INTRODUCTION:The Palestinian territories, especially Gaza and the West Bank, are suffering a severe humanitarian and medical crisis due to ongoing conflict, blockades and resource shortages. Healthcare infrastructure is devastated, limiting access to care - especially for patients with chronic conditions like congenital bleeding disorders (CBDs). METHODS:A detailed medical perspective on the healthcare situation in Palestine Territories was investigated via publications in the scientific literature, reports form non-governmental organizations, personal interviews with patient associations. RESULTS:Hospitals in Gaza are beyond capacity, prioritizing trauma over chronic disease management. Medical facilities face damage and medicine shortages due to blockades, worsening patient outcomes. Healthcare workers endure extreme workloads, poor protection and frequent attacks, leading to burnout and high mortality. Continuous violence results in widespread trauma and mental health issues, particularly affecting children and vulnerable groups. Moreover, patients with CBD face chronic shortages of clotting factor medications, lack of comprehensive treatment centres and reliance on episodic rather than prophylactic therapy. This leads to increased complications and disability for approximately 562 Palestinians with CBD. Patient stories illustrate the reality of displacement, delayed surgeries and inadequate care. International aid efforts, such as support from the World Federation of Hemophilia and Haemo-Pal project, aim to improve care but are hampered by ongoing conflict, restricted movement and bureaucratic delays. CONCLUSION:Immediate humanitarian action is needed to protect healthcare infrastructure, ensure unrestricted medical access and allow safe patient evacuation, supported by international advocacy to safeguard health rights during conflict. PLAIN LANGUAGE SUMMARY:People living in the Palestinian Territories - especially in Gaza and the West Bank - are going through a major crisis. Because of ongoing conflict, blockades and not enough resources, hospitals and clinics are damaged and overcrowded. This makes it very hard for people, especially those with long-term health problems like bleeding disorders, to get the care they need. In Gaza, hospitals are so full that they mostly take care of people injured in the conflict. There are not enough medicines or staff, and many medical buildings have been damaged. Doctors and nurses are working under a lot of stress and danger, which makes their jobs even harder and puts their health at risk. As a result, many patients get sicker or even die. The constant violence also causes a lot of mental health problems, especially for children and other vulnerable people. For people with bleeding disorders, the situation is even more difficult. There are not enough special medicines to help their blood clot, and there are not enough treatment centres. Most patients can only get medicine when they are already having a bleeding episode, instead of getting regular treatments to prevent problems. This leads to more health issues and disabilities for about 562 Palestinians living with these conditions. The stories of patients show how hard it is for them - they often face delays in getting surgery, must move from one hospital to another, and do not always get the right care. People around the world have a responsibility to speak up for safe paths to deliver aid, for an end to attacks on hospitals and for everyone to have basic health care, no matter the political situation.

Desmopressin increases plasma factor VIII and von Willebrand factor in non-severe hemophilia A (Hem A) and type 1 von Willebrand disease (VWD), following intravenous infusions, subcutaneous injections, or nasal spray. This medication, with almost 50 years of clinical experience and proven safety and efficacy, is often unavailable. Thus, there is a need to establish how many patients can benefit from it and how many bleeding episodes can be treated. We reviewed the literature to estimate the global prevalence of symptomatic patients with VWD type 1 and non-severe Hem A, the incidence of bleeds, and the rate of responsiveness to desmopressin. Real-world data indicate that 1.7 patients with VWD per 100,000 seek care in specialized centers. Of them, 1.15 per 100,000 have type 1 VWD and 80% are reported to respond to desmopressin. In type 1 VWD, the estimated frequency of bleeds treatable with desmopressin are 2.5 events per patient year. Non-severe cases are 45% of all Hem A cases, with a much lower incidence of bleeds than in severe disease (0.4 events / patient / year). Based on epidemiology, data on the rates of bleeding, and desmopressin responsiveness, we estimated that 84,000 people with VWD type 1 would benefit from desmopressin to treat 210,000 yearly bleeds, and that 81,000 people with non-severe Hem A can be treated yearly for 13,000 bleeds. Desmopressin is an essential therapeutic tool in non-severe Hem A and type 1 VWD that can treat more than 220,000 bleeding episodes successfully, safely, and economically, also in low-income settings with poor access to costly replacement therapies.

