Hemophilia Inhibitor Patients Research Articles

Gene-based FVIIa prophylaxis modulates the spontaneous bleeding phenotype of hemophilia A rats

AbstractA sizable proportion of hemophilia inhibitor patients fails immune tolerance induction and requires bypass agents for long-term bleed management. Recombinant human-activated coagulation Factor VII (rhFVIIa) is an on-demand bypass hemostatic agent for bleeds in hemophilia inhibitor patients. Prophylactic use of rhFVIIa may enable sustained hemostatic management of inhibitor patients, but the critical relationship of rhFVIIa circulating levels and clinical outcome in that setting remains unclear. To address this in vivo, we used the rat hemophilia A (HA) model that exhibits spontaneous bleeds and allows longitudinal studies with sufficient statistical power. We simulated activated Factor VII (FVIIa) prophylaxis by adeno-associated virus (AAV) gene transfer of a rat FVIIa transgene. Compared with naive HA animals, rat FVIIa continuous expression affected the overall observed bleeds, which were resolved with on-demand administration of recombinant rat FVIIa. Specifically, although 91% of naive animals exhibited bleeds, this was reduced to 83% and 33% in animals expressing less than 708 ng/mL (<14 nM) and at least 708 ng/mL (≥14 nM) rat FVIIa, respectively. No bleeds occurred in animals expressing higher than 1250 ng/mL (>25 nM). Rat FVIIa expression of at least 708 ng/mL was also sufficient to normalize the blood loss after a tail vein injury. Continuous, AAV-mediated rat FVIIa transgene expression had no apparent adverse effects in the hemostatic system of HA rats. This work establishes for the first time a dose dependency and threshold of circulating FVIIa antigen levels for reduction or complete elimination of bleeds in a setting of FVIIa-based HA prophylaxis.

A Neutralizing Monoclonal Antibody (PF-06741086) Against Tissue Factor Pathway Inhibitor in Combination with Activated Prothrombin Complex Concentrate Increases Hemostasis in Inhibitor Hemophilia Plasmas without Excessive Thrombin Generation

Hemophilia A and B are hereditary bleeding disorders caused by intrinsic coagulation pathway deficiencies of Factor VIII or Factor IX, respectively. Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor that negatively regulates thrombin generation within the extrinsic pathway of coagulation. PF-06741086 is a fully human monoclonal antibody which binds the Kunitz-2 domain and neutralizes the inhibitory activity of human tissue factor pathway inhibitor and is currently under development as a potential prophylactic treatment to prevent bleeding episodes in hemophilia A and hemophilia B patients with and without inhibitors. Activated prothrombin complex concentrate (aPCC) is used as bypass treatment for the resolution of bleeding in some hemophilia patients with inhibitors. Hemophilia inhibitor patients receiving PF-06741086 have a possibility to also receive treatment with aPCC. The aim of the current study was to assess the potential additive effect of PF-06741086 with aPCC added in vitro to Hemophilia A and B inhibitor plasmas using a thrombin generation assay (TGA).Thrombin generation in the presence of 1 pM tissue factor and 4 µM phospholipid, was measured using the calibrated automated thrombogram (CAT) system in citrated platelet poor hemophilia A inhibitor (88-160 Bethesda Units) donor plasma or hemophilia B inhibitor (FIX immune-depleted and spiked with FIX neutralizing antibody, 14 Bethesda Units) plasma following the addition of PF-06741086 or aPCC (FEIBA) either alone or in combination. All donors had less than 1% coagulation factor activity. Non-hemophilic plasma from healthy donors alone or spiked in vitro with 16 µg/mL of PF-06741086 was also included in the analysis. Non-hemophilic plasma would have the full complement of coagulation factors. Dose-dependent increases in peak thrombin were observed with the addition of aPCC alone or PF-06741086 alone to the hemophilia plasmas. For combination studies, the aPCC concentration of 1 Unit/mL was selected to correspond to plasma levels that could be achieved clinically post-dosing. The concentration of PF-06741086 at 16µg/mL in these studies was chosen to approximate the Cmax concentration following a single 300 mg subcutaneous dose. Both PF-06741086 (16 µg/mL) and aPCC (1 Unit/mL) decreased the lag time in hemophilia plasma, however, there was not an additive decrease in the lag time with the combination of PF-06741086 and aPCC. The addition of PF-06741086 in combination with aPCC to hemophilia plasma resulted in an increase in thrombin generation including a higher peak thrombin concentration compared to the addition of either alone, but was within the range reported in studies for non-hemophilic normal plasma. To summarize, the addition of aPCC (1 Unit/mL) in combination with PF-06741086 (16µg/mL) in vitro resulted in increased thrombin generation in hemophilia A and hemophilia B inhibitor plasmas without inducing excessive coagulation. DisclosuresRakhe:Pfizer: Employment. Bowley:Pfizer: Employment. Murphy:Pfizer: Employment. Pittman:Pfizer: Employment.

