Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature

Summary.  Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven^®) is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 μg kg⁻¹ bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences.     

Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery

We have evaluated the haemostatic efficacy of plasma derived, highly purified, solvent-detergent treated factor IX concentrate (Nanotiv®), to which a nanofiltration step has recently been added to improve safety with regard to parvovirus B19, hepatitis A and other nonlipid enveloped viruses. Thirteen surgical procedures, including eight orthopaedic operations, were carried out using continuous infusion of Nanotiv in 10 haemophilia B patients (nine severe and one mild). Tranexamic acid was used for 11 of the 13 procedures. The mean factor IX levels on the day of surgery and postoperative days 1–3 were 0.77, 0.89, 0.80 and 0.73 IU mL^–1, respectively. The haemostatic effect was rated as normal or excellent and no blood transfusions were needed. One patient had thrombophlebitis twice at the infusion site. The remaining cases received heparin, 5 units per 100 IU of Nanotiv, and had neither superficial nor deep venous thromboembolic complications. The requirement for factor IX in the four joint replacement operations was 663 IU kg^–1 during the first 9 days, which compares favourably with previous materials. Thus, continuous infusion with this highly purified factor IX concentrate with improved viral safety is effective for surgery in haemophilia B.     

Orthopaedic surgery in haemophilia patients with inhibitors: a practical guide to haemostatic, surgical and rehabilitative care

Summary.  All but essential surgery is generally avoided in haemophilia patients with inhibitor antibodies, because of concern about the reliability with which haemostasis can be achieved and maintained in such patients. Orthopaedic surgical procedures which are not required to preserve life fall under this category. As a result, patients with inhibitors may be denied operations, which could greatly enhance their quality of life, and which are routinely offered to other haemophilia patients. While caution is appropriate in recommending surgery in any circumstance, we believe that the threshold for offering validated surgical procedures to patients with inhibitors should be re-evaluated in the light of current surgical and rehabilitative techniques, and the long experience with safe and effective factor VIII inhibitor bypassing agents, namely activated prothrombin complex concentrates and recombinant activated factor FVII. In this article, we review the haematological, surgical and rehabilitative considerations relevant to orthopaedic surgery in haemophilia patients with inhibitors, and provide recommendations for carrying out such procedures.     

The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: a retrospective case series

Summary.  Prophylactic infusion of factor concentrates is a safe, effective intervention for preventing arthropathy in patients with haemophilia; on-demand treatment is insufficient to prevent the orthopaedic complications and subsequent haemophilic arthropathy that stem from recurrent joint haemorrhages. The usefulness of prophylaxis in haemophilia patients without inhibitors suggests that patients with haemophilia and inhibitors could derive similar benefits. In patients with haemophilia and high-titre (>5 BU mL⁻¹) inhibitors, bleeding episodes are treated with bypassing agents such as activated prothrombin complex concentrates (APCCs) and recombinant activated factor VII (rFVIIa, N ovo S even ^®; Novo Nordisk A/S, Bagsvaerd, Denmark). It is possible to administer bypassing therapy regularly to prevent haemorrhages, with the goal of limiting arthropathy and serious life- and limb-threatening bleeding. The data evaluating the efficacy and safety of this approach in patients with inhibitors are limited, consisting of results from one prospective trial and retrospective case reports. This report describes our experience with the prophylactic use of the APCC Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA™; Baxter AG, Vienna, Austria). Data from patients at one treatment centre were retrospectively evaluated. Case records of six patients with haemophilia A or B and high-titre inhibitors were identified. When APCC was administered regularly, most patients exhibited a reduction in the numbers of haemorrhages, an improvement in orthopaedic status, and an improvement in quality of life. Prophylaxis with APCC can reduce haemorrhages and halt further joint deterioration in patients with haemophilia and inhibitors.     