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.

INTRODUCTION:Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations.AIM:The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process.METHODS:A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia.RESULTS:A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care.CONCLUSION:The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.

IntroductionTreatment of congenital thrombotic thrombocytopenic purpura (cTTP), a disease characterized by the congenital deficiency of ADAMTS13, remains a challenge as there are no specific treatments available yet, other than therapy based on the use of fresh frozen plasma (FFP). Since cTTP is caused by low levels of ADAMTS13 protein, commercially available coagulation factor concentrates have been considered as potential ADAMTS13 source in place of FFP. The study aimed to validate the therapeutic potential of a plasma-derived factor VIII (FVIII) product as a source of ADAMTS13.MethodsThe quantitation of ADAMTS13 activity levels in eight lots of a plasma-derived FVIII product, (Koāte®) was carried out with three different methodologies: a Fluorescence Resonance Energy Transfer (FRET) assay, a chemiluminescence assay, and a chromogenic ELISA. ADAMTS13 protein antigen levels were measured by the FRET technique as well. In addition, von Willebrand factor (VWF) activity (VWF ristocetin cofactor, VWF:RCo, and VWF collagen binding, VWF:CB) and antigen (VWF:Ag) were measured using chemiluminescence assays. Qualification protocols were applied to the methods used.ResultsThe results showed high levels of ADAMTS13 in all eight Koāte® lots analyzed, with antigen and activity levels respectively of 10.72 IU/ml ± 3.94 and 5.62 IU/ml ± 1.39. Despite the significant content of ADAMTS13, VWF integrity seems not to be affected (0.81 ± 0.15 VWF:RCo/VWF:Ag and 0.75 ± 0.15 VWF:CB/VWF:Ag ratios).ConclusionsThese findings suggest that Koāte® could be a potential candidate for the treatment of cTTP, warranting evaluation in a clinical trial.

