ALBERT

Description: l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.

Description: Background The development of an immunogenic response to FVIII and the appearance of neutralizing antibodies - "inhibitors" - against FVIII is the most important adverse event in hemophilia treatment. Immune Tolerance Induction (ITI) via the long-term, intravenous administrations of high-dose FVIII is the only proven strategy to eradicate inhibitors. The success rate is about 60-70% and no formal demonstration of its mechanism of action has been provided yet. Indeed, the mechanisms underlying successful ITI have been unclear, and not much is known about the major factors determinant of success vs. failure. Our aim is to understand the process of activation and immune regulation in response to FVIII in patients undergoing ITI, and comparing the immunological events in patients who successfully eradicate anti-FVIII antibody to those in patients failing to achieve FVIII tolerance. Methods This is a multicenter, observational, prospective cohort study enrolling severe HA patients who developed high-titer inhibitors, candidate to ITI. A blood sample has been collected before starting and during the course of ITI, until ITI ends (5 blood samples during the first year, 3 during the second year if ITI treatment is not already ended, plus a final sample 30 days after ITI conclusion). Total PBMCs have been used to establish cell cultures where cells are re-stimulated with the same FVIII used during the ITI or medium alone. To identify candidate genes, key proteins and cell subsets associated to differential outcomes to ITI, immune cells are used for gene expression profiling (Human Inflammation & Immunity Transcriptome Targeted RNA Panel, Qiagen) together with extensive phenotypic characterization of immune cells via the CyTOF (Cytometry by Time Of Flight mass spectrometry) technology. To identify potential biomarkers predictors of ITI outcomes metabolomics analysis and multiplex cytokine arrays are performed in plasma collected at each time point during ITI and in supernatants from cells cultures. Plasma samples, are collected at each time point and stored at -80°C for cytokine determination and metabolomic analysis. Total anti-FVIII antibody (and their isotypes) and inhibitor titer are also determined in plasma samples by Nijmegen methodology in the central laboratory as described previously (1). Results Currently, 18 subjects have been enrolled among 8 Hemophilia Centers. Among these 5 subjects, two patients reached the study endpoint of ITI success by study criteria (negative inhibitor titer, a normal FVIII recovery, a normal FVIII half-life and the absence of anamnesis upon further FVIII exposure) while three were assessed as ITI failure. The analysis of anti-FVIII antibody isotypes revealed the presence of IgG4 as the most relevant component of the total anti-FVIII antibodies. The inhibitor clearance was also accompanied by the disappearance of IgG4 anti-FVIII antibodies in both tolerized patients, while those who failed to eradicate the inhibitor showed a sustained IgG4 anti-FVIII response (Fig. 1). The evaluation of the cytokines in the supernatants from in vitro cultured cells showed a consistent increase in production of pro-inflammatory cytokines in response to FVIII (IL-1β, IL-6, IL-12, IL-17A, IL-15) at all time points only in patients who continued to produce high-titer inhibitors. Conclusions Here we report an interim analysis of a prospective study of the immunological mechanisms of immune tolerance induction. The preliminary results obtained so far suggest that anti-FVIII IgG4 are a major component of the total anti-FVIII antibodies and their persistence is associated with unfavourable ITI outcome. We expect that the ongoing immune gene expression profiling, immune-phenotypic characterization and determination of soluble marker of activation/regulation of the immune system in supernatants and plasma in this cohort of patients will provide substantial knowledge to increase our current understanding of the complex immunological pathways involved in the development of tolerance to FVIII. Ultimately, this could lead to the discovery of biomarkers of ITI success/failure and to the generation of focused and strategic intervention to modulate the immune system during this treatment. References 1. Matino D, Gargaro M, et al. "IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII". J Clin Invest. 2015 Oct 1;125(10):3766-81. doi: 10.1172/JCI81859. Figure 1. Figure 1. Disclosures Matino: Sobi: Speakers Bureau. Peyvandi:Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Shire: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Shire: Speakers Bureau; Octapharma US: Honoraria; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy. Santagostino:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Iorio:NovoNordisk: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Novo Nordisk; Shire: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Shire; CSL: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with CSL; Grifols: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Grifols; Octapharma: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Octapharma; Bayer: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Bayer; Pfizer: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Pfizer; Roche: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Roche.

