Hemophilia is the most common bleeding disorder in the US, and is estimated to affect one in 5,000 males.1 The disorder is the result of a deficiency in either factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B). The main treatment for the condition is through replacement therapy with either recombinant or plasma-derived factor concentrates. The most serious complication resulting from treatment with replacement therapy is the development of inhibitors to FVIII, which occurs in approximately 15–30% of patients with FVIII deficiency and 3–5% of patients with FIX deficiency.2–5 The development of inhibitors results in the lack of response to replacement therapy and can result in severe bleeding complications, including multiple joint bleeds, muscle bleeds, and deep-tissue bleeds that can be life- or limb-threatening.6
Patients with inhibitors can be characterized as having high- or low-risk inhibitors. Patients with low-responding inhibitors (peak titers ≤5 Bethesda units (BU)/ml) can often be treated successfully with higher doses of the deficient factor.7 Unfortunately, many hemophilia patients with inhibitors are high responders and develop high-titer inhibitors (>5BU/ml).8 In these patients, immune tolerance therapy (ITT) has been used successfully to eliminate inhibitors, although approximately 30% of patients with inhibitors fail to respond to ITT and have inhibitors for life.9 In patients who do not achieve tolerance to inhibitors, bypassing agents are administered to treat bleeds. Activated prothrombin complex concentrate (aPCC) in the form of FEIBA (factor VIII inhibitor-bypassing activity; Baxter, Deerfield, IL, US) has been used as a bypassing agent in high responders for decades. More recently, recombinant activated factor VII (rFVIIa; Novoseven; Novo Nordisk, Bagsvaerd, Denmark) has been added to the therapeutic armamentarium. These agents have demonstrated efficacy in treating bleeds in patients with inhibitors.10,11
Bleeding episodes can lead to the development of arthropathy and, potentially, permanent disability. This risk is even greater in patients with inhibitors.6,12 Thus, surgery is often advisable in patients with hemophilia because it may lead to an improved quality of life. While surgical procedures in hemophilia patients without inhibitors is normally performed with FVIII concentrates, in inhibitor patients FVIII is ineffective and can cause an anamnestic response, which can lead to a tendency to avoid or postpone elective surgery in this group of patients.13 However, the use of bypassing agents such as rFVIIa and aPCC to initiate and maintain hemostasis during and after surgery has been shown to reduce the risks associated with surgical procedures in hemophilia patients with inhibitors.14–20
The Efficacy of Bypassing Agents in Surgery in Hemophilia Patients with High-titer Inhibitors
The majority of the data for the efficacy of bypassing agents in surgery with hemophilia patients with inhibitors are based on small series or case studies. There is also a lack of comparative data for aPCC versus rFVIIa in the surgical setting.
Activated Prothrombin Complex Concentrate
aPCC in the form of FEIBA contains the pro-enzymes of the prothrombin complex factors prothrombin, FVII, FIX, and FX, but—with the exception of FVIIa—only very small amounts of their activation products.17,21 aPCC has been shown to generate thrombin and shorten clotting time. aPCC administration triggers the formation of prothrombinase complex, thus enhancing thrombin production and resulting in the formation of a clot. In a retrospective multicenter French study including 21 surgical episodes (18 minor and three major surgery), aPCC doses varying between 78 and 210IU/kg for minor surgery procedures and 210IU/kg for major surgery obtained good response in 95% of the episodes.14 Rodriguez-Merchan et al. reported a series of 47 minor and four major elective orthopaedic surgical procedures in hemophilia patients with inhibitors treated with FEIBA.18 The results of the study suggested that hemophilia patients with inhibitors can undergo such procedures with a high expectation of success. Quintana-Molina et al. reported the 20-year single-center experience in the treatment and subsequent management of hemophilia patients with inhibitors in surgery. aPCC was associated with excellent results, with only one hemorrhagic complication in 32 procedures.20 Tjønnfjord and colleagues reported results of 14 minor and five major surgical procedures performed with aPCC in patients with hemophilia and high-titer inhibitors.22 A pre-operative dose of 100IU/kg of aPCC was administered followed by three doses of 200IU/kg/day. Following this regimen, no adverse bleeding occurred; however, one case of myocardial infarction was reported.
aPCC has been linked to thrombotic complications, including acute myocardial infractions. However, these events are rare and it has been recommended that the risk of a thrombotic event may be mitigated by limiting the maximum daily dose of FEIBA to 200IU/kg.23 FEIBA has also been associated with anamnesis.14 The use of aPCC for surgery in hemophilia patients with inhibitors needs further study to determine its potential.
