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.     

Orthopaedic surgery in haemophilic patients with inhibitors: an overview

Our experience and a review of the literature on inhibitors have shown that, with the availability of recombinant factor VIIa (rFVIIa), haemophilic patients with high inhibitor titres requiring elective orthopaedic surgery can undergo such surgery with a high expectation of success. The advent of rFVIIa has made major elective orthopaedic surgery possible in haemophilic patients with high-titre inhibitors, resulting in an improved quality of life. Recombinant FVIIa appears to be an efficient haemostatic product for surgery in patients suffering from haemophilia A and B with inhibitors. The series of major elective orthopaedic surgical procedures using rFVIIa (n=53) is the largest ever reported in haemophilic patients with inhibitors, despite the long-standing presence of other treatment modalities, such as high-dose human factor VIII (FVIII), porcine FVIII (n=8), and prothrombin complex concentrates/activated prothrombin complex concentrates (n=9). Thorough analysis of each case as part of a multidisciplinary team will allow us to perform elective orthopaedic procedures in 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.     

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.     

Recombinant activated factor VII safety and efficacy in the treatment of cranial haemorrhage in patients with congenital haemophilia with inhibitors: an analysis of the Hemophilia and Thrombosis Research Society Registry (2004–2008)

Summary. Cranial haemorrhage (CH) is a potentially serious complication in patients with severe congenital haemophilia with inhibitors (CHwI). Treatment includes bypassing agents, such as recombinant activated factor VII (rFVIIa). To examine the US experience in treating CH with rFVIIa, a retrospective review of the Hemophilia and Thrombosis Research Society 2004–2008 database was conducted. Among 29 patients with CHwI, 56 of the reported haemorrhages met the study criteria. Of these, 75% were traumatic and 80% were extracranial (ECH). The majority (8/11, 73%) of intracranial haemorrhages (ICHs) developed spontaneously. Conversely, most ECHs (39/45, 87%) followed trauma. ICHs were treated with a median/mean of 23/58 rFVIIa infusions over a median/mean of 7/9 days while ECHs were treated with a median/mean of 1/3 infusions (P = 0.011) over a median/mean of 1/1 day. The median/mean initial rFVIIa doses for all CHs were 106/137 μg kg⁻¹, and were similar for ICHs and ECHs. All ECHs were effectively controlled with rFVIIa; 44/45 bleeds were controlled within 24 h, one bleed was successfully treated perioperatively, and 27 ECHs required only a single dose. Nine out of 11 ICHs were effectively treated with rFVIIa; six ICHs were controlled within 24 h, one within 72 h and in two cases haemostasis was achieved during the perioperative period. No serious treatment‐associated adverse events were reported. One patient died as a result of ICH despite the reported control of bleeding. In conclusion, standard dosing of rFVIIa was found to be safe and effective in treating CH with an efficacy rate of 100% for ECH and 82% for ICH.     

Elective surgery in patients with congenital coagulopathies and inhibitors: experience of the National Haemophilia Centre of Venezuela

Summary. Elective surgery in patients with congenital haemophilia with inhibitors carries a high risk of bleeding. However, inhibitor patients also have a high risk of haemarthroses and other orthopaedic complications, and surgery could improve their quality of life. Successful elective surgery has been reported in inhibitor patients under haemostatic cover with plasma‐derived activated prothrombin complex concentrate (pd‐aPCC) or recombinant activated factor VII (rFVIIa). Recombinant FVIIa has recently become available in Venezuela and, unlike pd‐aPCC, has not been associated with an anamnestic response. The aim of this study was to assess our experience using rFVIIa as a first‐line and sustained treatment in elective invasive surgical procedures at the National Haemophilia Centre in Venezuela. Surgical procedures were classified as major or minor, under haemostatic cover with rFVIIa. A total of 13 patients (12 with haemophilia A with high‐responding inhibitors and one with von Willebrand’s disease type 3) underwent a total of 19 surgical procedures under rFVIIa cover. Thirteen procedures were classified as major surgeries. Intraoperative haemostasis was achieved in the majority of patients. Only two patients required an additional dose of rFVIIa, at 30 min and 75 min, respectively, with good results. Postoperative haemostasis was considered effective in 16 of 18 (89%) of the procedures in haemophilia A patients. Treatment was considered to be ineffective in two patients because of excessive postoperative bleeding. Data from the study provide no safety concerns, and demonstrate that rFVIIa provides effective haemostatic cover in elective surgery in patients with inhibitors; research is ongoing to determine the optimal dose for such procedures.     

