Surgery In Haemophilia Patients Research Articles

National survey of hepatobiliary and pancreatic surgery in hemophilia patients in Japan.

Approximately 8300 hemophiliacs are registered in Japan, but no comprehensive reports on hepatobiliary and pancreatic surgery (HBPS) have been conducted. This report investigates the current status of HPBS in hemophilia patients in Japan. The subjects were hemophiliac patients seen between January 1 2007, and December 31 2017, at facilities participating in this study among the facilities for performing high-difficulty cases nationwide designated by the Japanese Society for HBPS. A retrospective examination of short-term outcomes in 49 cases was conducted to assess patient background, disease, surgical procedure, and complications. The types of hemophilia were A: 43 cases, B: four cases, and von Willebrand disease: two cases (hemophilia severity: mild 32, moderate seven, severe 10). The target malignant diseases for surgery were hepatocellular carcinoma (HCC) in 20 cases, intrahepatic cholangiocellular carcinoma (CCC) in four cases, combined HCC-CCC in two cases, hilar CCC in two cases, and pancreatic cancer in four cases. As for the surgical procedure, limited resection (subsegmentectomy and partial hepatectomy) was performed in 16 cases of HCC even with normal liver function tests. Pancreaticoduodenectomy and distal pacreatectomy were performed for pancreatic cancers as in the standard procedure. Postoperative complications were postoperative bleeding in two cases after hepatectomy and one after pancreatectomy in one case. When compared with Japanese National Clinical Data base, the complication rates after hepatectomy and pancreatectomy were not conspicuous in hemophilic patients. As long as they are performed in qualified centers, complication rate is not increased in hemophilic patients undergoing HBPS.

Sequential bypassing agents during major orthopedic surgery: a new approach to hemostasis.

Sequential bypassing agents may be a safe and effective treatment during major orthopedic surgery in hemophilia patients with inhibitors.

Achievements, challenges and unmet needs for haemophilia patients with inhibitors: Report from a symposium in Paris, France on 20 November 2014.

Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non-genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen-specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper.

SURgical interventions with FEIBA (SURF): international registry of surgery in haemophilia patients with inhibitory antibodies

Factor VIII Inhibitor Bypassing Activity (FEIBA) can effectively achieve haemostasis in haemophilia patients with inhibitors. Further evaluation of FEIBA in surgical settings is of significant interest considering the relatively limited prospective data published to date. The aim of the study is to evaluate the perioperative efficacy and safety of FEIBA in haemophilia patients with inhibitors. Haemophilia patients with inhibitors who underwent surgical procedures and received FEIBA for perioperative haemostatic control were prospectively enrolled in an open-label, noninterventional, postauthorization study [SURgical interventions with FEIBA (SURF)]. Outcome measures included haemostatic efficacy, safety, FEIBA exposure and blood loss associated with the perioperative use of FEIBA. Thirty-five surgical procedures were performed at 19 centres worldwide in patients with congenital haemophilia A, congenital haemophilia B, or acquired haemophilia A. Haemorrhagic risk was severe in 37.1% (13 of 35) of the procedures, moderate in 25.7% (9 of 35) and mild in 37.1% (13 of 35). One moderate risk surgery was excluded from the efficacy analyses because it did not meet all protocol requirements. Haemostasis was judged to be 'good' or 'excellent' in 91.2% (31 of 34) of surgical procedures and 'fair' in 8.8% (3 of 34). Among the 12 adverse events, three were serious adverse events (SAEs), two of which were unrelated to FEIBA therapy; one SAE, a clot in an arteriovenous fistula, was deemed to be possibly related to therapy. This prospective investigation confirms that FEIBA can be safely and effectively used when performing surgical procedures in haemophilia patients with inhibitors.