Recombinant Activated Factor VII in Surgery
rVIIa is structurally similar to human plasma FVIIa. It has a complex mechanism of action that includes tissue-factor-dependent and -independent triggering of coagulation. It can bind to the surface of activated platelets, thereby directly activating FX, leading to improved generation of thrombin.24 rFVIIa has been shown to be effective in achieving hemostasis in hemophilia patients with inhibitors in about 80% of cases.25
rFVIIa in surgery has been evaluated in one prospective randomized trial, one open-label randomized trial, and several case study reports. One of the earliest case studies was reported by Hedner et al. in 1988. Hemostasis was achieved successfully using rFVIIa with no serious side effects or abnormal bleeding after surgery for open knee synovectomy in a hemophilia patient with an FVIII inhibitor.26 Ingerslev et al. reported data on 12 patients undergoing lifesaving or essential surgery.27 Administration of rFVIIa was used to promote hemostasis during surgery and the overall efficacy was reported as excellent in 92% of cases (n=11).
The highest-quality evidence for the use of rFVIIa in surgery comes from the prospective randomized trial, which included 28 patients undergoing minor and major surgery, 12 of whom were under 12 years of age.16 The patients were split into different dosage groups and significant differences were noted post-operatively (three to five days after surgery) between the doses in favor of a 90μ/kg of bodyweight dose. However, the 35μ/kg dose was still effective in patients undergoing minor surgery. Treatment with rFVIIa was successful in 89% of children under 12 years of age. One four-year-old boy suffered from a side effect and developed internal jugular thrombosis. However, he was also noted to have an anatomical abnormality, with difficulty in catheter placement resulting in increased vessel trauma, which could have contributed to the thrombic occurrence. Additional support for the use of the 90μ/kg rFVIIa dose was provided by a study evaluating the effect of rFVIIa in 22 patients aged one to 70 years during surgery and post-operatively.28 Administration of 90μ/kg rFVIIa gave a 91% hemostatic success rate.
Following this result, rFVIIa was used successfully in 66 patients undergoing orthopaedic operations using a pre-operative dose of 150μ/kg and post-operative doses of the same at two-hour intervals.18 In most cases, antifibrinolytic drugs were used alongside rFVIIa. Studies to date indicate that rFVIIa allows surgeons to perform elective orthopaedic surgery with hemophilia patients with inhibitors by providing adequate hemostatic treatment. Most of these procedures would not have been possible without rFVIIa because of the difficulties in overcoming the inhibitors even with the use of high doses of FVIII or FIX.
Central line insertion is necessary to administer large doses of factor concentrate during ITT in children with hemophilia with inhibitors.29 Recombinant FVIIa has been used successfully to provide hemostatic prophylaxis for central catheter insertion in adults,30 hence there is much interest in the use of the factor in the pediatric population. The experiences in three children with severe hemophilia and high-responding inhibitors undergoing four central catheter insertions have been judged excellent or effective.31 The children in the study were treated with 90μ/kg of rFVIIa administered two-hourly for one day and four-hourly for a further two days, together with tranexamic acid.
The optimal dosing regimen for rFVIIa bypassing therapy in surgery has yet to be defined. Lower doses are much less effective at controlling bleeding, and continuous infusion with rFVIIa is not approved and has been associated with dissemination intravascular coagulation;32 however, a recent study reported that the hemostatic efficacy and safety of bolus infusion and continuous infusion of rFVIIa were comparable for the surgical management of hemophilia subjects with inhibitors.33 As seen with aPCC, infrequent thrombotic adverse events have been reported for rFVIIa.34 However, rFVIIa has not been associated with anamnestic response as has been reported for aPCC.
Synergistic Use of Recombinant Activated Factor VII and Activated Prothrombin Complex Concentrate
The synergistic use of rFVIIa and aPCC has also been studied. A 56-year-old Caucasian woman with high-titer factor VIII autoantibody presented with hematuria, lower abdominal and hip pain, and marked ecchymosis of both lower extremities. The patient initially showed a sub-optimal response to rFVIIa. However, an in vitro test showed that this patient had an exceptionally strong response to rFVIIa when it was added to whole blood after the patient received aPCC therapy.25 One patient in this series—a 27-year-old African-American male with severe factor IX deficiency and inhibitors presenting with bleeding into the mesentery of the small bowel—suffered from disseminated intravascular coagulation, indicating that the dosage of the two-factor regimen needs to be adjusted to increase safety.
The use of rFVIIa alongside aPCC in hemophilia has been associated with thrombosis and hence few studies have been performed.35 In 2004, combination therapy with rFVIIa and aPCC was successful at treating bleeds in five severe hemophilia patients with inhibitors under the recommendation of administration for severe bleeds only and in the inpatient setting under constant supervision.36 As a follow-up to this study, four further patients with severe hemophilia A with inhibitors were treated for severe bleeds with the combination therapy, successfully demonstrating its safety in this setting.37 A larger randomized, prospective study is required to evaluate the effects of dual treatment in hemophilia patients with severe bleeds.
Monitoring Bypassing Treatment
Neither aPCC nor rFVIIa is as effective as native FVIII or FIX in controlling bleeding. In addition, some patients react differently to the same treatment regimens, making it difficult to predict whether rFVIIa is the correct treatment to use.38 Furthermore, as yet there is no reliable laboratory parameter that can predict the response to therapy in the same manner in which FVIII and FIX levels predict response in non-inhibitor patients.
Proposed methods include activated clotting time, thrombin generation assay (TGA), thromboelastography (TEG), activated partial thromboplastin time (aPTT), and waveform analysis, although none is universally accepted.38–41 There are advantages and disadvantages to each of the assays. The ideal assay needs to be able to assess the clinical response to treatment inexpensively, and easily and rapidly provide reproducible results. TEG is a device used to measure clot formation over time in whole blood, and has been used to monitor treatment with rFVIIa and aPCC in three separate patients in whom it allowed improvements to be made in each of their treatment regimens.38 This device is promising for the monitoring of bypass therapy in the future, possibly during surgery, and merits further study.
Another method that has been used to monitor bypass treatment in hemophilia patients with inhibitors is the TGA. This assay measures the overall thrombin capacity of plasma after treatment with aPCC.41,42 This assay has shown potential for the monitoring of patients treated with aPCC and therefore could be a useful tool in surgery for assessing the success of the treatment.
Cost of Bypassing Agents in Surgery
The development of inhibitors in a hemophilia patient has a major impact on treatment costs.43 Indeed, the mean cost of treatment for patients with high-titer inhibitors is estimated to be approximately three times more than that for non-inhibitor hemophilia patients over a period of two years.44
Currently, there are few alternatives to bypassing agents in surgery for hemophilia patients with inhibitors, hence the main issue of cost-effectiveness is whether the surgery is necessary. Cost is assessed on the severity of the surgical requirement of the patient: for example, if the patient presents with appendicitis, surgery is the definitely required; however, if the patient has specific joint complaints, the benefits of surgery are assessed carefully. Surgery is usually performed in inhibitor patients only if the condition is life-threatening or if the perceived benefits of the surgery outweigh the risks.
The development of inhibitory antibodies to the transfused clotting factor in hemophilia patients is a serious complication. Major surgery in patients with hemophilia with inhibitors was extremely rare before 1990; however, since then substantial experience of surgery has been accumulated in these patients. Moreover, the dramatic improvements in the management of hemophilia seen in the last few decades now mean that, with proper planning, major and minor surgical procedures can be performed safely in hemophilia patients with inhibitors using aPCC or rFVIIa. Several investigations are currently under way to further investigate the clinical usefulness of prophylactic administration of bypassing agents. Further prospective randomized trials comparing aPCC with rFVIIa in the surgical setting will also help to guide clinicians in the choice of therapeutic interventions. Finally, a validated assay to help clinicians assess treatment will be an invaluable addition to the treatment options. ■