The haemophilic (sic) presents a social problem of considerable magnitude often requiring a sheltered occupation and having to spend a lot of time in hospital.1 This quote perhaps encapsulates best the haemophilia care landscape on the cusp (1965) of the therapeutic revolution made possible by the development of accessible factor concentrates. The availability and further processing of cryoprecipitate following Judith Pool's findings led to the rapid improvements most dramatically illustrated by the increase in the life expectancy of patients over the 1970s. The current global prevalence of haemophilia A, even though partially due to the diagnosis rate, is strongly affected by the availability of clotting factor concentrate (CFC)2 (Figure 1A), and while this has been proposed as a modification of cost-benefit theory (Figure 1B), another perspective bears consideration. The prevalence (a surrogate for survival) peaks at ≅ 4 IU/capita, yet usage rates far in excess of this are now the norm in developed countries,3 and were recorded even in the earliest World Federation of Hemophilia (WFH) survey. Clearly, the increasing availability (for a price) of CFC has allowed more than survival. It has allowed the increase in overall health status and health-related quality of life which has characterized the modern era of haemophilia treatment in the developed world. This is exemplified by the close relationship between orthopaedic joint scores (OJS) and factor consumption in adult patients.4 Patients’ expectations have risen together with the increasing availability of CFC5: progressing from simply a rapid recovery from a bleed, through its prevention, to a life fully lived: patients could aspire to similar social integration, academic achievements and job opportunities.6 Ever-increasing freedom from bleeding and from the bleeding risk itself, as a result of an expensive and demanding therapy, has called attention to the importance of health-related quality of life (HRQoL). Its measurement has been used not only to support the efficacy of new treatments and therapeutic approaches, but also to support the pharmaco-economic assessment of such treatments. Moreover, an issue has emerged: Can we further increase therapy expenditure to allow sport participation of people with haemophilia? In this issue of Haemophilia, one of the most dramatic of treatment improvement and its benefits, in the form of access to sports, is addressed by the Department of Sports Medicine of the University of Wuppertal in Germany,7 an expert group with a considerable body of work in this area. In the third of a series of papers, the group continue to extract valuable data from their trial, which randomized patients into an intervention group (IG) composed of a programmed sports therapy (PST) over a 6-month period, and a control group (CG), who continued in their daily activities without undergoing the intervention. The physical fitness outcomes of the trial (RCT),8 the subjectively assessed physical performance and HRQoL9 and the follow-up of the cohort following the study10 have been previously published. This series of papers now continues with an economic assessment of the same study, applying a conventional cost-utility analysis (CUA) of the intervention. In previous commentaries in this journal,11, 12 we have noted the increasing engagement of health technology assessments (HTA) within the haemophilia therapeutic landscape, in areas such as the use of prophylaxis and the treatment of inhibitors. The concerns of payers on the increasing costs of haemophilia therapy are contributing to the use of HTA by payers and providers alike. Depending on which financial analyst one listens to (and there are many), the haemophilia treatment market in the developed economies is expected to reach a value of 8-25 billion US dollars by the mid-2020s.13 This remarkable range in projections may well decrease their credibility; nevertheless, haemophilia is an increasingly expensive disease, as, with other health interventions, technological advances improve only treatment convenience in some cases, while raising expectations. A scrutiny of the benefit allocations by even the US insurance industry shows (justifiable) caution in assessing reimbursement of extended half-life (EHL) factor VIII (page 5 in reference14). When considering the position of the state HTA bodies in the social market economies, the situation is even more unequivocal; of three “innovative” factor VIII products submitted for the allocation of an increased reimbursement, the German National Institute for Quality and Efficacy in Health Care (IQWIG) rejected all the products’ claims, based on a lack of evidence and cost-effectiveness (see individual assessments for simoctocog alfa, turoctocog alfa and efmoroctocog alfa within reference.15 Which brings us to the CUA in this issue. In their study, the Wuppertal University group have followed conventional evidence-based (EBM) principles through progressively establishing efficacy,8 patient-reported outcomes (PROs)9 and now cost-effectiveness. The CUA extracts quality-adjusted life years (QALYs) for the IG and CG through the EQ-5D-3L. The QALY estimates had to be adjusted because of a higher baseline QALY in the CG, yielding a statistically significant but apparently tiny difference, which can be attributed at least partially to the short follow-up (6 months). More significant was the small difference in costs between the two groups which are mostly due to the lower usage of non-CFC medication in the IG. This is useful information as it indicates, crucially, that supervised and instructed sport activity does not increase costs; moreover, pain medication usage, for example, is lower for the IG and farther augments the case for sports therapy. Intriguingly, this difference in non-CFC costs contributes to the outcome despite this study's confirmation that the vast majority of haemophilia treatment costs arise from the costs of substitution with CFC; in this study as with others, these constitute 99% of total costs. The authors describe a complex multiple imputation (MI) approach to analysing their data given the relatively high proportion of patients with missing data; a mitigation of this problem may have been possible using a recently described Value of Information method to design a clinical trial in a small population and optimize a health economic utility function.16 Another methodological issue lies in the choice of a CUA, which, unlike other authorities in England and Australia, is not used by the German HTA authority, rather than the efficiency frontier method which is used by the German authority.17 It is possible that the small differences in cost/QALYs would be even more obvious in this methodology than with the various cost-effectiveness acceptability curves offered by the authors. These comments on the detailed metrics around this CUA, however, are not intended to deflect from the authors’ key outcome, somewhat submerged in the statistics, that “individual sports therapy does not lead to a rise in the coagulation factor,” pointing out that for this adult study population, “sports had been prohibited and avoided in their childhood and past.” We heartily concur that “for these people, the fact that sports do not necessarily lead to a higher need for substitution is a very important and new information.” The commendable work of the Wuppertal University group provides an important component to the literature supporting the performance of sport by people with haemophilia. The group's subsequent work on the challenge of compliance in following up the patients10 accentuates the need for developing programs which can be maintained over life, as in other areas like prophylaxis. We should underline not only the “physical” importance of sports in people with haemophilia, but also the “nonphysical” importance as an indicator of emancipation.18 This is illustrated by the growing importance of the Paralympic Games. Nonphysical aspects of sports activities include aspects concerning socialization (eg the patient feels belonging to a group, is socially accepted, is doing something with friends and is not alone), self-esteem (eg feeling of being like others, becoming more self-confident) and body control. These nonphysical aspects of sports activities can lead to a better management of the health condition.19 On the other hand, the haemophilia-treating physicians and the community of patients and their caregivers should also keep in mind that even the best treated and most physically fit patient can bleed if participating in sport activities at high risk of trauma.20 It is to be hoped that the current improved landscape of haemophilia care, through the work of the Wuppertal group and others, will contribute to the continuing development of a population of fully emancipated, socially integrated people with haemophilia, of all ages. Albert Farrugia and Alessandro Gringeri provide compensated services to manufacturers of haemophilia treatment products, and Sylvia von Mackensen reports no conflicts.