Orthopaedic limb salvage with a mega prosthesis in a patient with haemophilia A and inhibitors – a case report

Summary.  Inhibitors against FVIII or FIX in patients with haemophilia are a common and serious complication. Until recently, elective surgery was associated with major bleeding despite the availability of a sufficient substitution therapy. We report about the major orthopaedic reconstruction of the right limb in a patient with severe haemophilia A and inhibitors. This reconstruction was the after effect of a traumatic periprosthetic fracture of the right femur after total knee replacement 6 months ago. This fracture could be stabilized by internal fixation. Two months later, a non-traumatic femur fracture occurred. Therefore, we removed the distal part of the femur and the joint replacement, and implanted a custom made tumour prosthesis (Type MUTARS ©, Münster). These three successive operations, which included emergency and elective surgery, were performed within 8 months. This is, to the best of our knowledge, the first patient with inhibitors undergoing such a complicated reconstruction of a limb. We conclude that successful elective orthopaedic surgery could be accomplished safely in this patient with high responding inhibitors using recombinant FVIIa. After a follow-up of 9 months, no major complications were seen.     

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations

Summary.  Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14 days; for liver biopsy, 70–100%, 1–7 days; tonsillectomy: 90–100%, 5–11 days; indwelling venous access device insertion: 100%, 3–10 days; circumcision: 50–60%, 2–4 days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better-designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.     

Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open‐label guardian^? clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight^®), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4–59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as ‘excellent’ or ‘good’ haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg^?1. The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery.     

Health economics of treating haemophilia A with inhibitors

Summary.  Haemophilia is a rare, inherited blood disorder in which blood clotting is impaired such that patients suffer from excessive internal and external bleeding. At present there is no cure for haemophilia A and patients require expensive, life-long treatment involving clotting factor replacement therapy. Treatment costs are perceived to be higher for patients who have developed inhibitory antibodies to factor VIII, the standard therapy for haemophilia A. However, initial cost analyses suggest that clotting factor therapy with alternative haemostatic agents, such as recombinant activated factor VII or activated prothrombin complex concentrate, is no more expensive for the majority of haemophilia A patients with inhibitors than for those without inhibitors. With the availability of effective alternative haemostatic agents, orthopaedic surgery for haemophilia A patients with inhibitors is now a clinical option, and initial cost analyses suggest this may be a cost-effective treatment strategy for patients with inhibitors whose quality of life (QoL) is severely impaired by joint arthropathy. In an era of finite healthcare resourcing it is important to determine whether new treatments justify higher unit costs compared with standard therapies and whether such higher costs are justified from an individual perspective in terms of improved QoL, and from a societal perspective in terms of improved productivity and reduced overall healthcare costs. This paper examines current data on the health economics of treating haemophilia A patients with inhibitors, focusing on the overall costs of clotting factor replacement therapy and the cost consequences of joint replacement.     

Rehabilitation of patients with haemophilia after orthopaedic surgery: a case study

Summary.  Preoperative and postoperative rehabilitation may be useful for improving the recovery of patients undergoing orthopaedic surgery, particularly in those with co-morbidity or special requirements. This case study, of a patient with haemophilia and inhibitors to factor VIII undergoing total knee replacement, demonstrates the benefits of 6 weeks' preoperative physiotherapy ('prehabilitation') combined with 6 weeks' postoperative rehabilitation. The supervised physiotherapy regimen was individually tailored to specifically increase range of motion and muscle strength, enabling rapid mobilization and recovery of function, whilst minimizing the risk of bleeding.     

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven®] in elective orthopaedic surgery in haemophilic patients with inhibitors

Summary.  Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120–180 μg kg⁻¹ to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.     

Cases of surgery in high-responder haemophilia patients

Summary.  We present 11 cases of surgery in haemophilia patients with inhibitors (high responders). They were: one haemorroidectomy, one vesical surgery in a high responder, one adenoidectomy, seven orthopaedic procedures (one bone fixation of a femoral neck fracture, four total knee arthroplasties, two total knee arthroplasties), and one retroperitoneal haematoma that required emergency surgery. We conclude that surgery in haemophilia patients with inhibitor can be considered feasible but nevertheless remains difficult. When applied to high-responding patients the treatment must take into account both the haemorrhagic risk and the risk of anamnestic response. Use of activated fractions as first-line therapy makes it possible (if the titre of the antibody allows it) to resort to conventional replacement therapy with FVIII or FIX concentrates. NovoSeven^® or FEIBA^® can be equally used as first-line therapy including therapy for major surgeries. It can be useful to alternate one with the other in case of occurrence of haemorrhagic complications.     

