that all patients receiving plasma-derived concentrates be vaccinated against hepatitis A and B as an additional precaution (23). There are no screening tests available for the detection of prions, including the presumed causative agent of vCJD and precautions are largely based on donor exclusion. It is therefore reassuring that plasma fractionation techniques appear quite fortuitously to eliminate substantial amounts of prions (24.)
In the case of factor IX concentrates, high-purity concentrates have been shown to induce less activation of coagulation than the less pure prothrombin complex concentrates (25). The latter should no longer be employed in the routine management of haemophilia B in view of case reports of thrombosis (including venous thromboembolism, disseminated intravascular coagulation and myocardial infarction) associated with their use (26, 27, 28).
Standardisation of factor IX assays has presented fewer problems than that of factor VIII. The one stage factor assay is used for both plasma and concentrates. Potency of concentrates is assigned as "international units" with reference to a WHO standard which is used as a reference for both the US and European regulatory authorities.
Clinical studies of recombinant factor IX for the routine treatment for both previously -treated and untreated patients with haemophilia B have been conducted, as well as in the setting of surgery (29, 30, 31). These have demonstrated that recombinant and plasma-derived factor IX concentrates have similar plasma-half lives of around 18 hours, longer than that of factor VIII which is around 12 hours. This has positive implications for prophylactic therapy, with most patients requiring just two infusions a week (rather than three typically needed in conventional haemophilia A). Whilst prophylaxis is now widely advocated, there is still no consensus on even such major issues as the age at which it should be started or the desirable trough factor IX levels. It is generally started in early childhood, in the range of 1-4 years of age and the dosing should be individualised to minimise or abolish the incidence of spontaneous "breakthrough" joint bleeds (32, 33). A stepwise start (infusions given weekly into peripheral veins from the age of 12-18 months) is the usual approach although much depends on the tolerance of the child and his family. Central venous lines can be used, but their can be associated with complications such as infection and central venous thrombosis. It must be emphasised that the aim of prophylaxis is not to restore the level of the deficient coagulation factor to the normal range, but to ensure that the trough level is sufficient to prevent spontaneous bleeds. Patients on prophylaxis are therefore still vulnerable to bleeding after even minor injury. The patient (and their parents and physicians) should not be lulled into a false security with regard to prophylactic therapy. The group in Malmö (Sweden) who pioneered prophylaxis advocated a target trough factor level of not less than 1 iu/dl and a typical regime would be 20-40 iu/kg body weight twice a week. However, more recently it has been recognised that prophylaxis regimes should be individually tailored according to the incidence of spontaneous bleeds and not just the trough levels (34).
Although recombinant and conventional plasma-derived concentrates have similar half-lives, a reduction in in vivo recovery of the order of 20% has been observed with the recombinant concentrate (35, 36, 37). This phenomenon is particularly marked in young children and In other words, a higher dose is required to obtain a target plasma value and this has important cost implications when comparing treatments (38). The underlying reason for this reduction in functional activity is unclear, but has been tentatively attributed to slight variations in molecular structure including reduction in sulphation of Tyr155 and phosphorylation of Ser158. A recovery study prior to starting prophylactic treatment is advisable.
Antifibrinolytic drugs and other agents:
Several agents in this category are useful as adjunctive haemostatic agents. During normal fibrinolysis, inactive circulating plasminogen binds to fibrin through an active site which binds lysine. The bound plasminogen is then converted to plasmin by activators (such as tissue plasminogen activator, t-PA) and converted to plasmin, which breaks down the fibrin. e-aminocaproic acid and tranexamic acid are structural analogues of lysine, which bind irreversibly to the lysine-binding sites on plasminogen, thus inhibiting binding to fibrin and thus the whole process of fibrinolysis . These agents inhibit the natural degradation of fibrin and thus stabilise clots. Antifibrinolytic agents are particularly useful in the management of recurrent bleeding from mucosal surfaces in patients with congenital and acquired coagulation disorders, such as epistaxis, oral bleeding and dental surgery in patients, and menorrhagia. Some adverse reactions are associated with all antifibrinolytic agents, reflecting their effect on clot stability. Dissolution of extravascular blood clots may be resistant to physiological fibrinolysis. These drugs should not to be used to treat haematuria due to blood loss from the upper urinary tract as this can provoke painful clot retention and even renal failure associated with bilateral ureteric obstruction. Side-effects of tranexamic acid are rare and mainly limited to nausea, diarrhoea or abdominal pain. These symptoms are usually associated with high doses, and usually subside if the dose is reduced. Hypotension is occasionally observed, typically after rapid intravenous infusion. Myopathy associated with elevated levels of creatine kinase and even myoglobinuria has occasionally been reported in association with aminocaproic acid therapy. This complication is very rare, and is usually associated with the administration of high doses for several weeks. Full resolution may be expected once drug treatment is stopped.