Multidisciplinary management of patients with haemophilia with inhibitors undergoing surgery in the United States: perspectives and best practices derived from experienced treatment centres

Since the 1980s, major surgical interventions in patients with congenital haemophilia with inhibitors have been performed utilizing bypassing agents for haemostatic coverage. While reports have focused on perioperative management and haemostasis, the US currently lacks consensus guidelines for the management of patients with inhibitors during the surgical procedure, and pre- and postoperatively. Many haemophilia treatment centres (HTCs) have experience with surgery in haemophilia patients, including those with inhibitors, with approximately 50% of these HTCs having performed orthopaedic procedures. The aim of this study was to present currently considered best practices for multidisciplinary care of inhibitor patients undergoing surgery in US HTCs. Comprehensive haemophilia care in the US is provided by ~130 federally designated HTCs staffed by multidisciplinary teams of healthcare professionals. Best practices were derived from a meeting of experts from leading HTCs examining the full care spectrum for inhibitor patients ranging from identification of the need for surgery through postoperative rehabilitation. HTCs face challenges in the care of inhibitor patients requiring surgery due to the limited number of surgeons willing to operate on this complex population. US centres of excellence have developed their own best practices around an extended comprehensive care model that includes preoperative planning, perioperative haemostasis and postoperative rehabilitation. Best practices will benefit patients with inhibitors and allow improvement in the overall care of these patients when undergoing surgical procedures. In addition, opportunities for further education and outcomes assessment in the care of this patient population have been identified.

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.

Combined treatment with APCC (FEIBA®) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A – a two‐centre experience

The management of bleeding in haemophilia patients with inhibitors can be challenging when using monotherapy with either activated prothrombin complex concentrate (APCC) or recombinant activated FVII (rFVIIa) fail. The antifibrinolytic agent tranexamic acid (TXA) increases clot stability and is used concomitantly with coagulation factor replacement to improve haemostasis in haemophilia patients without inhibitors in many countries in Europe. Combined treatment with TXA and rFVIIa is not contraindicated in haemophilia patients with inhibitors. However, the combined approach of TXA and APCC has not been investigated due to safety concerns of increased risk of thrombosis or disseminated intravasal coagulation (DIC). The aim of this study is to report our experience of concomitant use of APCC and TXA in haemophilia A patients with inhibitor and in patients with acquired haemophilia A with respect to safety and efficacy. Seven (n = 6) haemophilia A patients with inhibitors and one (n = 1) with acquired haemophilia A from Oslo (Norway) and Stockholm (Sweden) were included in the study. The APCC was given at doses consistent to the manufacturers' recommendation. TXA was administered concomitantly either 10 mg kg(-1) every 6-8 h intravenously or 20 mg kg(-1) every 6-8 h orally. Haemostatic response was assessed by thromboelastography (TEG) and thrombin generation assay (TGA) in three of the patients. A total number of three bleeding episodes and two minor and six major surgical procedures were performed under the coverage with APCC and TXA. Haemostatic outcome was rated excellent or good in 10 of 11 (91%) treatment episodes. One episode was rated with poor effect. No episodes of arterial, venous thrombosis or DIC occurred during or after the treatment. Data from TEG and TGA analysis showed no signs of hypercoagulability following the combined treatment. This report demonstrates that, in a limited number of patients, combined treatment with APCC and TXA seemed to be safe, tolerated and relatively effective in management of bleeding episodes and in preventing haemorrhage during surgery in haemophilia patients with inhibitors and in a patient with acquired haemophilia A. Further studies should be performed to confirm these data.

First 20 years with recombinant FVIIa (NovoSeven)

This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma-derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non-inhibitor patients have been the efficacy of rFVIIa in home-treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270 μg kg(-1) instead of three injections of a dose of 90 μg kg(-1). The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell-based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30 nm or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well-structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation.

Cardiovascular disease in haemophilia patients: a contemporary issue

Improvements in treatment options and healthcare provision mean that haemophilia patients now have a life expectancy approaching that of the normal male population. An increased life expectancy, however, also brings an increased risk of developing age-related disorders, the foremost of which is cardiovascular disease. The epitome of age-related morbidity, cardiovascular disease is also a leading cause of mortality in elderly individuals, and presents a particular challenge when it occurs in persons with haemophilia. While the exact incidence of cardiovascular disease in haemophilia is unknown, incidence rates from conditions such as ischaemic heart disease (IHD) have steadily risen over the last 20-30 years, suggesting that cardiac problems are increasingly relevant for these patients. Management of cardiovascular disease in haemophilia warrants close cooperation between cardiologists and haematologists, and evidence-based guidelines are not available. In the absence of such guidelines, antithrombotic treatment is currently based on local clinical experience and adaptation of the general guidelines used in the non-haemophilic population. In this article, we outline the local guidelines used by our two centres in the antithrombotic treatment of IHD, coronary bypass and valve surgery, and atrial fibrillation in patients with haemophilia. Strategies for the management of haemostasis and thrombosis during cardiovascular surgery in haemophilia patients are also briefly reviewed. Finally, we present the cases of three elderly haemophilia patients with cardiovascular and other age-related health problems in whom such treatment strategies were applied.