How to manage invasive procedures in children with haemophilia

Invasive procedures can be performed safely in children with haemophilia due to the availability of factor VIII/IX for patients without inhibitors. Most guidelines are based on the experiences in adults, but still there is no established consensus on the optimal factor levels or duration of replacement therapy for adults undergoing surgery. Few publications have focused on surgery in children with haemophilia. Children who have developed inhibitors to factor VIII/IX have to be treated with bypassing agents and constitute a group at higher risk for bleeding complications during surgery. The aim of this review is to summarize the experiences and opinions in the literature on replacement treatment of children with haemophilia, with and without inhibitors, during and after surgery, with a focus on the most prevalent clinical situations.     

Evaluation of outcome of care in patients with haemophilia

Haemophilia is a potentially disabling condition associated with high financial costs, and so the need for robust measures to evaluate outcome of care is essential. This paper is a review of some of the outcome measures commonly used to evaluate treatment in haemophilia and includes quality of life measures, evaluation of the musculoskeletal system and orthopaedic surgical procedures. Quality-of-life questionnaires are discussed with particular reference to the SF36 and AIMS2. Results of published studies to date have demonstrated variable results. Overall, haemophilia appears to reduce quality of life compared to normal population figures. Several factors are perceived to reduce quality of life, and these include being human immunodeficiency virus (HIV) positive, having impairments, and a history of orthopaedic surgery. The evaluation of the musculoskeletal system is important in order to detect any deterioration over time. Various standardized measurement tools are described. Orthopaedic surgical procedures have also been evaluated in patients with haemophilia. To date, the Hospital for Special Surgery Knee rating scale has been the most commonly used to evaluate the outcome of total knee replacement. The limitations of this system for patients with haemophilia are outlined. Overall, these measures provide useful tools for evaluating outcome, but none have been specifically developed for patients with haemophilia. Further studies would be useful to evaluate these tools and others in more depth.     

European Study on Orthopaedic Status of haemophilia patients with inhibitors

Development of inhibitors against factor VIII (FVIII) or factor IX (FIX) in haemophilia patients is one of the most serious complications of repeated exposure to replacement therapy and has major clinical and economic consequences. To evaluate the relationship between inhibitor status of haemophilia patients and their quality of life (QoL) and degree of arthropathy and to compare the orthopaedic status of patients with/without inhibitors. An observational, cross-sectional, case control study enrolling: group A (n = 38), males aged 14-35 years, with severe congenital haemophilia A or B who had inhibitors against FVIII/FIX >5 years; group B (n = 41), as group A, but aged 36-65 years and group C (n = 49), as group A, but without inhibitors. Socio-demographics: medical history, clinical characteristics and QoL were assessed. In groups A and B, 16% and 27% were hospitalized for orthopaedic procedures vs. 4% in group C. Patient mobility was also severely reduced in groups A and B, with 24% and 22% using wheelchairs vs. 4% in group C, and 50% and 51% needing a walking aid vs. 29% in group C. Significantly more joint pain was reported by patients in group A vs. those in group C; clinical/radiological orthopaedic scores were also worse in group A vs. group C. Significantly more joint abnormality was reported by patients in group A vs. group C. The burden of orthopaedic complications and the impact on QoL are more severe in haemophilia patients who have developed inhibitors than in those without inhibitors.     

Experience of recombinant activated factor VII usage during surgery in patients with haemophilia with inhibitors

Inhibitor development is one of the most challenging complications of haemophilia management. Haemostatic control in patients with haemophilia with inhibitors can be difficult, and is especially risky in those undergoing surgical interventions. Most haemophilia patients with inhibitors suffer from chronic joint disease requiring surgical correction due to recurrent bleeding episodes. The aim of this study was to assess the use of recombinant activated factor VII (rFVIIa) as haemostatic therapy during orthopaedic surgery in haemophilia patients with inhibitors. A series of case reports was retrospectively collected to describe clinical experience of rFVIIa use in inhibitor patients undergoing a range of orthopaedic surgical procedures at a single centre. All surgeries were performed using standard methods. All patients received rFVIIa at a starting dose of 120 μg kg^?1 with the subsequent regimens depending on the type of surgery. rFVIIa provided effective haemostasis in 23 patients with haemophilia A and inhibitors (15 with high inhibitor titres) undergoing orthopaedic surgery. The majority (70%) of surgical procedures were major (joint and extra‐articular surgery). The doses and intervals of rFVIIa treatment used varied depending on the severity of bleeding, and the type (major or minor) or site of surgery. In all cases, administration of rFVIIa achieved good haemostasis. In all 23 patients with haemophilia with inhibitors, rFVIIa treatment in orthopaedic interventions proved to be an efficient haemostatic agent, providing effective intra‐operative and postoperative haemostasis.     