Frequency and epitope specificity of anti–factor VIII C1 domain antibodies in acquired and congenital hemophilia A

AbstractSeveral studies showed that neutralizing anti–factor VIII (anti-fVIII) antibodies (inhibitors) in patients with acquired hemophilia A (AHA) and congenital hemophilia A (HA) are primarily directed to the A2 and C2 domains. In this study, the frequency and epitope specificity of anti-C1 antibodies were analyzed in acquired and congenital hemophilia inhibitor patients (n = 178). The domain specificity of antibodies was studied by homolog-scanning mutagenesis (HSM) with single human domain human/porcine fVIII proteins and antibody binding to human A2, C1, and C2 domains presented as human serum albumin (HSA) fusion proteins. The analysis with HSA-fVIII domain proteins confirmed the results of the HSM approach but resulted in higher detection levels. The higher detection levels with HSA-fVIII domain proteins are a result of antibody cross-reactivity with human and porcine fVIII leading to false-negative HSM results. Overall, A2-, C1-, and C2-specific antibodies were detected in 23%, 78%, and 68% of patients with AHA (n = 115) and in 52%, 57%, and 81% of HA inhibitor patients (n = 63). Competitive binding of the human monoclonal antibody (mAb) LE2E9 revealed overlapping epitopes with murine C1-specific group A mAbs including 2A9. Mutational analyses identified distinct crucial binding residues for LE2E9 (E2066) and 2A9 (F2068) that are also recognized by anti-C1 antibodies present in patients with hemophilia. A strong contribution of LE2E9- and 2A9-like antibodies was particularly observed in patients with AHA. Overall, our study demonstrates that the C1 domain, in addition to the A2 and C2 domains, contributes significantly to the humoral anti-fVIII immune response in acquired and congenital hemophilia inhibitor patients.

Platelet-Targeted rFVIIa-Xten Improves Thrombin Generation and Fibrin Formation Compared to Recombinant FVIIa