Surgery in haemophilia patients with inhibitors, with special emphasis on orthopaedics: Madrid experience

We report on a series of 92 surgical procedures (90 patients). It includes 35 orthopaedic procedures (33 patients) and 57 non-orthopaedic procedures (57 patients). The orthopaedic procedures include 27 radiosynovectomies (minor surgery) and eight major orthopaedic procedures. The non-orthopaedic procedures include 52 minor interventions and five major procedures. The average age of patients was 34 years (range: 8-56), and the average follow-up time was 3 years (range: 1-6). Of the 92 surgical procedures, 42 were performed with activated prothrombin complex concentrates [factor eight inhibitor bypassing agent (FEIBA)] and 47 with recombinant-activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Regarding FEIBA treatment in minor surgery, the initial dose was 100 IU kg(-1). After 6 h, we continued with 50 IU kg(-1) every 12 h for at least 4 days (radiosynovectomies). In minor non-orthopaedic procedures, the dose was continued until day 14. In patients who underwent surgery with the haemostatic control achieved by means of rFVIIa, the initial dose of rFVIIa in minor procedures (both orthopaedic and non-orthopaedic) was 90-120 microg kg(-1). In postoperative days 1-5, the dose was 2-4 x 90-120 microg kg(-1) q3-6 h for 24 h. In major procedures (both orthopaedic and non-orthopaedic), the dose was 120 microg kg(-1) pre-operatively, 120 microg kg(-1) q 3 h day 2/day 3-5, and then 90-120 microg kg(-1) q 6 h until day 14. There were 87 good results, four fair results and one poor result. Our study has shown that haemophilic patients with inhibitors requiring surgery can undergo orthopaedic and non-orthopaedic procedures with a high expectation of success. In other words, surgery (orthopaedic and non-orthopaedic) is now possible in haemophilia patients with inhibitors, leading to an improved quality of life for these patients.

Risk‐sharing approach for managing factor VIIa reimbursement in haemophilia patients with inhibitors

Managing orthopaedic surgery in haemophilia patients with inhibitors [1] raises formidable economic issues that are similar to those raised by the new targeted anticancer agents [2]. 1 The payment-by-results approach [3,4] has been designed to manage high-cost therapeutic problems in which an immediate decision is needed in terms of access to treatment and reimbursement, but effectiveness data and therapeutic guidelines are still preliminary. Thus far, this approach has been mainly used to handle innovative antineoplastic agents as well as high-cost medical devices [3–5]. At our institution, an experimental reimbursement model for managing peri-operative treatment with factor VIIa in haemophilia patients with inhibitors has been developed in which the economic risk of a more than average expenditure per patient is equally shared by the third payer (our regional health system) and the manufacturer. This model is conceptually very simple: in fact, all FVIIa doses exceeding the cumulative limit of 5 mg kg in a given patient are subjected to 50% discount; in addition, an appropriate registry is set up to document analytically the dosing history of all operated patients. According to this model, the so-called excess dose is first calculated as follows:

Co‐morbidity in the ageing haemophilia patient: the down side of increased life expectancy

Because of an increased life expectancy, (age-related) co-morbidity is becoming a common occurrence in haemophilia patients. In this review, haemophilia-related and non-haemophilia-related medical problems, treatment recommendations and psychosocial consequences in ageing haemophilia patients are discussed. Haemophilic arthropathy is an important cause of pain and disability, and a frequent indication for surgery in haemophilia patients. In addition, many adult patients are infected with hepatitis C or HIV, the consequences and treatment of which can add to physical and mental discomfort. Moreover, inhibitors against factor VIII can also develop in adulthood, especially in patients with mild haemophilia. Hypertension is reported to occur more often in haemophilia patients than in the general population. Other internal problems, like renal abnormalities, overweight, diabetes mellitus and hypercholesterolemia are discussed. Haemophilia seems to protect against cardiovascular disease, although the incidence is increasing. Recommendations are given on dealing with tooth extractions, surgical interventions and sexuality problems in patients with haemophilia. In addition to haemophilia in itself, co-morbidity has a major psychological impact, and an important effect on quality of life. It can also result in complex treatment regimens, in which coordination between health care workers is essential.