Patients with haemophilia should avoid the use of aspirin and non-steroidal anti-inflammatory agents, as these can exacerbate the bleeding tendency through inhibition of platelet function. Paracetamol (acetominophen) has no such effect and is therefore perfectly safe to use as an alternative simple analgesic. Similarly, the use of intramuscular injections should be avoided as this can result in the formation of a haematoma. This applies to vaccines, which should be given by the subcutaneous route.
Options for the developing world:
The prognosis for people with haemophilia is still bleak in many parts of the world and the World Federation of Haemophilia estimates that two thirds of the people with haemophilia in the world still receive little or no treatment for their condition. The principal barrier to development of haemophilia care is, of course, cost of the blood products. The discovery by Judith Pool in 1964 that a fraction of thawed plasma contained factor VIII was a major landmark in the development of products for the treatment of haemophilia A. Cryoprecipitate is still used to treat patients with haemophilia A in the less affluent countries of the developing world as the cost of coagulation factor concentrates is prohibitively high. However, although rich in factor VIII (and also von Willebrand factor, factor XIII and fibrinogen) it contains no factor IX and is therefore of no value in the treatment of haemophilia B. Fresh frozen plasma (FFP) contains all coagulation factors and is still the only option for the treatment of haemophilia B in countries unable to afford the use of factor IX concentrate. It is difficult to obtain high levels of factor IX with fresh plasma alone, and there is also the associated risk of fluid overload. Quality control, involving the assay of factor IX content of plasma packs, is also very important. The major problem is the risk of viral transmission, although packs of FFP subjected to some form of virucidal treatment (including solvent/detergent treatment) are already available. Certain additional steps can be taken to minimize the risk of transmission of viral pathogens. These include careful selection of donors to eliminate and producing packs from single donors. Once collected, the plasma should be quarantined until the donor has been recalled and retested for markers of infection: if the donor does not return, the plasma should not be used. PCR (polymerase chain reaction) testing is a technology which has a potentially much greater relevance for the production of fresh frozen plasma (and cryoprecipitate) than concentrates, as the latter are subjected to viral inactivation steps. The possibility of severe allergic reactions to infused plasma, including TRALI (transfusion-related acute lung injury) attributed to cytotoxic antibodies of donor origin in the infused plasma, have been recognised for some time (39). An additional benefit of solvent/detergent treated FFP is a significant decrease in the incidence of such allergic reactions (40).
One important positive consequence of the progressive switch to recombinant products in developed countries is that this will help to secure effective and safe treatment for people in developing countries. As patients in more affluent parts of the world as North America, Europe and Australia and Japan convert inexorably to recombinant products, manufacturers of plasma-derived products will be forced to seek new markets in the developing world and these will also have to be competitively priced. It is clear that there will continue to be a global requirement for plasma-derived as well recombinant coagulation factor concentrates for many years to come.
Inhibitory antibody development in haemophilia B:
Approximately 30% of patients with severe haemophilia A can be expected to develop inhibitory antibodies to factor VIII at some stage. The development of such antibodies poses considerable problems in treatment as these immunoglobulins (IgG) are capable of rapidly inactivating infused factor VIII, and furthermore the antibody titre may rise dramatically by after exposure to treatment with clotting factor concentrate. By contrast, inhibitor development in haemophilia B is much rarer and encountered in just 1-6% of patients. In most cases, the underlying molecular defect is a large gene deletion (41). Inhibitors in haemophilia B are typically high titre and appear quite soon after beginning treatment (after 9-11 exposure days). There is no suggestion that the incidence is higher amongst recipients of higher purity coagulation factor concentrates. These rare patients with haemophilia B and inhibitory antibodies pose a particular challenge. These inhibitory antibodies, in contrast to those seen in haemophilia A, often retain the ability to fix complement or provoke IgE-mediated responses. Allergic reactions, including anaphylaxis, may develop after infusions of concentrate (42). Indeed, such a reaction may be the very first manifestation of inhibitor development and it is for this reason that it is the practice in many centres to administer the first infusions of factor IX concentrate to young patients with haemophilia B in a hospital (with resuscitation equipment and medication available discretely in the background). Information derived from genetic studies done at diagnosis may help to identify those patients who are particularly vulnerable by virtue of having factor IX gene deletions or stop codon abnormalities.