The development of inhibitors to replacement plasma factors in hemophilia is an ongoing clinical complication. Bypass therapies, such as recombinant factor VIIa (rFVIIa), have emerged as important alternative on-demand strategies for hemophilic patients with inhibitors to treat spontaneous bleeds and prevent bleeding during surgery. However, general prophylaxis strategies for hemophilia inhibitor patients are lacking. An attractive approach for effective prophylaxis and on-demand treatment includes engineering potent rFVIIa variants with prolonged pharmacokinetics. Because the primary mechanism of action of rFVIIa is thought to occur on the platelet surface, we combined rFVIIa with platelet-targeting and XTEN half-life extension technologies to improve its pharmacokinetic profile and procoagulant activity. Platelet-targeting was achieved by recombinant fusion of an antibody fragment which binds the human alpha IIb integrin. Half-life extension was achieved by fusion of an XTEN polypeptide which increases the hydrodynamic radius, and therefore half-life, of rFVIIa. We have shown that these rFVIIa modifications improve the pharmacokinetics and efficacy of rFVIIa in vivo in humanized alpha IIb transgenic hemophilia A mice. The goal of the current study was to evaluate and compare thrombin generation and fibrin formation kinetics in hemophilic platelet-rich plasma in the presence of platelet-targeted rFVIIa-XTEN or rFVIIa. To achieve this, platelet-rich plasma from normal human donors was treated with an inhibitory factor VIII antibody to model hemophilia A and spiked with doses of platelet-targeted rFVIIa-XTEN or rFVIIa. Reactions were triggered with low tissue factor and recalcification. Thrombin generation (n=9) was monitored by calibrated automated thrombography and fibrin formation (n=7) was monitored optically on a plate reader. Non-linear regression analysis of dose responses was used to determine EC50 values for each parameter for each donor. Platelet-targeted rFVIIa-XTEN increases the rate and peak of thrombin generation with 2- to 6-fold lower EC50 values (peak and rate, respectively) than rFVIIa. These data were confirmed by thrombin generation in platelet-rich plasma from 1 hemophilia A donor and 1 hemophilia B donor which demonstrated similar responses to platelet-targeted rFVIIa-XTEN with 2.5- to 5-fold lower EC50 values (peak and rate, respectively) than rFVIIa. Notably, platelet count-dependent changes in thrombin generation activity were similar between platelet-targeted rFVIIa-XTEN and rFVIIa. Fibrin formation analysis indicated platelet-targeted rFVIIa-XTEN increases the rate and time to plateau of fibrin formation with 5- to 13-fold lower EC50 values (rate and time to plateau, respectively) than rFVIIa. Analysis of fibrin network structure by confocal microscopy indicated platelet-targeted rFVIIa-XTEN increases fibrin network density in platelet-rich plasma clots. Together, these data show platelet-targeted rFVIIa-XTEN has more procoagulant activity than rFVIIa by supporting more thrombin generation and faster fibrin formation and suggest our approach has the potential to be an effective alternative for the treatment and prevention of bleeds in hemophilia patients with inhibitors. DisclosuresAleman:Biogen: Employment, Equity Ownership. Kistanova:Biogen: Employment, Equity Ownership. Moore:Biogen: Employment, Equity Ownership. Schellenberger:Amunix Operating Inc: Employment. Peters:Biogen: Employment. Salas:Biogen: Employment, Equity Ownership.

Thrombin generation and bleeding in haemophilia inhibitor patients during immune tolerance induction.

Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg-1 day-1 ) and low-dose (LD) (50 IU kg-1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels. We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent. There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII<1.0 BU, the prevalence of non-neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti-VIII titer, r = 0.73 [95% CI: 0.55, 0.88]. In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority.

Rapid rFVIIa enhanced on-demand dosing in haemophilia inhibitor patients.

Recombinant factor VII activated (rFVIIa) is a bypassing agent widely used in haemophilia A and B patients with antibodies against coagulation factors VIII or IX. When used according to the correct doses, rFVIIa may control bleeding, subclinical bleeding and rebleeding, avoiding the effect of neutralising inhibitors. Because of the fast action of the rFVIIa, haemostasis occurs promptly and enables a fast bleeding control with on-demand treatment in home or in surgical setting. Rapidity is also a distinguishing feature in preparation and injection of rFVIIa to cope the restraining times of busy patients and parents. The effective haemostatic activity of rFVIIa enables a sustained bleeding control, which is implemented with every other day (eod) administration and suited for enhanced on-demand therapy and short-term repeated infusions use of rFVIIa to prevent microhaemorrhages or rebleeding. Comprehensive appreciation of these pharmacological and pharmacodynamic' characteristics will likely be a further stimulus to the wider enhanced on-demand use of rFVIIa.