Major orthopaedic surgeries for haemophilia with inhibitors using rFVIIa

Summary. Between 2000 and 2008, 11 major orthopaedic surgeries for 7 congenital haemophilia patients with inhibitors were performed by the first author as the primary doctor using recombinant activated factor VII (rFVIIa). Orthopaedic surgical treatments were performed for six surgeries for four high‐responder haemophilia A patients, three surgeries for two high‐responder haemophilia B patients and two surgeries for one low‐responder haemophilia B patient. This low‐responder patient is allergic to factor IX products, so he usually uses rFVIIa as a haemostatic agent. All of the surgeries were major, such as joint arthroplasty, arthroscopic synovectomy, and a combination of both, and excellent surgical results were achieved. Seven cases were controlled by bolus infusion of rFVIIa, and the other four cases were controlled by combined bolus and continuous infusion of rFVIIa. An anti‐fibrolytic agent was used for all cases. There were no thrombogenic adverse effects, only two bleeding episodes. As for haemostatic control, nine surgeries were excellent, one was good and one was fair. This report is the largest clinical report on major orthopaedic surgeries at a single institute. We have concluded that the combination of bolus and continuous infusion of rFVIIa is safe and effective, and more convenient to administer than simple bolus infusion therapy to achieve haemostasis at peri‐operative periods. In addition, our data also concurs with the data of several previous reports which showed that orthopaedic surgery for haemophilia patients with inhibitors by means of rFVIIa is safe and effective.     

Cost minimization analysis to compare activated prothrombin complex concentrate (APCC) and recombinant factor VIIa for haemophilia patients with inhibitors undergoing major orthopaedic surgeries

Summary. Benefits of bypassing agents for maintaining haemostasis in major surgeries have been described in the literature; however, their use has a substantial economic impact. This study assessed the cost of FEIBA, an activated prothrombin complex concentrate and recombinant factor VIIa (rFVIIa) when used in inhibitor patients undergoing major surgeries. After reviewing published literature, a cost minimization model was developed describing dosing regimens recommended and used during major surgeries for FEIBA (pre‐operative: 75–100 U kg⁻¹; postoperative: 75–100 U kg⁻¹ q 8–12 h days 1–5 and 75–100 U kg⁻¹ q 12 h days 6–14) and rFVIIa (pre‐operative: 90 μg kg⁻¹; intra‐operative: 90 μg kg⁻¹ q 2 h; postoperative: 90 μg kg⁻¹ q 2–4 h days 1–5 and 90 μg kg⁻¹ q 6 h days 6–14). Using a 75 kg patient and US prices, total drug cost was calculated for three scenarios: use of FEIBA or rFVIIa alone and a third case combining rFVIIa pre‐ and intra‐operative and FEIBA throughout a 14‐day postoperative period. Dosage amounts of modelled bypassing agents were similar to cases in the literature. Using FEIBA instead of rFVIIa would decrease total drug cost by >50% and save over $400 000 per surgery. Sequential use of both bypassing agents would increase total drug cost by 9% when compared with FEIBA alone, but would remain >40% lower than rFVIIa alone. Univariate sensitivity analyses confirmed robustness of results. As large amounts of bypassing agents are necessary for patients with inhibitors to undergo major surgeries, cost is a major consideration. Use of FEIBA alone or in combination with rFVIIa has emerged as a cost‐saving approach.     

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

Summary.  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.     

Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

Summary. This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2 ± 9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80–120 μg kg^?1 every 2 h and APCC 100 IU kg^?1 every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg^?1) were used at 2‐h intervals followed by additional three doses at 6‐h intervals. The initial dose of APCC was 75 IU kg^?1 followed by a second and third dose of 50 IU kg^?1 at 12‐h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor‐positive haemophiliacs, allowing both major and minor surgery to be successfully performed.     

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

Summary.  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.     

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.     

Results of the WIRK prospective,non‐interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders

Recombinant activated factor VII (rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors (CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real‐life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 ± 545.8 μg kg^?1 and 3.6 ± 4.6 respectively. No drug‐related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders.     