The best treatment for acute bleeds in these patients is recombinant activated factor VIIa (NovoSeven) (43).The relatively short half-life of this product at around two hours precludes its use on a prophylactic basis. The use of prothrombin complex concentrates such as FEIBA should be avoided as these contain significant amounts of factor IX. In the longer term, the strategy is to eradicate the inhibitor. Desensitisation, with exposure to increasing doses of factor IX concentrate, may be successful. Conventional immune tolerance has a greater chance of success although the overall response rate is much lower than in haemophilia A. Only 5/34 (15%) in the International Society on Thrombosis and Haemostasis (ISTH) registry achieved tolerance with 100 iu/kg/day and this requiring a median duration of treatment of 10 months (43). The development of nephrotic syndrome associated with membranous glomerulonephritis on biopsy has also been recognized as a presumably immune-complex mediated complication of immune tolerance with large dose of factor IX in some of these patients (44, 45). This complication was reported in 13/34 (38%) of patients enrolled in the ISTH registry. Although resolution has been reported in some cases after stopping treatment with factor IX, this is not invariably the case. Urine analysis should be performed on a regular basis in patients with haemophilia B receiving immune tolerance.
The development of transgenic dairy animals also offers the potential for the production of production of recombinant products which can be extracted from their milk. Transgenic products of antithrombin and a2-antitrypsin are already undergoing clinical trials and a transgenic factor IX molecule derived from pigs is also in the early stages of development (46). The advantage of this approach is that it could result in the production of large amounts of coagulation factor concentrate ant relatively low cost. In order to express a recombinant protein in the milk of animal, expression vectors containing a gene encoding the protein of interest are fused to milk-specific regulatory elements (such as casein, lactalbumin or lactoglobulin) and introduced by microinjection of a one-cell embryo, or alternatively transfected into a cell line suitable for somatic cell nuclear transfer. The mammary-gland specific transgene is transmitted in a Mendelian fashion following integration into the germline. If expressed, it becomes a dominant genetic characteristic that will be predictably inherited by offspring of the animal and the yield of transgenic protein in the milk is often high in the range of grams per litre. Transgenic expression delivers the advantages of mammalian cells (such as sophisticated molecular refolding machinery and glycosylation), as well as the potential for flexibility of scale in production and relatively low costs.
Haemophilia provides an attractive model for correction and cure by gene therapy, and several clinical trials in both haemophilia A and B are already underway (47, 48). The basic principle involves gene transfer using (retro-, adeno- or lenti-) viral vectors. Haemophilia B is potentially an easier condition to approach in this way as the gene is so much smaller than that of the factor VIII and is therefore easier to accommodate in viral particles. The first study involved 8 patients with haemophilia B who received an intramuscular injection of a transfected adeno-associated viral vector (49). A favourable but transient effect on plasma levels, paralleled by a reduction in concentrate requirement, was reported in three of the subjects. Whilst gene therapy undoubtedly offers the prospect of a true cure for haemophilia, it is clear that much work still remains to be done and it probably will not be a realistic option for at least another twenty years.
Haemophilia B is now an eminently treatable condition and recombinant factor IX should be regarded as the product of choice. There is only one such brand available commercially (BeneFIX). Modern treatment consists of the prophylactic intravenous infusion of factor IX in order to prevent bleeds. This reduces the risk of development of significant joint damage and at the same time minimises disruption of he life of the patient and at the same time eliminates A typical regime would be 20-40 i.u./kg body weight twice a week. However, regimes should be individually tailored according to the incidence of spontaneous bleeds and not just the trough levels of factor IX in the plasma. There is no suggestion that the use of recombinant factor IX is associated with an increased incidence of inhibitor development. The post-infusion recovery of recombinant factor IX is reduced when compared to that of plasma-derived concentrate and this has important cost implications when comparing treatments.