Description: Background: Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels 〉10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (〉10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

Description: Background: von Willebrand disease (vWD) is the most common inherited bleeding disorder characterized by quantitative or qualitative defect of von Willebrand factor (vWF) production. Patients with vWD are at high risk of bleeding during surgery. We aimed to evaluate the efficacy and safety of factor VIII (FVIII)/vWF concentrates and DDAVP for bleeding prevention in vWD patients who undergo surgery or an invasive procedure. Methods:The electronic searches were performed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases. The articles published from inception to January 2016 were eligible for inclusion in this review. Studies will be included if they are observational studies or clinical trials of pediatric or adult patients who were laboratory confirmed vWD (type 1 or type 2 or type 3). We excluded case report or case series with less than 5 patients, acquired vWD and incomplete outcome reports. The primary outcome was the efficacy of hemostatic control as defined by studies. We calculated pooled incidence of the patient who achieve good or excellent hemostatic control with corresponding 95% confidence interval using single proportion meta-analysis. The secondary outcomes were adverse outcomes from FVIII/vWF and DDAVP. Results: After screening, there were 54 studies included in the meta-analysis. Forty-five studies investigated the efficacy of vWF/FVIII. Pooled analysis revealed that 98.4% (95% CI; 97.8-99.1%, I2=45.5%) of FVIII/vWF treated patients achieved excellent or good hemostasis. Subgroup analysis according to type of surgery revealed that excellent or good hemostasis was 99.4% (95%CI; 98.4-100%, I2=0%) in major surgery and 99.0% (95%CI; 98.2-99.9%, I2=0%) in minor surgery, Table 1. Adverse effects were observed in 0.2% (95% CI; 0-0.4, I2=85.1%) patients who received FVIII/vWF. The reported adverse effects from FVIII/vWF concentrates included phlebitis, shortness of breath, chest tightness, urticaria, pruritus, chill, malaise, fever, paresthesia, transient elevation of liver function test, nausea, vomiting, dizziness, headache and parvovirus B 19 seroconversion. Thromboembolism occurred in 0.17% of patients who received vWF/FIII. There were 26 studies investigating DDAVP during surgery. Hemostasis was excellent or good in 98.0% (95%CI; 97.0-99.0%, I2=26.3%. In dental procedure, 99.0% of patients receiving DDAVP (95%CI; 97.6-100%, I2=0%) achieved excellent or good hemostasis. Subgroup analysis showed that good/excellent hemostasis was found in 96.9% of pediatric patients (95%CI; 95.1-98.7%, I2=58.8%) and 96.9% (95%CI; 92.7-100%, I2= 0%) in adult patients, Table 2. Adverse effects from DDAVP were reported in 1.2% (95%CI; 0.4-2.1%, I2=95%). Hyponatremia of any level was observed in 16.1% (95%CI; 8.9-22.4%, I2=94.1%). The other reported adverse effects were headache, fatigue, rash, seizure (from hyponatremia), flushing, dizziness, peripheral edema, nausea and vomiting. No thromboembolic event was found in DDAVP treated patients. Conclusions: Both FVIII/vWF concentrates and DDAVP are effective and safe for bleeding prevention during surgery or an invasive procedure in vWD patients. Table 1 Efficacy of hemostatic control in patients receiving vWF: Factor VIII concentrate Table 1. Efficacy of hemostatic control in patients receiving vWF: Factor VIII concentrate Table 2 Efficacy of hemostatic control in patients receiving DDAVP Table 2. Efficacy of hemostatic control in patients receiving DDAVP Disclosures No relevant conflicts of interest to declare.