Background Recombinant protein technologies have facilitated the development of novel factor VIII (FVIII) therapeutics with improved production efficiency, potency and half-live, and a low risk of viral transmission. The increasing number of recombinant FVIII (rFVIII) products and information on their efficacy, safety and cost allow patients and healthcare professionals to adjust treatment to individual needs. Nonetheless, 20-32% of previously untreated patients with severe hemophilia A develop inhibitory antibodies to rFVIII following treatment. The root cause of the immunogenicity of rFVIII products is not well understood. Data for human interferon and human insulin products suggest that critical quality parameters such as soluble protein aggregates (SPAs) and subvisible particles (SVPs) influence the immunogenicity of protein therapeutics. Therefore, we analyzed SPA and SVP concentrations in commercially available rFVIII products and determined how these parameters change upon exposure of rFVIII products to relevant stress conditions. Objectives Compare critical quality parameters such as SPA and SVP concentrations in rFVIII products under intended use and use-relevant stress conditions. Methods Nine rFVIII products ( 3 lots each) were analyzed by high-performance liquid chromatography-size exclusion chromatography (HPLC-SEC) and flow cytometry-based particle analysis. Results/conclusions SPAs and SVPs were present at different concentrations in all freshly reconstituted rFVIII products: SPA concentrations ranged from 0.2% to 11.6%; SVPs were 0.7 x 10(6) to 114.0 x 10(6) / 1000 IU. Under use-relevant stress conditions (agitation and shear stress) the products formed additional SPAs and SVPs to different degrees. The collected data indicate that product quality determines its propensity to form SVPs and SPAs, and highlights differences between marketed rFVIII products.

The development of high‐titre inhibitory antibodies (inhibitors) against factor VIII ( FVIII ) remains a challenge in the management of patients with haemophilia A ( HA ). Patients with high‐titre inhibitors are more likely to experience uncontrolled bleeding, physical disability from chronic arthropathy and premature death compared with those without this complication. Immune tolerance induction ( ITI ), utilizing repeated infusions of FVIII , is an effective therapeutic approach to eliminating inhibitory antibodies. This strategy can eradicate FVIII inhibitors, so that FVIII ‐specific tolerance is induced. However, patients undergoing ITI are still vulnerable to the development of serious and/or repeated bleeding events. The efficacy of bypassing agents in preventing bleeding episodes has been widely proven in patients with HA and inhibitors to FVIII . Evidence suggests that reducing bleeding during ITI can also shorten the time to tolerance. There are concerns with the use of bypassing agents, including the cost of treatment, short half‐life, management of non‐responders and the risk of thrombosis. Despite these concerns, and the still limited evidence from prospective studies and consensus reports, the use of prophylaxis with bypassing agents during ITI has been gaining support. This review presents a rationale and current data supporting the use of prophylactic bypassing agents as effective and safe therapies to reduce the incidence of joint bleeding due to inhibitors and improve quality of life in patients with HA undergoing ITI .

IntroductionOutcome data on treatment of patients with haemophilia A spanning several years of real‐world evidence collection are currently very limited.Aim and methodsThe global prospective long‐term Advate® Haemophilia A Outcome Database (AHEAD) cohort study collects real‐world data from patients with severe and moderate haemophilia. We report an interim data read‐out after three years of observation.ResultsA total of 522 patients were enrolled from 21 countries: 334 completed year 1 follow‐up, 238 completed year 2 and 136 completed year 3, with an overall follow‐up of 811 patient‐years. Median annual bleeding rates (ABR) were 1.7 in the prophylaxis group and 8.9 in the on‐demand group at year 1 visit, 1.6 and 13.0, respectively, at year 2 visit and 2.2 and 10.3, respectively, at year 3 visit. Moreover, about 42% of patients on prophylaxis vs 12% of patients on on‐demand had zero annual joint bleeding rates (AJBR). Effectiveness of prophylaxis and on‐demand treatment was deemed excellent/good in the majority of cases. Octocog alfa (Advate®) was well tolerated. The inhibitors that developed in nine patients all disappeared spontaneously. Three patients had been previously exposed to FVIII for ≤50 exposure days (EDs), 3 for >50 EDs and 3 showed a borderline positive inhibitory activity (≤0.6 BU/mL).ConclusionsThese data confirm that the goal of zero bleeds is achievable, although not yet achieved in all patients. Understanding reasons behind the lower response to standard prophylaxis regimens in some patients and personalizing prophylactic treatment may further improve outcome in patients with haemophilia A.

Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII (rFVIII) concentrates. Wecarried out a systematic literature search and meta-analysis for all randomized clinical trials and observational studies published from 1 January 1988 to 31 August 2015, to assess the incidence of inhibitor development and the relationship with rFVIII product used in PUPs and minimally treated patients (MTPs,<= 5 previous exposure days), with severe haemophilia. The primary outcome measure was development of all inhibitors and high-titre inhibitors. We computed pooled meta-analytic estimates according to the rFVIII product used with the inverse-variance method, assuming a fixed, or a random-effects model if significant between-studies heterogeneity was present. Out of 781 articles, 16 published between 1998 and 2015 were included in the meta-analysis, involving a total of 2094 haemophilia A PUPs or MTPs. The pooled estimate of all inhibitors was 0.27 (95% confidence interval 0.23-0.31). No significant difference in pooled inhibitor incidence across products was found (P = 0.72). Meta-analysis of studies reporting inhibitor hazard ratios with different rFVIII products, adjusted to different risk factors, showed that PUPs/MTPs treated with Advate had a pooled inhibitor hazard ratio estimate of 0.63 (95% confidence interval 0.48-0.83) as compared with Kogenate FS. The overall inhibitor incidence in PUPs/MTPs was 27%. Differences between products were found considering hazard ratios in which potential confounders were taken into account. (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Introduction: Hemophilia is a rare congenital bleeding disorder that requires coagulation factor replacement therapy to treat or, better, to prevent life- and limb-threatening bleeding and its complications. Personalized treatment of patients with hemophilia is crucial for improving outcomes in an environment with increasing health budget constraints.Areas covered: Unmet needs for a more effective and efficient use of factor concentrates are examined. The current approach is described with its limits and recent improvements, i.e. pharmacokinetic assessments and dosing tools/models. Future approaches to personalization were researched in the literature and discussed, including biomarkers, genotyping, decision-making tools, goal attainment tools and digital health systems.Expert opinion: A paradigm shift in hemophilia management personalization is necessary in order to improve outcome and ensure long-term sustainability in a landscape of growing and aging patient populations, increasing expectations and rising healthcare costs. Hemophilia management should gradually move from a reactive toward a more proactive approach, based on patient profiling precision, accurate treatment and outcome monitoring and a service-centered approach. This shift will require increased cooperation between clinicians, patients, caregivers and home service operators, as well as digital health systems and patient empowerment.