Major surgery in severe haemophilia A with inhibitors using a recombinant factor VIIa and activated prothrombin complex concentrate hybrid regimen

Major surgery in persons with haemophilia A and inhibitors is increasingly being performed. Both recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC) are used to cover surgery but it remains unclear what the optimal dosing schedules are. We describe the use of a hybrid regimen in four inhibitor patients undergoing eight major surgical procedures using rFVIIa in the initial 2–6 postoperative days followed by FEIBA^® for the remaining period. All patients were also treated with tranexamic acid while receiving rFVIIa. We performed six major orthopaedic procedures, one emergency orchidectomy and one open appendectomy. The dosing schedules were at the higher end of those described in the literature but within the recommendations of the summary of product characteristics. Despite this, we encountered non‐surgical bleeding in four of eight episodes. Three of these occurred in one individual suggesting a patient factor. The overall outcome was good for all episodes. The hybrid regimen combines flexibility of dose and dosing frequency of rFVIIa in the immediate postoperative setting with the advantage of a reduced dosing frequency with FEIBA^® in the subsequent days. This study also emphasizes that surgical procedures in this patient group remain a challenge.     

Elective orthopaedic surgery for haemophilia patients with inhibitors: single centre experience of 40 procedures and review of the literature

Summary. With the introduction of safe and effective factor VIII/IX‐bypassing agents – recombinant activated factor VII (rFVIIa) and plasma‐derived activated prothrombin complex concentrates (pd‐APCC) – elective orthopaedic surgery (EOS) is a viable option for haemophilia patients with inhibitors. We report a series of patients with haemophilia and inhibitors undergoing EOS between 1997 and 2008 using bypassing agents to provide haemostatic cover. All inhibitor patients undergoing EOS and receiving rFVIIa, plasma‐derived prothrombin complex concentrates (pd‐PCC) or pd‐APCC as haemostatic cover were included. Patients were operated on by the same surgeon and were managed by the same haemophilia treatment centre. Forty procedures (25 minor and 15 major) were conducted in 18 patients. Twenty‐one minor cases were covered using rFVIIa, three with pd‐PCC, and one with pd‐APCC; all major cases were covered using rFVIIa. Bleeding was no greater than expected compared with a non‐haemophilic population in all 25 minor procedures. In the major procedure group, there was no excessive bleeding in 40% of cases (6/15) and bleeding completely stopped in response to rFVIIa. For the remaining nine cases, bleeding response to rFVIIa was described as ‘markedly decreased’ or ‘decreased’ in 4/15 cases and ‘unchanged’ in 5/15 cases. Overall, efficacy of rFVIIa, based on final patient outcome, was 85%. One death occurred as a result of sepsis secondary to necrotizing fasciitis. Good control of haemostasis can be achieved with bypassing agents in haemophilia patients with inhibitors undergoing minor EOS; rFVIIa was used as an effective bypassing agent, enabling EOS in patients undergoing minor and major procedures.     

Elective orthopaedic surgery for inhibitor patients

We report on a series of 108 elective orthopaedic surgical procedures. It includes 88 radiosynoviortheses and 20 major orthopaedic procedures, performed on 51 patients at nine centres worldwide. The average age of patients was 28.5 years (range 5-40 years), and the average follow-up time was 2 years (range 1-5 years). There were 82 good results, 15 fair and 11 poor. In the synoviorthesis group (41 patients, 88 synoviortheses) the average age was 14.3 years (range 5-40 years) and the average follow-up was 6.5 years (range 1-10 years). There were 66 good results, 14 fair and eight poor. There were no complications. In the group of major orthopaedic procedures, the average age of the 10 patients was 32.5 years (range 27-40 years), and the average follow-up was 2.3 years (range 1-5 years). There were 16 good results, one fair and three poor. Postoperative bleeding complications occurred in three of the 20 major orthopaedic procedures performed (15% complications rate). They occurred in three patients treated with insufficient doses of recombinant activated factor VII. Despite such complications, the study has shown that haemophilic patients with inhibitors requiring elective orthopaedic surgery (EOS) can undergo such procedures with a high expectation of success. In other words, EOS is now possible in haemophilic patients with inhibitors, leading to an improved quality of life for these patients. Thorough analysis of each case as part of a multidisciplinary team will allow us to perform elective orthopaedic procedures in patients with inhibitors.     