Description: Background: The development of inhibitors is the most serious complication a patient with hemophilia can experience on treatment with clotting factor concentrates. In a cohort of 100 severe hemophilia A patients, we have recently found that the inhibitor-positive status was associated with dysfunctional indoleamine 2,3-dioxygenase 1 (IDO1)1. The mechanisms whereby IDO1 promotes regulatory effects include production of tryptophan catabolites, collectively known as kynurenines. Some of those tryptophan derivatives are endogenous in nature and act as activating ligands for the Aryl hydrocarbon receptor (AhR), a transcription factor that belongs in the family of basic helix-loop-helix transcription factors2. Specifically, in dendritic cells (DCs), tryptophan-catabolite interactions with AhR promote the transcriptional induction of anti-inflammatory cytokines and the emergence of T regulatory (Treg) cells. Here, we report on the potential of tryptophan-related AhR ligands for inhibiting the formation of anti-FVIII antibodies in hemophilic (F8 KO) mice, a finding that could be important in developing novel strategies to prevent or eradicate FVIII inhibitors. Methods: Four different endogenous AhR ligands have been selected and used in these experiments. All molecules were administered in vivo to F8-deficient mice at incremental doses and by different routes (orally or intravenously), either concomitantly or after rhFVIII immunization. In specific experiments, AhR knockout mice and co-administration of AhR antagonist were used to analyze the impact of AhR deficiency. To co-deliver AhR ligands and FVIII antigens to APCs in vivo and induce antigen-specific Tregs, we administered molecules via a nanostructured delivery system3. Specifically, we engineered four types of nanoparticles (NPs), 60 nm in diameter, that were stabilized by a thiol-polyethyleneglycol (PEG) layer. Overall, we used 1) unloaded NPs, 2) NPs loaded with AhR ligands, 3) NPs loaded with rhFVIII, and 4) NPs loaded with AhR ligands and rhFVIII. Results: Administration of one of the four AhR ligands prevented the generation of anti-FVIII antibodies in nearly 80% of F8 KO mice. Similar effects were obtained with both the NPs-based approach and the oral delivery of ligands. Of note, the protective effect was negated by co-administration of the AhR antagonist CH-223191. Conclusions: Our results suggest that AhR is a possible molecular partner whereby tryptophan catabolites will control the immune response to FVIII. These findings might lead to novel interventions for preventing or eradicating inhibitors in hemophilia A patients. Bibliography: 1.Matino D., et al. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII. J Clin Invest. 2015 Oct 1;125(10):3766-81. 2. Yeste A, Nadeau M, Burns EJ, Weiner HL, Quintana FJ. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109(28), 11270-11275 (2012). 3. Bessede A, et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway.Nature. 2014;511(7508):184-190. Disclosures No relevant conflicts of interest to declare.

Description: Background: Management of hemophilia A with exogenous factor VIII (FVIII) infusions can result in the development of alloantibodies that neutralize FVIII activity (inhibitors). The presence of FVIII inhibitors is associated with high morbidity and a decreased quality of life. Hemophilia A mouse models are a valuable tool for studying inhibitor development and hemophilia A. These models have been shown to develop inhibitor upon treatment with human FVIII. However, there are numerous hemophilia A mouse models, each with potentially varying patterns of inhibitor development. Objective: To identify existing hemophilia A mouse models and characterize anti-FVIII antibody and inhibitor development patterns. Methods: A systematic literature review was conducted using Ovid MEDLINE and EMBASE. The Databases were searched from inception through May 2019 for full-length publications, published abstracts, and conference proceedings that reported use of mouse models of hemophilia A to investigate total anti-FVIII antibody levels and/or inhibitor titers. The search strategy used the categorical search terms: "hemophilia A" AND "mouse" AND "animal model" AND "inhibitor" (Figure 1). Results: Our review consisted of a total of 88 studies which reported the use of 11 different hemophilia A mouse models. Out of the 88 studies, 19 studies only reported total anti-FVIII antibody data without reporting inhibitor data. In 30% of the studies that reported both total anti-FVIII antibody and inhibitor data, not all mice that developed anti-FVIII antibodies had positive inhibitor titres. Our systematic review identified the E16 - C57BL/6 model as the most frequently used model, as 27 studies (31%) reported using this model. The E16 - C57BL/6, E16 - Balb/c, E16 - C57BL6/129, E17 - C57BL/6, E17 - C57BL6/129, and FVIII total knockout (TKO) models demonstrate high immunogenicity to exogenous FVIII and were used in 65% of the studies. These mice all consistently develop anti-FVIII antibodies and inhibitors at 〉95% incidence following treatment with at least 4 doses of full-length recombinant human FVIII (rhFVIII). The E16 - R593C model and the E17 - HLA-DRB1*1501 model both display anti-FVIII antibody and inhibitor development patterns that are representative of the human clinical scenario (~30% inhibitor development incidence). The only model completely immunotolerant to rhFVIII is the E17 - subline E model generated by van Helden et al. (2011) which is a transgenic mouse line on the hemophilic E17 background that expresses human full-length F8 cDNA. Treatment with 8 weekly doses of native human FVIII resulted in no anti-FVIII antibody or inhibitor development in this model. Conclusions: This systematic review demonstrated that mice of the most frequently used models almost always develop inhibitors when treated with full-length rhFVIII. Humanized models may be ideal for use in studies that aim to replicate human inhibitor development patterns. In addition, immunotolerant models may be best used for in vivo studies in hemophilia A that aim to avoid both antibody and inhibitor development. Lastly, this systematic review emphasises that it is important to report both anti-FVIII antibodies and neutralizing activity in Bethesda Units since in 30% of the studies that reported both values, the incidence of inhibitor development was less than the incidence of anti-FVIII antibody development in mice. Disclosures Matino: Bioviiix: Honoraria; Roche: Research Funding; Sanofi: Honoraria; Sobi: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Description: Background : Double filtration plasmapheresis (DFPP) is a form of therapeutic plasma exchange (TPE) that removes high-molecular-weight (HMW) pathological mediators from the plasma with two filters: a plasma separator and a plasma fractionator. Relative to simple TPE, the semi-selectiveness of DFPP reduces protein loss and the need for substitution fluid. However, depending on the choice of plasma fractionator, DFPP may negatively impact hemostatic components such as HMW coagulation factors. Aim: To determine the impact of DFPP on various hemostatic parameters (i.e. FVIII activity, fibrinogen level, vWF level and activity, ADAMTS13 level and activity, protein C (PC) activity, protein S (PS) activity, antithrombin (AT) activity, prothrombin time (PT), and activated partial thromboplastin time (aPTT)). Methods: Fourteen patients undergoing weekly, bimonthly, or monthly DFPP sessions for hematologic conditions (n=11) or nervous system disorders (n=3) were recruited. Hemostatic parameters were measured immediately before and after 27 DFPP sessions (1-4 sessions/patient). The treatment volume was standardized at one plasma volume, and anticoagulation was performed with ACD-A citrate dextrose solution. EC-30W and EC-50W were used as the plasma fractionators in 4 and 23 sessions, respectively. In addition to primary data collection, we systematically searched PubMed, MEDLINE, and EMBASE for studies that investigated the impact of DFPP on hemostasis. No restriction was placed on filter choice. Results: In our cohort of 14 patients, all hemostatic changes were statistically significant. After a routine DFPP session, the level and/or activity of HMW proteins (〉100kDa: FVIII, fibrinogen, vWF, ADAMTS13) were decreased more than those of low-molecular-weight (LMW) proteins (