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

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.

Orthopaedic surgery in haemophilia patients with inhibitors as the last resort

Haemophilia patients with inhibitors commonly present much more severe musculoskeletal problems than patients without inhibitors. With haematological advances using recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), it is now possible to perform orthopaedic procedures in these patients with a high rate of success. In Spain, the healthcare system sets no financial limits for the treatment of haemophilia, and children with haemophilia today have a much better musculoskeletal status than 30 years ago. However, the children of 30 years ago are now adults and are afflicted by severe articular deformities that frequently require the intervention of an orthopaedic surgeon. Our view is that the well-known concepts of prophylaxis in patients without inhibitors should be followed and applied to patients with inhibitors. In fact, prophylaxis seems to be the only way to prevent the development of haemophilic arthropathy in patients with haemophilia. Until this goal can be achieved, major and minor orthopaedic procedures will be necessary in patients with inhibitors more frequently than in patients without inhibitors.

Economic evaluation of major knee surgery with recombinant activated factor VII in hemophilia patients with high titer inhibitors and advanced knee arthropathy: exploratory results via literature-based modeling

ABSTRACTObjectives: People with severe hemophilia suffer from frequent intra-articular hemorrhages, leading to pain, swelling, reduced flexion, and arthropathy. Elective orthopedic surgery using factor VIII (FVIII) replacement to prevent uncontrolled bleeding has been endorsed as an effective treatment option for patients with severe or advanced hemophilic arthropathy. These surgeries reduce pain, restore mobility and function, and reduce the frequency of recurrent joint bleeds. Unfortunately, some patients with hemophilia develop inhibitors to FVIII, which neutralize FVIII activity and render the use of even massive amounts of FVIII replacement ineffective and surgery very risky. For this reason, elective surgical procedures in high-titer inhibitor patients had largely been abandoned until the introduction of new agents, such as recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Denmark). rFVIIa has been shown effective for prophylaxis during elective surgery and has therefore improved the feasibility of orthopedic surgery in hemophilia patients with high-titer inhibitors. The present research explored, from a modified US payer perspective, the direct economic and quality of life benefits of four different elective knee surgeries (total knee replacement [TKR], knee arthrodesis [KA], proximal tibial osteotomy, and distal femoral osteotomy) with rFVIIa coverage in hemophilia patients with high-titer inhibitors.Methods: An exploratory literature-based life-table model was developed to compare the direct medical costs and quality of life of two hypothetical cohorts of high-titer inhibitor patients with frequent bleeding episodes: one undergoing and the other not undergoing elective knee surgery. Knee surgery costs included perioperative rFVIIa costs, inpatient and rehabilitation care, and repeat procedures due to surgery failure, prosthesis loosening or deep infection. Based on efficacy studies, knee surgery was assumed to reduce mean annual bleeding episodes at the affected joint from 9.13 to 1.64. The cost of managing each bleeding episode was estimated at $15 298. Thus, by reducing bleeding episodes, surgery was expected to result in related cost offsets. All costs were expressed in 2006 US dollars. Surgery was also assumed to result in gains in quality of life by reducing pain and reducing bleeding episodes. The impact of pain reduction on quality of life and utility was estimated by simulating EQ-5D scores for a typical patient with and without knee surgery.Results: Based on the model, average knee surgery costs are predicted to range from a low of $694 000 (for KA) to a high of $855 000 (for TKR). However, knee surgery is also expected to reduce the subsequent number of bleeding episodes and resultant costs, leading to long-term costs savings. Due to improvement in pain levels, surgical patients are expected to experience improvements in quality-adjusted life-years (QALYs). Thus, surgery appears to be the preferred strategy (i.e., saves costs and increases QALYs). Based on the assumptions used in the model, the initial cost of knee surgery was offset during the 8th and 10th years for KA and TKR, respectively, with intermediate break-even time for the other surgeries. As expected, cost savings and gains in QALYs increased over time, as well as the cost effective­ness of knee surgery. Specifically, the cost per QALY with KA and TKR fell under $50 000/QALY during the 6th and 8th years, respectively, with intermediate time for the other surgeries.Conclusions: The present exploratory analysis is based on the long-term extrapolation of data from a small number of patients without inhibitors and short-term studies. It suggests that major knee surgery utilizing rFVIIa in hemophilia patients with inhibitors may be cost-effective on average, with expected cost savings apparent within a decade of knee surgery. The present exploratory results should be validated with real-world, longitudinal patient data.