Thrombin Generation and Bleeding in Hemophilia Inhibitor Patients during Immune Tolerance Induction

Background: Among the most serious complications of hemophilia A is anti-VIII inhibitor formation, which occurs in ~25% of patients, typically in childhood within the first 20 exposures. Morbidity is high, hospitalization is frequent, and healthcare cost is high. Thus, immune tolerance induction (ITI), a program of regular F.VIII therapy, is used to eradicate the inhibitor. A landmark study demonstrated ITI was equally effective with high-dose (HD) (200 IU/kg/day) or low-dose (LD) (50 IU/kg 3x/week) F.VIII, but found a bleeding rate 2-fold greater in the LD arm. As the inhibitor neutralizes F.VIII, no difference in bleeding was expected. We hypothesized that thrombin generation assay (TGA), a global measure of tissue factor-induced thrombin generation that predicts bleeding in hemophilia better than F.VIII, might clarify this question.Methods: Following IRB approval, TGA was performed on thawed, re-calcified CTI /citrate plasma samples from the ITI repository, using re-lipidated tissue factor and a BioTek Synergy 4 fluorescence plate reader. TGA parameters, i.e. peak thrombin (peak T), estimated thrombin potential (ETP), maximum rate (MaxR), lag time (LAG), were compared by dose group, and repeated after F.VIII spike to neutralize the inhibitor and enhance TGA sensitivity. Significance was calculated by fitting generalized estimating equations linear models to account for serial measurements, with log-transformed TGA as outcome and dose group as predictor. Wilcoxon rank sum test was used to compare bleeds by dose group. Spearman correlation was used to compare TGA and bleeds, and TGA and inhibitor titer. The first TGA sample per subject was used in the analysis; and, separately, all TGA samples per subject. Sensitivity analysis was performed by 95% bootstrap confidence intervals to account for multiple measurements per subject. Total F.VIII antibody (NNA+NA) was analyzed by fluorescent immunoassay (FLI) and compared with anti-VIII (BU/ml) by Pearson correlation.Results: Samples (n=83) from 31 subjects, 14 LD and 17 HD, were available. There was no difference in peak T, ETP, MaxR, or LAG between LD and HD; after VIII spike (Table); nor between non-tolerized (n=56) and tolerized (n=27) subjects, all p>.05. There was no correlation between TGA and bleeding, nor between TGA and anti-VIII titer, all p>.05. In 19 subjects in whom anti-VIII fell to <1.0 BU, including 12 (70.6%) HD and 7 (50.0%) LD, the NNA+NA prevalence was 17/19 (89.5%). Anti-VIII titer and total F.VIII antibody (NNA+NA) were highly correlated, r=.807, p<.001. [Display omitted] Discussion: Despite ITI, the majority of inhibitor patients have detectable non-neutralizing inhibitors. Further, TGA is detectable despite the presence of inhibitors, but does not predict bleeding by ITI dose arm, suggesting thrombin generated after F.VIII dosing may be too low or too short-lived to detect. Limitations include the small sample size and random post-F.VIII sampling. Future studies should evaluate TGA prospectively, early after dosing to determine if thrombin generation predicts bleeding in inhibitor patients. DisclosuresNo relevant conflicts of interest to declare.

Tranexamic acid as adjunct therapy to bypassing agents in haemophiliaApatients with inhibitors

Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N=5) and haemophilia inhibitor patients (N=6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20mgkg(-1) orally (O.R.) Patients were treated with aPCC 75IUkg(-1) intravenous (I.V.) on day 1 followed by TXA 20mgkg(-1) O.R. combined with aPCC 75IUkg(-1) I.V. on day 2. A 14-day washout occurred before crossover to rFVIIa 90μgkg(-1) I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF+tissue plasminogen activator-based assay. Healthy controls showed a 20-fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P<0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P>0.05). Infusion of aPCC or rFVIIa alone induced only 3-10 fold increase in MCF from baseline, with a decline in MCF starting after 60-120min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.