Description: Background: Congenital Factor XI (FXI) deficiency is the most common rare bleeding disorder, characterized by production defect of FXI. Bleeding manifestation is usually mild and associated with trauma or surgery. The treatment options during surgery include plasma, FXI concentrate, recombinant activated factor VII (rFVIIa), etc. This study aimed to investigate the efficacy of hemostatic control and thrombotic complications in patients with congenital FXI deficiency who underwent surgery or an invasive procedure. Methods: We conducted a systematic search in MEDLINE, EMBASE and CENTRAL database from inception to March 2016. We included the case reports and case series of patients with congenital FXI deficiency. Studies must report the perioperative treatment regimen, hemostatic outcome and thromboembolic complication. The pre- and post-FXI levels were collected. The primary outcome was the efficacy of hemostatic control and the safety outcome was thromboembolic complication. Results: There were 87 studies included in this review, involving 310 patients with congenital FXI deficiency. Median age was 49.5 years (range 0.3 to 94). Forty percent of the patients were male. Median baseline FXI level was 6.0% (range

Description: Abstract 26 Introduction: Clinically relevant antibodies neutralizing the hemostatic effect of fVIII occur in approximately 20–25% of patients with hemophilia A on replacement therapy, and they are associated with significant mortality, morbidity, and a poorer life quality. Many factors predisposing to inhibitor formation have been advocated, but the reasons why some patients develop a neutralizing antibody response to FVIII remains unclear. Evidence suggests that hemophilia-associated mutations (resulting in the absence or severe truncation of the FVIII protein) are associated with the highest risk of inhibitor formation on replacement therapy, as those mutations may have prevented the early development of physiologic tolerance to human fVIII. Recent evidence suggests a role for professional antigen-presenting cells (APC) in the initiation of immunogenic versus tolerogenic responses to fVIII. In particular dendritic cells (DC) actively establish and maintain both central and peripheral tolerance to self. Several mechanisms contribute to DC tolerogenicity and the tryptophan catabolic pathway involving indoleamine 2,3-dioxygenase (IDO) may be at work. IDO is responsible for multiple regulatory effects on immune cells, including inhibition of activated T and B cell proliferation, apoptosis, and lymphocyte differentiation towards T or B cell regulatory phenotypes. The role of IDO and tryptophan catabolytes in immunoreactivity versus tolerance to self prompted us to investigate whether IDO has a role in peripheral tolerance to exogenous fVIII. Objectives: The goal of this multi-centre study was to examine IDO expression and function in peripheral blood mononuclear cells (PBMC) from hemophilic subjects to test the hypothesis that IDO is involved in the modulation of fVIII-specific responses and, particularly, that inhibitor-positive patients might have impaired IDO induction/activity and therefore higher propensity to develop anti-fVIII responses. Methods: Blood was collected from 21 severe (