Uncomplicated neurosurgical resection of a malignant glioneuronal tumour under haemostatic cover of rFVIIa in a severe haemophilia patient with a high-titre inhibitor: a case report and literature review of rFVIIa use in major surgeries

Summary.  The development of inhibitors following factor VIII replacement therapy is a serious complication in severe inherited haemophilia. Whereas significant experience, notably in orthopaedic surgery, is now obtained with the use of bypassing agents in haemophilia with high-titre inhibitor, new surgical challenges might occur due to patients' increasing life expectancy. A 56-year-old severe haemophilia A patient with a high-titre inhibitor was diagnosed for probable right temporoparietal malignant glioneuronal tumour on cerebral magnetic resonance imaging (MRI) (4 cm x 3 cm cerebromeningeal tumour with perilesional oedema and transfalcial herniation) requiring total resection. Then recombinant activated FVII (rFVIIa) was chosen as the haemostatic agent: bolus of 270 μg kg⁻¹ every 2 h during the first 24 h, 180 μg kg⁻¹ every 3, 4 and 6 h, respectively, at days 2–3, from days 4–10 and finally from days 11–15. Tranexamic acid was associated. Pre- and postoperative courses were uneventful, the surgical procedure being assessed at optimal haemostatic condition without any unusual haemorrhage on MRI controls, diffuse intravascular coagulation criteria or thromboembolic event. Intensive rFVIIa therapy has shown to be safe and effective in this first reported neurosurgery about a malignant tumour exhibiting to a high-bleeding risk notably in haemophilia with high-titre inhibitor. The use of lower doses of rFVIIa might have been possible; however, in the absence of accurate test for monitoring rFVIIa therapy, the potentially life-threatening complications of this procedure required maximum haemostasis with high rFVIIa doses.     

U.S. survey of surgical capabilities and experience with surgical procedures in patients with congenital haemophilia with inhibitors

General guidelines exist for the use of recombinant activated factor VII (rFVIIa) to maintain haemostasis during surgery in congenital haemophilia A and B patients with high responding inhibitors (CHwI). Individual surgical plans are required and based upon historical therapy response, adverse events and anticipated procedure. Surgical interventions are feasible, yet it remains unclear how many US hemophilia treatment centres (HTCs) perform procedures in this fragile population. To better understand the US HTC surgical experience in CHwI patients and the number/types of procedures performed, a 21-question survey was sent to 133 US HTCs, with follow-up for response clarification and to non-responders. 98/133 HTCs (74%) responded, with 87 currently treating CHwI patients. In the last decade, 76/85 HTCs performed 994 surgeries on CHwI patients. Sites were experienced in the following procedures: central line insertion/removal (73 HTCs), dental (58), orthopaedic (52), abdominal (23), cardiovascular (14) and otolaryngologic (11). Experience with orthopaedic surgeries included synovectomies - arthroscopic (23 HTCs), radioisotopic (22), and open (7); joint replacement (18); fracture repair (14); and arthrodesis (8). Treatment modalities included rFVIIa bolus (83 HTCs) or continuous infusions (9), plasma-derived activated prothrombin complex concentrate (pd-aPCC) (55), antifibrinolytics (51), topical haemostatic agents (29), factor VIII (16) and fibrin sealants (14). Protocols for bypassing agents were used by 31/92 (33%) HTCs. Most US HTCs surveyed care for CHwI patients (74%) and have experience in minor surgery; fewer HTCs reported complex orthopaedic surgical experience. Identification of best practices and surgical barriers is required to guide future initiatives to support these patients.     

