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.     

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.     

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.     

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.     

Ten‐year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.     

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.     

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.     

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.     

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.     

Management of haemophilic patients with inhibitors in major orthopaedic surgery by immunadsorption, substitution of factor VIII and recombinant factor VIIa (NovoSeven®): a single centre experience

Inhibitors of factor VIII or FIX in haemophilic patients are a common and serious complication associated with an increased risk of life-threatening bleeding during elective surgery. Substitution therapy fails to be effective, therefore an alternative treatment is needed. We have performed six major elective orthopaedic interventions in four patients with haemophilia A and inhibitors. A preoperative immunadsorbant therapy with Therasorb to eliminate inhibitors was successful in four cases, but during FVIII substitution inhibitors increased on day 4 to day 6 after surgery, leading to decreasing FVIII levels. Therefore, therapy was changed to recombinant FVIIa (rFVIIa; NovoSeven). Two interventions had to be covered with sole rFVIIa therapy as immunadsorbant therapy failed to be effective in one case and the need for acute intervention did not allow pretreatment in the other. We did not see increased bleeding during or after surgery when compared to our experience with non-inhibitor haemophilic patients. In conclusion, a preoperative decrease of inhibitors from immunadsorbant therapy, perioperative substitution of FVIII and changing treatment to rFVIIa when inhibitors are increased, is a safe and economic therapy for guaranteeing haemostasis in major elective orthopaedic surgery. On the contrary, sole therapy with rFVIIa allows immediate surgical intervention without a long hospital stay prior to surgery and a need for laboratory monitoring of inhibitor titres and FVIII levels. Our findings support data previously published.     

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.     

Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey

Long used in established industrialized nations to treat patients with haemophilia and inhibitors, factor eight inhibitor bypassing activity (FEIBA) has, in recent years, been introduced into more geographically diverse settings. Data are needed on how successfully FEIBA therapy has been implemented in new regions. To determine the efficacy and safety of FEIBA for the treatment of acute bleeding and surgical haemostasis in a newly industrialized country. A multicentre registry of haemophilia A patients with inhibitors receiving FEIBA treatment was established in Turkey. With a standardized case report form, data were collected retrospectively on: patient demographics; characteristics of acute bleeding episodes and surgical interventions; FEIBA regimen; and treatment outcomes. Thirty-seven patients received a total of 112 FEIBA treatment courses, 90 for acute bleeding and 22 for surgical haemostasis. The median FEIBA dose per infusion for acute bleeding was 50 IU kg(-1), and for surgery was 100 IU kg(-1). For both acute joint and muscle/soft tissue bleeding and in surgery, haemostasis was attained in a median of two FEIBA infusions. FEIBA was judged effective in 92% of treatment courses for acute bleeding, with a 95% confidence interval (CI) of 85-97%. Rates of haemostatic efficacy did not differ significantly between anatomical sites of acute bleeding. The haemostatic efficacy rate of FEIBA in surgery was 86% (CI, 65-97%). No thromboembolic complications or other adverse events occurred during any treatment course. FEIBA has been successfully integrated into clinical practice in Turkey, with rates of haemostatic efficacy comparable to those reported in countries with a longer history of FEIBA usage.     

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.     

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.     

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.     

Aspects of current management: orthopaedic surgery in haemophilia

Summary. If continuous prophylaxis is not feasible due to expense or lack of venous access, we must aggressively treat major haemarthroses (including arthrocentesis) to prevent progression to synovitis, recurrent joint bleeds, and ultimately end‐stage osteoarthritis (haemophilic arthropathy). For the treatment of chronic haemophilic synovitis, radiosynovectomy should always be indicated as the first procedure. If, after three procedures with 6‐month interval, radiosynovectomy fails, an arthroscopic synovectomy must be indicated. Between the second and fourth decades, many haemophilic patients develop joint destruction (arthropathy). At this stage possible treatments include alignment osteotomy, arthroscopic joint debridement, arthrodesis (joint fusion) and total joint arthroplasty. For the hip press‐fit uncemented components (hemispherical acetabulum, flanged femoral stem, metal‐to‐polyethylene) are recommended whilst for the knee a posterior‐stabilized (PS) cemented design is advised. Muscular problems must not be underestimated in haemophilia due to their risk of developing compartment syndromes (which will require surgical decompression) and pseudotumours (which will require surgical removal or percutaneous treatment). Regarding patients with inhibitors, the advent of APCCs and rFVIIa has made major orthopaedic surgery possible, leading to an improved quality of life for haemophilia patients. Concerning local fibrin seal, it is not always necessary to achieve haemostasis in all surgical procedures performed in persons with haemophilia. However, it could be a good adjunct therapy, mainly when a surgical field potentially will bleed more than expected (i.e. patients with inhibitors), and also in some orthopaedic procedures (mainly the surgical removal of pseudotumours).     

Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity. This was a multicentre, open-label, compassionate-use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life- or limb-threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for FVII-deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing. During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well-tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.     

A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: a pharmacokinetic and efficacy evaluation

After surgery in haemophilia, haemostasis is difficult to maintain in the presence of an antifactor VIII antibody. This study assessed the pharmacokinetics of recombinant activated factor VII (rFVIIa) and its efficacy in securing post-operative haemostasis in haemophiliacs with inhibitors. Continuous infusion of rFVIIa was evaluated for elective major orthopaedic surgery in nine patients with neutralizing antibodies to FVIII and at high risk of bleeding. After an initial preoperative bolus of 90 micro g/kg, rFVIIa was infused at a fixed rate of 50 micro g/kg/h for a median of 20 d (range 7-20 d). The median plasma FVII coagulant activity (FVII:C) at 24 h, 72 h and 20 d after surgery was 38 IU/ml (range 22-169 IU/ml), 45 IU/ml (range 17-88 IU/ml) and 31 IU/ml (range 27-46 IU/ml) respectively. The median plasma FVIIa:C at the same time points was 51 (range 24-211), 63 (range 22-99) and 44 (range 28-76) IU/ml respectively. Median total rFVIIa clearance remained stable during the rFVIIa continuous infusion period and was 40 (range 9-70), 34 (range 17-86) and 48 (range 32-55)ml/kg/h at the end of 24 h, 72 h and 20 d infusion respectively. Post-operatively, there were bleeds in six patients, which settled readily after a single bolus of rFVIIa (60 micro g/kg). There was a good clinical outcome for all patients. These data indicate that rFVIIa infusion at 50 micro g/kg/h achieves continuous plasma FVII procoagulant activity in excess of 30 IU/ml (12-15 nmol/l) and provides adequate haemostatic control for inhibitor patients during major orthopaedic surgery.     

Experience of four UK comprehensive care centres using FEIBA® for surgeries in patients with inhibitors

Summary. Increasing evidence indicates that factor VIII (FVIII) inhibitor bypassing agents (FEIBA^® and NovoSeven^®) can provide effective peri‐operative haemostasis in haemophilia patients with high‐responding inhibitors. We report the collected experience of all major and minor surgeries, conducted between December 1998 and September 2008, at four UK haemophilia Comprehensive Care Centres with FEIBA^® as the first‐line bypassing agent in patients with inhibitors. A total of 26 surgical procedures were performed in 18 patients of ages 34–83 years including five patients with acquired FVIII inhibitors. A single pre‐operative infusion of FEIBA was followed by 6–12 h interval dosing for major surgeries at the discretion of the physician to approximate a maximum of 200 U kg^?1 day^?1, with tapering when postoperative haemostasis and wound healing permitted. Haemostatic outcomes were retrospectively reviewed against European consensus thresholds for blood loss and duration of treatment compared with expectations for equivalent procedures in non‐inhibitor patients. Peri‐operative haemostatic outcome with FEIBA was rated excellent or good in 78% of 18 major surgeries in 12 patients, including 11 major orthopaedic procedures. Haemostatic outcome was rated excellent in all seven procedures in five patients with acquired FVIII inhibitors and in all eight minor surgical procedures in six patients. FEIBA was well tolerated with no intra‐operative haemostatic complications. A single, transient postoperative thrombotic adverse event occurred in a patient with cerebrovascular disease. This case series adds significantly to existing evidence that FEIBA can provide adequate, well‐tolerated, peri‐operative haemostatic cover for a wide variety of major and minor surgical procedures.