Introduction The development of factor VIII (FVIII) inhibitory antibodies is one of the major challenges of the treatment of hemophilia, because it hinders FVIII replacement for the treatment and prevention of bleeding events (Leissinger 2015). Two products are currently available to control bleeding in patients with inhibitors: the activated prothrombin complex concentrate (aPCC; FVIII inhibitor bypassing activity, FEIBA VH; Shire plc, USA) and recombinant activated factor VII (rFVIIa; NovoSeven, Bagsvaerd, Denmark). Both agents have shown similar efficacy, with some patients responding better to one over the other (Astermark 2007). Both agents have been associated with the development of thromboembolic events (TEEs) (Aledort 2004). Aim of this study was to estimate TEE incidence in patients with congenital hemophilia with inhibitors and acquired hemophilia exposed to aPCC, by using a meta-analytic approach based on published scientific literature. Methods A systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The incidence rate of TEEs was estimated via a meta-analytic approach by using a Generalized Linear Mixed Model based on a Poisson distribution. Stratified analyses according to study design (prospective vs. retrospective), hemophilia type (congenital vs. acquired) and treatment modality (on-demand, prophylaxis and surgery) have been conducted. Results We identified a total of 144 papers through the electronic literature search and out of the 61 fully evaluated articles, 39 studies with TEE data related to the use of aPCC in patients with congenital hemophilia with inhibitor or acquired hemophilia were included in the meta-analysis. The studies included were published from 1980 to 2016, providing information on safety related to 678,447 aPCC infusions (7,291 infusions as on-demand treatment, 77,203 in prophylaxis, 3,296 in surgery and 590,657 in unspecified treatment modalities). In the 39 studies included overall, 46 TEEs were reported: 13 disseminated intravascular coagulation (DIC), 11 ischemic coronary syndrome (ICS), 4 pulmonary embolism (PE), 3 thrombotic cerebrovascular accidents (CVA), 3 deep vein thrombosis (DVT), 3 superficial vein thrombosis (SVT), 6 unspecified thrombosis (unreported location) and 3 fibrinogen reduction. No thrombotic microangiopathic events have ever been reported. Out of the 39 studies included, 31 (79%) reported no TEEs. The estimated pooled TEE incidence rate was 2.87 (95% CI 0.32-25.40) per 100,000 aPCC infusions. When stratifying for retrospective and prospective studies, 35 TEEs in 649,343 aPCC infusions (pooled incidence rate, 5.42 per 100,000 infusions), and 11 TEEs in 29,104 infusions (pooled incidence rate, 1.09 per 100,000 infusions) were respectively reported. TEE incidence rate in patients treated with aPCC on-demand was 5.09 per 100,000 infusions, while in patients treated with prophylaxis, no TEEs were reported. Five TEEs were reported in 11 studies in hemophilia patients with inhibitors undergoing surgery, being the pooled TEE incidence rate 112.03 per 100,000 aPCC infusions. Finally, pooled TEEs incidence rate in acquired hemophilia patients was 287.79 per 100,000 infusions, but less than 0.01 per 100,000 infusions in congenital hemophilia patients. Conclusions The pooled incidence rate was lower than 3 TEEs per 100,000 aPCC infusions, demonstrating a relatively low risk and confirming previous figures reported (Erlich 2002, Aledort 2004). Stratified analysis showed that the incidence is even lower in patients with congenital hemophilia and no TEE in prophylaxis. These findings provide robust evidence of safety of aPCC over almost 40 years of published studies. Disclosures Rota: ASHLEY COMMUNICATIONS ON BEHALF OF SHIRE FOR SHIRE SYMPOSIUM PARTICIPATION AS A SPEAKER AT THE ISTH 2017 CONGRESS: Honoraria. Cortesi: Shire: Research Funding. Crea: Shire: Employment, Equity Ownership. Gringeri: Shire: Employment. Mantovani: Daiichi Sankyo: Consultancy; Shire: Research Funding; Bayer AG: Consultancy; Boehringer Ingelheim: Research Funding; Janssen-Cilag: Research Funding.

Anti-inhibitor coagulant complex (AICC), an activated prothrombin complex concentrate, has been available for the treatment of patients with inhibitors since 1977, and thromboembolic events (TEEs) have been reported after infusion of AICC in patients with congenital or acquired hemophilia. With the aim of estimating the TEE incidence rate (IR) related to AICC exposure in these patients, a systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The IR of TEEs was estimated through a meta-analytic approach by using a generalized linear mixed model based on a Poisson distribution. Thirty-nine studies were included (1980-2016). Overall, 46 TEEs were reported; of these, 13 were reported as disseminated intravascular coagulations, 11 as myocardial infarctions, and 3 as thrombotic cerebrovascular accidents. The pooled TEE IR was 2.87 (95% confidence interval [CI], 0.32-25.40) per 100 000 AICC infusions (5.42 in retrospective studies [95% CI, 0.92-31.82]; 1.09 in prospective studies [95% CI, 0.01-238.77]). The TEE rate was 5.09 (95% CI, 0.01-1795.60) per 100 000 AICC infusions administered on demand, whereas no TEEs were reported with prophylaxis. Interestingly, the estimated IR in patients with congenital hemophilia was <0.01 per 100 000 infusions. These findings provide robust evidence of safety of AICC over almost 40 years of published studies.

Background: Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient-tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients' bleeding phenotype, levels of physical activity and a variety of other variables. Methods: A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations. Results: Twenty-eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended. Conclusions: We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia.