Concomitant infusion of low doses of rFVIIa and FEIBA in haemophilia patients with inhibitors

Summary.  Patients with severe haemophilia A and an inhibitor may become refractory to FEIBA and/or recombinant factor VIIa (rFVIIa). Sequential therapy with both products has been reported in such patients. In this pilot study, we examined the safety and efficacy of combined rFVIIa and FEIBA therapy in patients with haemophilia A and inhibitors during bleeding episodes. We also tried to evaluate whether thrombin generation (TG), by various mixtures of these agents, can serve as a guide for tailoring therapy. TG was measured in plasma taken from eight haemophilia A patients. Increasing concentrations of rFVIIa, FEIBA or both were added ex vivo to the plasmas, and TG was induced by recalcification. Since low concentrations of rFVIIa and FEIBA had either an additive or a synergistic effect in all patients, the lowest combination, yielding TG comparable or lower than TG achieved with either FEIBA 100 U kg⁻¹ or rFVIIa 160 μg kg⁻¹ alone, was selected for the treatment of bleeding episodes. Five patients with a high titre of an inhibitor (8–1300 BU), including one previously refractory to infusions of rFVIIa at doses up to 400 μg kg⁻¹ X4 daily, were treated with combinations of 30–70 μg kg⁻¹ rFVIIa and 20–30 U kg⁻¹ FEIBA during a total number of 400 bleeding episodes with excellent haemostatic effect. No adverse events and no DIC were observed following these infusions. Concomitant infusion of low-dose rFVIIa and low-dose FEIBA, seems to be safe, efficacious and economical in patients refractory to rFVIIa and probably other haemophilia A patients with an inhibitor.     

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

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

Prevention of haemarthrosis in a murine model of acute joint bleeding

Summary.  Preservation of normal joint function in patients with haemophilia is a goal of modern therapy. Regular injections of anti-haemophilic factor concentrate reduce the risk of joint bleeding, the optimal regimen for which remains under investigation. The goals of the experiment described here are: (i) to assess the capacity of a murine model of severe haemophilic arthropathy to predict the likelihood of success of a test product to prevent joint bleeding and the complications that follow and (ii) to compare the effectiveness of recombinant human activated factor VII (rFVIIa) to recombinant human factor VIII (rFVIII) to prevent acute joint bleeding in the mouse model of haemarthrosis. Mice lacking expression of FVIII received a single intravenous injection of human rFVIII (280 U kg⁻¹), rFVIIa (10 mg kg⁻¹) or vehicle prior to blunt trauma injury to the knee joint. Mice receiving rFVIII and rFVIIa developed less injury-induced joint bleeding, swelling and loss of range of motion compared to mice pretreated with vehicle. Despite the reduction in clinical symptoms, synovial hyperplasia was evident in all groups after 7 days although less pronounced in mice receiving rFVIII and rFVIIa. The data under these experimental conditions demonstrate: (i) that this model can be used to evaluate novel therapies designed to prevent joint bleeding (prophylaxis) and (ii) both rFVIII and rFVIIa reduced acute haemarthrosis but did not completely prevent synovitis, the sequelae of blood induced joint injury.     

Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic

Summary.  Identifying haemophilia patients with inhibitors for clinical trials is difficult due to the limited number of patients available. Registries are therefore being established as an additional means of data collection. The aim of this study was to investigate the effect of different recombinant activated factor VII (rFVIIa; NovoSeven^®) dose ranges and dosing schedules on the incidence of re-bleeding in haemophilia patients with inhibitors. In this retrospective, uncontrolled study, data on the bleeding patterns of adult haemophilia patients with high responding inhibitors were analysed. Only data from the Czech Republic, obtained by the HemoRec registry, were used. This study analysed 'real-life' clinical data and focused on the collection of the same parameters in different patients: time from bleeding onset to first injection, effect of first injection, number of re-bleedings, total number of injections and total amount of haemostatic drug used. Fifteen patients met the inclusion criteria and were included into the study (128 bleeding episodes). Patients treated within 2 h of bleeding onset experienced less re-bleeding than patients treated after 2 h of bleeding onset (5.2% vs. 13.7%, respectively). In addition, patients who were treated after 2 h of bleeding onset experienced fewer re-bleedings when high-dose rFVIIa was used (15.8% and 0%; <120 μg kg⁻¹ and >250 μg kg⁻¹, respectively). Initial high-dose rFVIIa was also associated with a decline in total rFVIIa consumption. This registry has provided a unique insight into the bleeding patterns of inhibitor patients, highlighting the importance of early treatment initiation and appropriate starting dose.     

Some recent developments regarding arthropathy and inhibitors in haemophilia

Summary.  In this paper, the most recent developments on arthropathy and inhibitors in haemophilia are reviewed. Firstly, early long-term prophylaxis is strongly recommended in children with severe haemophilia. Secondly, in joint bleeds not responding to substitution of factor VIII to normal factor VIII levels angiographic embolization might be considered as a promising therapeutic option. Thirdly, recent data indicate disruption of normal development for adolescents with inhibitors. Fourthly, some case reports indicate the benefit of secondary prophylaxis with recombinant factor VIIa (rFVIIa) or factor eight inhibitor bypassing activity (FEIBA) in patients with severe haemophilia A and inhibitors. Finally, surgical procedures in haemophilia patients with factor inhibitors can be accomplished safely and effectively with FEIBA and/or rFVIIa, although the risk of complications is higher than in haemophilia patients without inhibitors.     

Single-dose (270 μg kg−1) recombinant activated factor VII for the treatment and prevention of bleeds in haemophilia A patients with inhibitors: experience from seven European haemophilia centres

Summary.  Several studies have suggested that recombinant factor VIIa (rFVIIa) is effective and safe at doses >90 μg kg⁻¹. In March 2007, the European Medicines Agency approved the use of single-dose rFVIIa 270 μg kg⁻¹ for the treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors. The aim of this study was to describe the use of single-dose rFVIIa in a real-life setting. In November 2007, seven haemophilia specialists from five European countries convened to share and discuss their experiences with the single-dose rFVIIa regimen within haemophilia A. Case histories of eight patients were discussed in this retrospective study. Six adult and two paediatric patients (age range, 19 months–40 years) were treated with single-dose rFVIIa for a variety of target-joint bleeding, other bleeds and bleeding prevention. Treatment was successful in all the eight cases, with most patients requiring one dose to achieve bleeding resolution. No thrombotic or other safety concerns were raised by single-dose rFVIIa treatment. All patients and physicians preferred single-dose rFVIIa treatment to multiple injections; key benefits of single-dose rFVIIa treatment reported by patients and physicians included improved quality of life, greater convenience and ease of administration, improved compliance, faster control of bleeding, less injection-related pain and faster pain relief. In the patients reported here, single-dose rFVIIa 270 μg kg⁻¹ appears to be an effective and safe haemostatic treatment that improves the quality of life and convenience of treatment for patients. Such treatment might be of particular benefit for patients with difficult venous access or needle phobia.     

Efficacy of recombinant activated factor VII vs. activated prothrombin complex concentrate for patients suffering from haemophilia complicated with inhibitors: a Bayesian meta-regression

Summary.  The optimal on-demand treatment of joint bleeds in haemophilia patients with inhibitors is a source of debate, with studies reporting various efficacy levels for different drugs and dosage regimens. To analyse, in a unified Bayesian meta-regression model, the published efficacy of recombinant activated factor VII (rFVIIa) and/or activated prothrombin complex concentrate (aPCC) as on-demand treatments for joint bleeds in haemophilia patients with inhibitors. A systematic search was carried out to identify studies reporting on dosage and efficacy of rFVIIa and aPCC in the treatment of joint bleeds in the target patient population. Data were abstracted and included in the model and adjusted for potential sources of heterogeneity. Pooled efficacy levels for typical rFVIIa and aPCC regimens were estimated. Seventeen studies, collectively reporting on >2000 joint bleeds, were included. Medication type combined with dosage was the only significant explanatory parameter. The model predicts that a typical regimen of 90 μg kg⁻¹ rFVII repeated every 3 h if needed results in cumulative joint bleed resolution of 66%, 88% and 95% after 12, 24 and 36 h, respectively. In comparison, a typical regimen of 75 IU kg⁻¹ aPCC repeated every 12 h if needed results in cumulative joint bleed resolution of 39%, 62% and 76%, respectively. These differences were statistically significant and were also robust in sensitivity analyses. This analysis suggests that a typical rFVIIa regimen will resolve joint bleeds more effectively than a typical aPCC regimen after 12, 24 and 36 h.     

Thrombin generation in vitro in the presence of by-passing agents in siblings with severe haemophilia A

Summary.  Previous data have shown an inter-individual difference in the thrombin generating capacity in vitro as well as phenotypic bleeding pattern among patients with severe haemophilia A (FVIII:C activity below 1%). The reason for this is not known. In addition, there are no reports on how thrombin generation may correlate between siblings. In this study, we evaluated and compared thrombin generation in vitro using plasma samples in the presence of by-passing agents (FEIBA^® and NovoSeven^®) in 21 unrelated brother pairs with and without inhibitors enrolled in the Malmö International Brother Study (MIBS). Mean maximum thrombin formation in patients with a current inhibitor titer was 182.0 ± 52.8 mmol mL⁻¹ (FEIBA^®) and 130.7 ± 54.9 mmol mL⁻¹ (rFVIIa), respectively, and somewhat higher in those without inhibitors, 222.7 ±85.5 mmol mL⁻¹ (FEIBA^®) and 142.8 ±53.6mmol mL⁻¹ (rFVIIa) ( P  = 0.16 and 0.29). The variance regarding the maximum thrombin production within a family was significantly lower compared with the thrombin production between families ( P  < 0.001 for both FEIBA^® and NovoSeven^®). Our data indicate that genetically determined factors, other than the FVIII:C activity seems to influence the phenotypic variation in thrombin formation in the presence of by-passing agents. The nature of these determinants remains to be identified.     

Recombinant factor VIIa in continuous infusion during central line insertion in a child with factor VIII high-titre inhibitor

Recombinant factor VIIa (rFVIIa) is a recently added new tool for the treatment of haemophilia patients with inhibitors. A major drawback in the use of rFVIIa is its short half-life, which necessitates frequent bolus injections. Thus the use of rFVIIa in continuous infusion appears to be a good alternative. We describe the use of rFVIIa, administered by continuous infusion with a minipump during the insertion of a central venous catheter in a child with a high-titre factor VIII inhibitor. rFVIIa was administered as an intravenous bolus (90 μg kg⁻¹ [4.5 kIU kg⁻¹]), 1 h prior to central line insertion, after which the continuous infusion was immediately started for 5 days. The infusion rate was based on the clearance obtained from a previous pharmacokinetic study. Effective haemostasis and normal healing of surgical incisions were achieved after central line insertion. No local thrombophlebitis nor evidence of generalized activation of the coagulation cascade was observed. Single-dose pharmacokinetic parameter values were clearance (Cl) 34.6 mL h⁻¹ kg⁻¹, volume of distribution (Vd) 40.6 mL kg⁻¹ and mean residence time (MRT) 1.17 h. The recovery was 2.27% U⁻¹ kg⁻¹. rFVIIa showed a monophasic decay. Cl during continuous infusion was 23.4 ± 6.9 mL h⁻¹ kg⁻¹. The administration of rFVIIa by continuous infusion is effective, safe and more convenient when compared to other clotting factors. Moreover, continuous infusion provides significant economic savings (77% decrease in rFVIIa requirements).     

Thrombin generation and platelet activation induced by rFVIIa (NovoSeven®) and NN1731 in a reconstituted cell-based model mimicking haemophilia conditions

Summary.  Replacement therapy with factor VIII (FVIII) and factor IX (FIX) is routinely used in haemophilia patients with haemophilia A and B, respectively, while recombinant activated FVII (rFVIIa) has proven to induce haemostasis in haemophilia patients with inhibitors. To evaluate the effect of therapeutic intervention in patients with residual factor activities, the effects of increasing concentrations of rFVIIa or NN1731 on thrombin generation and platelet activation were measured in a cell-based model system mimicking severe, moderate and mild haemophilia A or B. Purified monocytes stimulated to express tissue factor and non-activated platelets from peripheral blood of healthy donors were incubated with a mixture of purified human coagulation factors in the absence or presence of increasing concentrations of FVIII or FIX. Sub-samples were analysed for thrombin activity and platelet activation measured as exposure of P-selectin by flow cytometry. Dose-dependent increases in thrombin generation and platelet activation were observed following increasing concentrations of rFVIIa or NN1731 in both haemophilia A- and B-like conditions. At 25 n m rFVIIa, which nears the peak levels in patient plasma after 90 μg kg⁻¹ intravenous dosing, the effects on maximum thrombin generation rate (maxTG) at 1–10% FVIII were comparable to those at 100% and 200% FVIII in the absence of rFVIIa. Normalization of maxTG required 500 n m rFVIIa and 25 n m NN1731 or 25–100 n m rFVIIa and 5 n m NN1731 in severe or moderate/mild haemophilia A and haemophilia B, respectively. This suggests that NN1731 holds its promise as a future bypassing agent for haemophilia patients with and without inhibitors.     

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.     

Factor VIIa analogue (V158D/E296V/M298Q-FVIIa) normalises clot formation in whole blood from patients with severe haemophilia A

This study evaluated and compared the haemostatic potential of a recombinant factor VIIa (rFVIIa) analogue (V158D/E296V/M298Q-FVIIa, NN1731, Novo Nordisk, Denmark) with rFVIIa (NovoSeven^®, Novo Nordisk). In vitro studies were performed using freshly drawn whole blood (WB) from 14 patients with severe haemophilia A and two patients with inhibitory antibodies to FVIII, comparing NN1731 and rFVIIa against a buffer control. Fourteen healthy males served as controls. Dynamic WB coagulation profiles were recorded, quantitatively illustrating the initiation [clotting time = CT (s)], propagation [maximum velocity = MaxVel (mm*100/s)] and termination [maximum clot firmness = MCF (mm*100)] as determined by thromboelastography with minute amounts of tissue factor (TF, Innovin^®– final dilution 1:50 000, c. 0·12 pM) serving as activator. WB clot stability was assessed using a separate set-up including TF plus tissue plasminogen activator (final concentration 2 nmol/l), evaluating the MCF as well as the area under the elasticity curve (AUEC) after 60 min (mm*100*s). NN1731 shortened the CT more markedly than rFVIIa. At the dose tested, NN1731 even shortened CT in haemophilia below the value of healthy males. NN1731 accelerated MaxVel giving a value indistinguishable from that in healthy males. Furthermore, NN1731 increased clot stability more markedly than rFVIIa. Altogether, these in vitro studies on WB revealed a favourable haemostatic potential of NN1731 compared with rFVIIa in severe haemophilia A, both in the absence and presence of enhanced fibrinolytic activity.     

Activated prothrombin complex concentrate (FEIBA®) treatment during surgery in patients with inhibitors to FVIII/IX: the updated Norwegian experience

Summary.  Non-activated and activated prothrombin complex concentrates have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 15 minor and six major surgical and invasive diagnostic or therapeutic procedures in eight inhibitor patients with congenital haemophilia A and in two patients with acquired haemophilia. Administration of a loading dose of 100 U kg⁻¹ of FEIBA^® followed by 200 U kg ⁻¹ day ⁻¹ in three doses every 8 h for 3 days and then tapering the daily dose to 150–100 U kg⁻¹, resulted in no severe or unexpected bleeding complications. One adverse event was observed. A 69-year-old man suffered a myocardial infarction the third postoperative day following sigmoidectomy. He was managed safely with opiate analgesia, nitrates and diuretics and the continued use of FEIBA^®.     

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.     

Long-term prophylaxis in severe haemophilia seems to preserve bone mineral density

Summary.  It has been previously shown that patients with severe haemophilia and not receiving any prophylactic treatment render a high risk of reduced bone mineral density. The purpose of this study was to evaluate bone mineral density (BMD) in patients with haemophilia of different severity types and treatment. The study group consisted of 26 patients with severe haemophilia (aged 33.6 ± 2.1) and 16 patients with mild haemophilia (aged 40.2 ± 3.3). The BMD (g cm⁻²) was measured by dual-energy X-ray absorptiometry (DXA). Physical activity was assessed by a self-report questionnaire. Physical activity was scored as duration (h week⁻) and as metabolic physical activity score by weighing the intensity (MET-h week⁻¹). Joints were evaluated according to a physical examination score. There was no significant difference in BMD at lumbar spine L1–L4 (mild, 1.214 vs. severe, 1.175; P  = 0.329), total hip (1.085 vs. 1.001, P  = 0.114), femoral neck (1.036 vs. 0.977, P  = 0.265), trochanter (0.896 vs. 0.820, P  = 0.131) and whole body (1.215 vs. 1.183, P  = 0.325) between those with mild and severe haemophilia. Based on Z -score, both groups had normal BMD (Z score >−1). In patients with severe haemophilia, there was a significant correlation between joint evaluation score and BMD at total hip ( P  < 0.0001), femoral neck ( P  = 0.0003) and trochanter ( P  = 0.003). Physical activity did not correlate to disease severity. We did not observe a correlation between BMD and severity of haemophilia. The results indicate that the use of factor prophylaxis since early childhood may preserve normal BMD in severe haemophilia.     