Patient-Related Outcomes of Elective Major Orthopedic Surgery in Severe Hemophilia Patients: A Review of the Literature and a Proposed Agenda for Research.

Objectives: Severe hemophilia patients experience frequent spontaneous joint hemorrhages, which lead to severe pain and swelling, reduced flexion and function, and ultimately debilitating arthropathy. Elective major orthopedic surgery (e.g., total joint replacement) in patients with advanced arthropathy is increasingly considered to reduce pain, improve function, and reduce joint bleeds. This analysis reviewed the impact of surgery on quality of life and other humanistic outcomes in hemophilia patients with advanced arthropathy.Materials and Methods: A systematic search of the published literature was conducted to identify studies reporting on the humanistic and patient-related outcomes of major orthopedic surgery in patients with hemophilia and advanced arthropathy. Studies were included if they reported quality of life (QOL), pain, functional status and work and productivity outcomes. Wherever possible, data were extracted and normalized across various scoring systems (WOMAC, WFH, HSS, Cleveland Rating, and Knee Society) for comparisons across studies.Results: A total of 32 studies were examined. Among those, only one included a formal, validated QOL instrument (WOMAC) with pre/post surgery data. This study documented dramatic improvements in objective and patient perceived QOL measures. Of the other 31 studies, 4 provided sufficient pre/post surgery data to facilitate a quantitative assessment of other key humanistic and patient-related outcomes. In 50 patients pooled across these four studies, all (100%) had moderate or severe pain in the targeted joint prior to surgery. After surgery 86% (43/50) reported no pain at follow up. Improvements were also reported regarding functional status, where 100% of 16 cases pooled across two studies had severe or moderate loss of function prior to joint surgery and 31% (5/16) regained full function upon follow up. Similar, if not better, results were reported in studies that reported only average scores across pain and function parameters. It was found that joint pain was the most prevalent complaint prior to surgery and was the primary indication for surgery. Anecdotal evidence from the 32 studies indicates that improvements in pain and function following surgery were so significant in some patients that they were able to rejoin the workforce and take part in recreational activities, including sports. There were several reports of patients who were unable to walk long distances or were confined to wheelchairs before surgery who became able to walk several blocks unaided following surgery.Conclusions: Major elective orthopedic surgery in hemophilia patients with advanced arthropathy is one of the most effective medical interventions, with success rates in terms of pain reduction over 80%. However, the broader impact of surgery on QOL outcomes, which appears excellent, remains to be better documented. To that effect, the systematic use of a set of validated instruments to be administered before and after surgery is recommended to help document the outcomes of these surgeries.

Case studies: orthopaedic surgery in adult patients with haemophilia A with inhibitors

Whilst orthopaedic surgery in haemophilia patients without inhibitors is now relatively common in specialized centres, until recently there have been only a few sporadic instances of surgery having been undertaken on patients with inhibitors. The availability of recombinant activated factor VII (rFVIIa) for haemostatic cover during surgery allows procedures to be performed that previously may not have been considered possible. Complications associated with thrombosis are rare in haemophilia patients with inhibitors, but bleeding complications remain a concern. Globally, experience of performing orthopaedic surgery in these patients is increasing and many successful outcomes have been reported. However, more knowledge relating to the incidence and type of bleeding complications liable to be encountered, together with further information about appropriate rescue treatment, would be valuable. Data relating to long-term follow-up after surgery would be useful, as would a comparison of outcomes between haemophilia patients with and without inhibitors. Optimal dosing regimens for rFVIIa as surgical cover are still to be determined and further information is required relating to the cost effectiveness of rFVIIa in surgery. Further study should address these issues.

Identifying and managing inhibitor patients requiring orthopaedic surgery – the multidisciplinary team approach

Until recently, surgery in haemophilia patients with inhibitors was strongly contraindicated and was therefore often not even contemplated. Inhibitor patients entering the surgical arena face unique challenges; the most frequently encountered problem during surgical intervention is bleeding, and thrombosis is occasionally observed. The activated prothrombin complex concentrate, FEIBA(TM), and recombinant activated factor VII (rFVIIa) are available as haemostatic cover during surgery. The use of rFVIIa enables inhibitor patients to undergo orthopaedic surgery with an expectation of success, and results are generally good. An organized team approach is critical to this success. However, further information is required to enable different procedures to be optimized in terms of both outcome and safety.