Surgery in haemophilic patients with inhibitor: 20 years of experience

Summary.  Surgery in haemophilic patients with inhibitor against factor (F)VIII or FIX is high risk. Surgery may be performed with the administration of sufficiently high dose of FVIII in patients with low-response inhibitor or who, despite having a high response, present a low inhibitor titre at the time of surgery. The use of high doses of FX is more complicated in patients with a low-titre FIX inhibitor, as there is a high risk of anaphylactic reactions. In the case of patients with high-titre inhibitors, several treatments have been proposed, such as porcine FVIII, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrate (APCC). We present our 20 years' experience in the treatment and subsequent management of haemophilic patients with inhibitor in surgery and evaluate the results obtained with the products available for haemostatic control in 64 surgical procedures. The efficacy we obtained with FVIII is good in 100% of the cases described; we had no haemorrhagic complication (HC) in the 18 procedures in which it was used (three major and 15 minor surgery). With APCC we obtained excellent results with only one HC in a synoviorthesis in the form of bleeding and haematomas out of 32 procedures. Good results were obtained with rFVIIa with few haemorrhagic episodes. Thus, in major surgery there was one HC out of three cases. In minor surgery, greater efficacy was observed using extremely large doses of rFVIIa (≥ 120 mg kg⁻¹ 2h⁻¹) because of the shorter half-life of this factor in this type of patients.     

Surgical interventions in a cohort of patients with haemophilia A and inhibitors: an experiential retrospective chart review

Strategies for the management of perioperative bleeding in patients with haemophilia and inhibitors have evolved rapidly as a result of the development of the bypassing agents Factor Eight Inhibitor Bypassing Activity, Anti-inhibitor Coagulant Complex (FEIBA) and activated recombinant factor VII (rFVIIa). However, there are currently no established guidelines for perioperative use of bypassing agents, and few controlled clinical studies have been carried out. Thus, case reports, such as those presented here, provide useful anecdotal evidence to guide the treatment of inhibitor patients. The purpose of this report was to describe experiences in the use of bypassing agents in a small cohort of patients with haemophilia A and inhibitors undergoing surgical procedures. Cases from five treatment centres were reviewed. Twenty-two procedures using FEIBA, rFVIIa or a combination of both agents were compiled from seven inhibitor patients (six with an alloantibody inhibitor and one with an acquired autoantibody inhibitor). Eleven procedures used FEIBA monotherapy, two employed rFVIIa monotherapy and nine were performed using combination therapy. Supplemental therapies were required to manage bleeding in some cases. Haemostatic control was achieved in all cases, and treatment regimens were generally well tolerated. One thrombotic adverse event was reported: evidence of disseminated intravascular coagulation (DIC) was found after rFVIIa use in one case, although the direct cause of DIC was unknown. The experiences in this case review demonstrate that both major and minor surgical procedures can be safely performed in patients with haemophilia and high-titre inhibitors under the cover of bypassing agents, with a high expectation of success.     

Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE)

Patients with congenital haemophilia with inhibitors experience acute bleeds managed with bypassing agents, such as recombinant FVIIa (rFVIIa). Home-based treatment and dosing patterns in the US remain poorly described. This study aimed to assess the prescribed and actual rFVIIa dosing in frequently bleeding inhibitor patients (≥4 bleeds in 3 months) prescribed first-line therapy with rFVIIa. Patients or caregivers recorded daily diaries, including the details of all bypassing agent infusions for 3-6 months. Median (range) initial rFVIIa dose prescribed for joint, muscle and other bleeds was 167.5 (61.0-289.0) mcg kg(-1). Additional rFVIIa doses prescribed were 90 (61-270) mcg kg(-1) at an interval of 2.5-3 (1-24) h. The actual initial rFVIIa dose reported by patients/caregivers for 158 bleeds was 212 (59-400) mcg kg(-1), with total dose per episode of 695 (74-21257) mcg kg(-1). Patient/caregiver-reported average dose per bleed was 146 (40-400) mcg kg(-1) across 5 (1-106) infusions. The initial rFVIIa dose was higher for haemarthrosis (223 [59-400] mcg kg(-1)) than muscle bleeds (148 [74-300] mcg kg(-1); P = 0.07). Initial and mean dose per day changed as treatment progressed. The DOSE study indicates that frequently bleeding inhibitor patients are prescribed and use higher rFVIIa dosing for all bleed types than recommended in the package insert (90 mcg kg(-1)). The rFVIIa dosing was highly variable within and across bleed types, with higher initial doses used for joint bleeds than muscle and other bleed types, particularly in the first days of treatment. This suggests that patients/caregivers have adopted home treatment strategies based on physician discretion and individual responses and experience.     

Orthopaedic surgery for inhibitor patients: a series of 27 procedures (25 patients)

We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8-53) and the average follow-up time was 2.5 years (range:1-5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9-26) and the average follow-up was 4.5 years (range: 1-7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg(-1,) except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg(-1). In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11-53) and the average follow-up was 2.5 years (range: 1-5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high-titre inhibitors, leading to an improved quality of life for these patients.