HIV-disease progression in Swedish haemophiliacs and the influence of replacement therapy

HIV-disease progression in terms of the decline in CD4⁺ cell count, the development of AIDS-related symptoms and death was studied in 100 Swedish HIV-positive haemophiliacs and correlated to age and haemophilia treatment.
On average 15 years after seroconversion, 66% of the patients had CD4⁺ cell counts of < 200×10⁶ L⁻¹, 48% had developed AIDS and 56% had died. Age was found to correlate to all three endpoints, also after adjustment for age, annual clotting factor concentrate (CFC) consumption and HIV-related therapy, i.e. pneumocystis prophylaxis and antiretroviral drugs ( P  < 0.05). Total annual CFC consumption showed no significant relationship to the decline in CD4⁺ cell counts but was inversely correlated to both the development of AIDS-related symptoms ( P  = 0.033) and mortality ( P  = 0.014). Prophylactic treatment was not associated with significantly better survival than on-demand treatment after adjustment for age, CFC consumption and HIV-therapy. The use of monoclonal-antibody-purified CFCs was not found to stabilize the decline in CD4⁺ cell counts. However, the use of these CFCs was inversely correlated both to the development of AIDS-related symptoms and to mortality ( P  = 0.042 and 0.027, respectively). A similar trend was associated with the use of low- and intermediate-purity CFCs. As compared with the severe haemophilia A subgroup, the moderate haemophilia A patients showed a trend toward slower disease progression, possibly attributable to a lower incidence of haemarthrosis and arthropathy among the latter.
We conclude that replacement therapy in HIV-infected haemophiliacs is important also for HIV-disease progression, whereas the purity of the CFCs and the regimen used are of minor importance.     

Dose and outcome of care in haemophilia – how do we define cost-effectiveness?

Summary.  Severe haemophilia (factor [F]VIII/FIX activity < 0.01 IU mL⁻¹) is characterized by repeated haemarthroses resulting in severe arthropathy in adulthood. In 1958, Professor Nilsson in Sweden introduced prophylactic infusions with clotting factor concentrates at regular intervals in order to maintain clotting factor levels above 0.01 IU mL⁻¹ and to prevent bleeding. Since then, evidence of the long-term beneficial effects of prophylactic treatment for severe haemophilia has been increasing and it has become the recommended treatment strategy for children with severe haemophilia by both the World Health Organization and the US National Hemophilia Foundation Medical and Scientific Advisory Committee. However, the implementation of this recommendation has been hampered by issues of cost and venous access. The high costs of prophylaxis have largely prevented its use in major parts of the world. The question therefore is whether the current models of replacement of clotting factor concentrates, while certainly being effective, are also optimal. Can the data on outcome at different levels of factor replacement be used to assess their cost-effectiveness?     

The plasma concentration of activated protein C appears normal in patients with haemophilia

Summary.  Increased concentration of activated protein C (APC) has been observed in patients with thromboembolic disorders, but whether the level of APC in patients with bleeding disorders is decreased remains unknown. Seventy patients with haemophilia A or B with mild, moderate or severe form were studied. Detailed information on bleeding, arthropathy and factor consumption was collected during a 10-year period. The clinical severity of the disease was expressed as the Hemophilia Severity Score (HSS). Plasma concentration of APC was measured as APC in complex with protein C inhibitor. The median concentration of APC-PCI complex in patients with haemophilia was 0.14 μg L⁻¹ and it did not differ between the types and forms. In 16 patients with severe haemophilia A and the inversion mutation in intron 22, there was no correlation between clinical severity and the concentration of APC-PCI complex. Patients with haemophilia appear to generate normal concentrations of APC during basal conditions. APC does not seem to be an important modulator of the phenotypic expression of haemophilia.     

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.     

Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors

Haemophilia patients with inhibitors are treated for acute bleeding with prothrombin complex concentrates (PCCs) or activated prothrombin complex concentrates (aPCCs). Despite this therapy, patients with high-level inhibitors are at increased risk of developing devastating joint disease. This paper examines available information that supports the study of PCCs and/or aPCCs as prophylactic therapy for haemophilia patients with inhibitors. This strategy would require that PCCs or aPCCs be administered repetitively in a dose that is sufficient to prevent haemarthrosis without causing thrombogenic events, or causing anamnestic response in inhibitor titre. PCC doses ranging from 30 to 50 U kg⁻¹ every other day for up to 8 months have resulted in subjective improvement both in bleeding associated with target joints and in the management of chronic joint inflammation. aPCC doses as low as 50–100 U kg⁻¹ every other day have been useful in postsurgical prophylaxis. The risk of developing a myocardial infarction or clinically relevant disseminated intravascular coagulation is linked to total dosages of either PCCs or aPCCs greater than 200 U kg⁻¹ day⁻¹. It is uncertain what anamnestic response would result from prophylaxis, but with typical therapy the aPCCs cause such a response in only a small percentage of patients. Based on these findings, a clinical trial of these products used in doses of 50–100 U kg⁻¹ every other day would appear to be warranted in patients who have permanent inhibitors and frequent joint bleeding.