An Open-Label, Randomized, Parallel, Multi-Center Trial Comparing the Safety and Efficacy of rFVIIa When Administered as I.V. Bolus or I.V. Continuous Infusion to Hemophilia Patients with Inhibitors during and after Surgery.

Background and Purpose: Bolus infusion (BI) of recombinant FVIIa (rFVIIa) is effective for the treatment of bleeding and surgical prophylaxis in congenital hemophilia A or B patients with FVIII or IX inhibitors. In principle, continuous infusion (CI) of rFVIIa could maintain the hemostatic effect at a steady state while avoiding the peaks and troughs of repetitive BI. The purpose of this study was to compare the efficacy and safety of rFVIIa CI with rFVIIa BI in major surgery in hemophilia patients with inhibitors. Methods: A 10-day, open-label, randomized, multicenter trial was conducted in hemophilia A or B patients (age > 5 yr) with inhibitors to FVIII or FIX who underwent elective major surgery. Patients received rFVIIa as an initial bolus dose of 90 μg/kg followed by intermittent i.v. bolus (90 μg/kg) or i.v. continuous (50 μg/kg/hr) infusion. BI was administered every 2 hours during surgery and through Day 5, then every 4 hours for Days 6 to 10. CI was administered at 50 μg/kg/hr through Day 5 and at 25 μg/kg/hr Days 6 to10. A third control group of 10 non-inhibitor hemophilia A or B patients who underwent similar surgery and were treated with FVIII or FIX (based on current standard of care and physician’s choice) was assessed to compare adverse event and coagulation profiles. Safety was assessed throughout the study periods. Efficacy was defined as having no treatment failures during the given time and was evaluated at 48 hours, 5 days, and 10 days postoperatively. Treatment was considered ineffective in patients who received more than 2 additional doses of rFVIIa beyond the protocol-defined doses during a 24 hour period. Patients who received alternative hemostatic therapy following the permitted two additional doses of rFVIIa were considered treatment failures. Results: Twenty-four patients (12 CI arm, 12 BI arm) underwent 9 major types of surgeries. Knee (n=11) and hip (n=3) replacements were the most common surgeries. Recombinant FVIIa efficacy in major surgeries was 92% (11 CI, 11 BI) at 48 hours; 83% (10 CI) and 92% (11 BI) at Day 5; 83% (10 CI) and 75% (9 BI) at Day 10. Sixty-six rescue doses (rFVIIa, 90 μg/kg) were administered in the CI group (54 in one patient), and 7 in 3 patients in the BI group. Adverse events occurred more frequently in the CI treatment group (239; 141 in one patient) compared to the BI group (89 AEs); 64 AEs occurred in the control group. Eight patients (3 CI, 4 BI, 1 control) experienced 10 serious adverse events (SAEs). SAEs occurred most frequently in the BI treatment group (3 CI, 6 BI, 1 control). The types of SAEs were equally distributed among the three groups. There were no serious thromboembolic events reported during the study. Conclusions: This summary of 24 major surgeries indicates that rFVIIa is effective as prophylactic therapy for major surgery in hemophilia A or B patients with inhibitors. The numbers of patients were too small to distinguish efficacy rates between the two groups. The safety profile for patients treated with rFVIIa (BI or CI) was similar to the profile for non-inhibitor patients treated with other factors. Presented on behalf of the NovoSeven in Surgery Study Investigators.

Consensus perspectives on surgery in haemophilia patients with inhibitors: summary statement.

Summary. Participants in an international workshop on surgery in haemophilia patients with inhibitors developed a consensus summary of the findings and conclusions of the meeting. In the consensus, participants agreed upon revised definitions for minor and major surgery, including an intermediate degree of surgery. An evaluation system of intraoperative and postoperative bleeding was developed. Recommended doses of FEIBA((R)) and rFVIIa (both in bolus injections and in continuous infusion) for surgery were agreed. Participants also agreed on the main blood tests to be performed peri-operatively. They also suggested the need of a prospective evaluation in the future. Finally, the approximate number of surgical procedures and costs performed on haemophilia patients with inhibitors were analysed.