Bypass therapy assay testing as a strategy to reduce costs for treatment of haemophilia patients with inhibitors

Published studies suggest that bypass therapy assay testing can be used to predict treatment response and dosing requirements for haemophilia patients with inhibitors. The aim of this study was to evaluate the costs of utilizing and not utilizing bypass therapy assay testing before treating mild-to-moderate bleeding episodes on-demand in haemophilia patients with inhibitors from a US third-party payer perspective. In our exploratory decision tree model, the average patient was assumed to be an adult weighing 75 kg. Based on existing head-to-head clinical trials, the efficacy of activated prothrombin complex (aPCC) and recombinant factor VIIa (rFVIIa) was assumed to be equivalent and based on expert opinion of the haematologist in our study it was conservatively assumed that assay testing improves the efficacy of both the bypassing agents by 10%. Probabilistic and one-way sensitivity analyses were used to determine the robustness of the results. Cost savings per bleeding episode were estimated at $6886 (95% CI = $4310-7978) for aPCC and $7647 (95% CI = $3134-10 388) for rFVIIa treatment. This translates in potential cost savings of 24.8% (95% CI = 15.5-28.8%) for aPCC use and 18.2% (95% CI = 8-24.7%) for rFVIIa use. Furthermore, if testing successfully predicts the optimum dose for concomitant therapy at the onset of bleeding, significant cost savings were observed compared with rFVIIa and aPCC therapies alone. Use of bypass therapy assay testing before treatment administration in haemophilia inhibitor patients can potentially reduce treatment costs significantly while optimizing dose and therapy response.

Immune Tolerance Induction (ITI) in Adults with Congenital Hemophilia: A Multicenter Experience

AbstractAbstract 1123 IntroductionMost inhibitors developing in adulthood are low titer inhibitors [Eckhardt 2012], however high titer inhibitors have been described [Kruse-Jarres 2010, Hay 2011]. The role of ITI in the management of adult inhibitors has not been established. Two large registries have suggested that age at ITI initiation could be a predictor of success. The North American ITI registry showed a trend toward a younger age in the ITI success group [DiMichele 2002], while the International ITI group showed a more definitive difference, where patients receiving ITI at age > 20 years had a 40 % success rate compared to a much higher success rate of 70 t0 78% in younger individuals [Mariani 2001]. Prospective therapy trials in an adult congenital hemophilia inhibitor population are difficult to conduct, as the number of patients is limited. The aim of the this multicenter retrospective review was to document our experience in the management of adult hemophilia inhibitor patients with ITI MethodsTwelve hemophilia treatment centers which are part of the Globally Emerging Hemophilia Expert Panel (GEHEP) with centers in Canada, Europe, South Africa and the US, who collectively look after over 3000 hemophilia patients, participated in this study. Each center obtained ethics approval prior to data collection. Retrospective record review was undertaken at each center to identify congenital hemophilia patients treated with ITI as an adult (started at ≥ 17 years of age)and who completed the treatment course between 1980 and 2012. The treatment course was defined as any of the accepted ITI regimens. Treatment success was defined as inhibitor eradication or >66% factor recovery. ResultsOf 21 patients who received ITI as an adult, 71% had partial (<5BU and FVIII was able to be reinstated) or complete success. All patients had hemophilia A and most were severe (One patient in the ITI failure group had a level of 2% and in the success group, one had a level of 1% and on of 3%). Of the 13 patients achieving complete success, 38% relapsed (mean follow up of 9.4 years, range 3 months to 29 years). Age at start of ITI did not seem to be a predictor of success: mean age in the success group was 32.0 years (range 17 –55) and in the failure group was 33.5 years (range 22 – 57). All patients in the failure group were white, where 3 patients in the success group were non-white. The success group included one low responding inhibitor and had an overall lower peak inhibitors (mean 89.75 BU, range 3 – 270 BU) than the failure group (mean 353.8 BU, range 89–600 BU). Fifty percent of the failure patients had received a prior ITI attempt, where only 8% of the success group had. More patients in the failure group had received plasma derived factor VIII product for their ITI (83%) than in the success group (69%) but dosing was not significantly different (mean of 416 units/kg/week in failure group, 455 U/kg/week in success group). Overall, patient who failed stayed on ITI slightly longer (mean 20 months) than the patients who succeeded (mean 16 months). ConclusionIn this limited series of adult inhibitor hemophilia patients treated with ITI, the success rate was high and comparable to that obtained in the pediatric population. Age at start of ITI did not seem to be a predictor of success, but prior ITI and historical peak inhibitor were negative predictors. Prospective clinical studies are required to expand on these preliminary findings. Disclosures:Kruse-Jarres:Bayer: Administrative and meeting support Other, Honoraria, Research Funding.

PSY18 The Future Characteristics of Bypassing Agents Improving Haemophilia Inhibitor Patients Care From an Economic and Health Related Quality of Life Perspective

Treatment for haemophilia inhibitor patients has improved substantially since the 1980's and 1990's. But from a health economic perspective, an unmet need persists for better treatment options in terms of health-related quality of life (HRQoL) and cost savings. Haemostatic products alone account for the biggest expense in the care of haemophilia patients. Congenital haemophilia with inhibitors involves lifelong treatment, and with it, substantial long-term costs and lowered HRQoL. A systematic review on cost and HRQoL findings for haemophilia treatments in economic terms was conducted on more than 280 scientific studies. Fifty-five articles were retained for the execution of the project analysis. The analysis shows that to counteract costs to payers (society) and to improve patient outcomes, improved treatments could increase HRQoL. This could be achieved with FVIII and FIX bypassing agents that have: greater convenience through subcutaneous administration (less-painful injections, avoidance of infusions), faster onset through a fast-acting rFVIIa analogue (faster resolution of bleeding episodes leading to faster pain relief, sustained control, less dosing), and longer duration through a long-acting rFVIIa derivative (fewer injections and rebleeds, arthropathy prevention). Improved FVIII/IX bypassing agents for treatment of haemophilia patients with inhibitors would be a cost-effective option for society, improving HRQoL associated with the clinical condition.

The expanding role of prophylaxis with recombinant activated factor VII.

The expanding role of prophylaxis with recombinant activated factor VII.

A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia

Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We describe a surprisingly useful approach to improve hemostasis in vivo using a variant of coagulation factor Xa (FXaI16L). This conformationally pliant derivative is partially inactive due to a defect in transitioning from zymogen to protease 1,2. Using mouse models of hemophilia, we show that FXaI16L has a prolonged half-life, relative to wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXaI16L is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXaI16L is more efficacious than FVIIa which is used to treat bleeding in hemophilia inhibitor patients3. Because of its underlying mechanism of action, FXaI16L may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions.

Future characteristics of bypassing agents to improve care of hemophilia inhibitor patients: an economic and health-related quality of life perspective

Treatment for hemophilia inhibitor patients has improved substantially since the 1980s and 1990s. However, from a health economic perspective, an unmet need persists for better treatment options in terms of health-related quality of life (HRQOL) and cost savings. Hemostatic products alone account for the biggest expense in the care of hemophilia patients. Congenital hemophilia with inhibitors involves lifelong treatment and, with it, substantial long-term costs and lowered HRQOL. To counteract these costs to payers (society) and to improve patient outcomes, improved treatments could increase HRQOL. This could be achieved with factor VIII and factor IX bypassing agents that have greater convenience through subcutaneous administration (less painful injections and avoidance of infusions) and a faster onset through a fast-acting recombinant activated factor VII analog (faster resolution of bleeding episodes leading to faster pain relief, sustained control and less dosing). In short, improved factor VIII/IX bypassing agents for treatment of hemophilia patients with inhibitors would be a cost-effective option for society, improving HRQOL associated with the clinical condition, which further decreases the already limited budget impact because costs per patient are reduced for the 3500 hemophilia inhibitor patients worldwide.