Successful angiographic embolization of recurrent elbow and knee joint bleeds in seven patients with severe haemophilia

Summary.  In haemophilic joints with high-grade arthropathy, bleeds occur that do not respond to replacement therapy of the deficient coagulation factor. The reason may be pathologically reactive angiogenesis in chronic synovitis. Seven patients with severe haemophilia A or haemophilia B experienced recurrent massive bleeds of one elbow joint or knee joint in the absence of trauma. After initial application of factor VIII or IX (fVIII/fIX; 50 IU kg⁻¹ bodyweight), there was only slow and never complete relief of symptoms. Despite intensive secondary prophylaxis maintaining the plasma level of factor concentrate at minimum 50%, new massive bleeds at the same location occurred. Vascular bleeding was suspected. Angiography of the arteries was performed via the femoral artery. Vessels identified as potential bleeding sources were embolized with embolization fluid (ONYX) in eight joints (six elbow and two knee joints). Under low-dose prophylactic treatment (15 IU fVIII or fIX per kg bodyweight for three times per week), no recurrent severe bleed unresponsive to coagulation factor replacement occurred after a mean observation time of 16 months after embolization. The consumption of factor concentrate decreased to one-third of the amount consumed before embolization. In conclusion, angiographic embolization with a non-adhesive liquid embolic agent might be considered as a promising therapeutic and coagulation factor saving option in joint bleeds not responding to replacement of coagulation factor to normal levels.     

Operative management and outcomes in children with congenital bleeding disorders: a retrospective review at a single haemophilia treatment centre

Establishing haemostasis for surgical procedures in children with inherited bleeding disorders is challenging. Providers are often hesitant to undertake surgeries in children with bleeding disorders out of fear of bleeding complications. To review the preoperative management and haemorrhagic complications of children with inherited bleeding disorders at our institution, we conducted a retrospective electronic medical record review from 1999 to 2010. Primary focus was review of bleeding complications and factor replacement strategies. A total of 168 procedures were performed in 66 children. Fifteen procedures (8%) in four children were performed in the presence of high-titre factor inhibitors. Procedures included central venous catheter (CVL) placement or revision (41%), otolaryngology procedures (23%), dental (11%), non-synovectomy orthopaedic procedures (8%), synovectomy (5%), circumcision (5%) and miscellaneous (7%). All patients received preoperative factor replacement (100% in haemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life-threatening bleeding occurred with any procedure. Twelve of 168 procedures (7%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by haemorrhage 4 of 15 (26%) followed by nasal surgery (3/7 bleeds = 43%). The CVL surgeries were remarkably free of complications with only 1/69 (1.4%) with bleeding. Surgical procedures are safe in children with bleeding disorders with adequate planning and factor replacement. Bleeding remains a problem in a subset of patients and requires ongoing haematological involvement and oversight. Delayed bleeding following T&A was especially common and suggests a need for close follow-up and ongoing factor coverage for this group of patients.     

Feasibility, safety and cost-effectiveness of transjugular liver biopsy following major surgery in patients with haemophilia

Prior to the introduction of virally inactivated clotting factor concentrates, the majority of patients with haemophilia became infected with the hepatitis C virus. Although transjugular liver biopsy can be safely performed in these patients, the procedure is associated with a significant financial burden mainly related to replacement therapy with clotting factor. The purpose of this study was to evaluate the feasibility and safety of transjugular liver biopsy in patients with haemophilia substituted with clotting factor concentrates for major surgical procedures. Over the last 5 years, transjugular liver biopsy was performed in nine patients with haemophilia within 1-10 days after orthopaedic (7), thoracic (1) or abdominal surgery (1). All patients had abnormal liver function tests and persistent hepatitis C viraemia. At the time of the biopsy, patients received recombinant factor VIII delivered by dose-adjusted continuous infusion through a central catheter inserted preoperatively in the left internal jugular (n = 8) or in an ante-cubital vein (n = 1). Before the biopsy, basal FVIII levels were raised to 80-100% by a bolus infusion and maintained above 80% for 24 h. The biopsy was informative in all cases. Only one patient developed an episode of supraventricular dysrhythmia. No bleeding or infectious complications were observed. When compared with elective liver biopsy performed outside the postsurgical period, the cost-savings per biopsy were 19 875 +/- 2660 euro. This study shows that intensive replacement therapy required by surgical procedures provides a safe and cost-effective opportunity for transjugular liver biopsy in patients with haemophilia and active hepatitis C.