Alterations of T cell receptor Vβ repertoire of CD8 T lymphocytes in immune tolerance induction in two hemophilia A patients with inhibitors

Hemophilia A patients with inhibitors are treated effectively with immune tolerance induction (ITI) therapy. Although anti-idiotypic antibodies may play a certain role in the underlying mechanism, the detailed mechanism by which ITI produces a curative effect remains unknown. The aim of this study was to clarify the immunological aspect of ITI. Longitudinal T-cell receptor (TCR) analysis was performed during ITI. TCR variable region alpha-chain and beta-chain repertoires were serially analyzed for peripheral blood mononuclear cells (PBMCs), CD4 T cells, and CD8 T cells from 2 hemophilia inhibitor patients treated with ITI (Patients 1 and 2). Furthermore, to see whether skewing observed in TCR analysis resulted from clonality alterations, T cell clonality was investigated using complementarity-determining region 3 (CDR3) size spectratyping. In the patient 1, inhibitor titer remained to be 19.6 BU/mL for 596 days after ITT commencement, and ITI was unsuccessful. In the patient 2, inhibitor titer disappeared 434 days after ITI commencement, and ITI was successful. In both cases, skewing of TCR variable region alpha/beta-chain repertoires was observed in CD8 T cell subset, whereas not in CD4 T cell subset. Alteration of TCR repertoires, especially TCR variable region beta-chain repertoire of CD8 T cells, was distinct between successful and unsuccessful cases, suggesting that immunological response in the early phase affected the ITI outcomes.

Randomized, Prospective Clinical Trial of rFVIIa for Secondary Prophylaxis in Hemophilia Patients with Inhibitors.

Introduction: Hemophilia patients with inhibitors experience frequent bleeds and reduced quality of life (QoL). This trial evaluated whether once−daily prophylaxis therapy with activated recombinant factor VII (rFVIIa; 90 or 270 μg/kg) for 3 months can effectively reduce bleed frequency compared with on−demand therapy, without compromising safety.Methods: Thirty−eight hemophilia inhibitor patients with frequent bleeds entered a 3−month observation period where on−demand therapy was continued according to local practice. Twenty−two patients with a stable bleed frequency (≥4 bleeds/month) were randomized 1:1 to once−daily dosing with 90 or 270 μg/kg rFVIIa in a double−blind, parallel−group design. To maintain blinding, the same volume was administered in both groups. Patients then entered a 3−month post−treatment observation period, where on−demand therapy was resumed.Results: The number of bleeds per month was significantly reduced by 45% and 59% with 90 or 270 μg/kg rFVIIa prophylaxis, respectively, compared with the observation period (Fig.). Similar reductions were seen for all bleeds, irrespective of site or cause. The majority of this reduced bleeding frequency was maintained in the 3 month post−treatment period (27% and 50% reductions, respectively). There were no treatment− or dose−dependent patterns in the number or type of adverse events. No thromboembolic events or withdrawals due to adverse events or ineffective treatment were reported. The benefits of reducing bleeding frequency in this trial translated into improvements in QoL.Conclusions: These results support the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds. Clinically relevant reductions in number of bleeds and improvements in quality of life were observed during prophylaxis compared with conventional on−demand therapy without raising any safety concerns. [Display omitted]

Anti-inhibitor Coagulant Complex (Autoplex) in Hemophilia Inhibitor Patients Undergoing Synovectomy

Surgical synovectomy employed in the management of hemophilic arthropathy has been contraindicated in patients with inhibitors because of potential difficulties in achieving hemostasis. However, the development of activated prothrombin-complex concentrates has improved the management of hemophiliacs with inhibitors, particularly those with high levels of inhibitor for whom other treatment modalities are of minimal benefit. With the use of one of these activated products, Autoplex, surgical procedures have been successfully accomplished in hemophiliacs with inhibitors. Two inhibitor patients who each had severe arthropathy of one knee underwent elective surgical synovectomy while being treated with Autoplex. Hemostasis was achieved during the perioperative period in both patients. Neither patient exhibited clinical signs of suggestive of consumptive coagulopathy or thrombosis, side effects potentially associated with the use of activated prothrombin-complex concentrates.