Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B.

BACKGROUND: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed. OBJECTIVES: To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health-related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE. MAIN RESULTS: Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion. Prophylaxis versus on-demand therapy in people with inhibitors Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on-demand therapy in people with inhibitors. Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD -22.80, 95% CI -37.39 to -8.21), treated bleeds (MD -20.40, 95% CI -35.19 to -5.61), and annualized spontaneous bleeds (MD -15.50, 95% CI -24.06 to -6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate-certainty evidence). Fitusiran also likely reduced ABR for all bleeds (MD -28.80, 95% CI -40.07 to -17.53), treated bleeds (MD -16.80, 95% CI -25.80 to -7.80), joint bleeds (MD -12.50, 95% CI -19.91 to -5.09), and spontaneous bleeds (MD -14.80, 95% CI -24.90 to -4.71; 1 trial; 57 participants; moderate-certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on-demand therapy on AtjBR. Concizumab may reduce ABR for all bleeds (MD -12.31, 95% CI -19.17 to -5.45), treated bleeds (MD -10.10, 95% CI -17.74 to -2.46), joint bleeds (MD -9.55, 95% CI -13.55 to -5.55), and spontaneous bleeds (MD -11.96, 95% CI -19.89 to -4.03; 2 trials; 78 participants; very low-certainty evidence), but not target joint bleeds (MD -1.00, 95% CI -3.26 to 1.26). Emicizumab prophylaxis resulted in an 11.31-fold increase, fitusiran in a 12.5-fold increase, and concizumab in a 1.59-fold increase in the proportion of participants with no bleeds. HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low-certainty evidence). Non-serious adverse events were higher with non-clotting factor therapies versus on-demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab. Prophylaxis versus on-demand therapy in people without inhibitors Two trials (208 participants) compared emicizumab and fitusiran with on-demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi-weekly). Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi-weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD -20.21, 95% CI -32.12 to -8.30) and emicizumab 3.0 mg/kg bi-weekly (MD -15.30, 95% CI -30.46 to -0.14), but not with emicizumab 1.5 mg/kg/week (MD -14.60, 95% CI -29.78 to 0.58). The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi-weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on-demand therapy. Emicizumab 1.5 mg/kg/week did not improve Haem-A-QoL physical and total health scores, EQ-5D-5L VAS, or utility index scores (low-certainty evidence) when compared with on-demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi-weekly may improve HRQoL measured by the Haem-A-QoL physical health score (MD -15.97, 95% CI -29.14 to -2.80) and EQ-5D-5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low-certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem-A-QoL total score (MD -7.06, 95% CI -11.50 to -2.62) and physical health score (MD -19.75, 95% CI -25.76 to -11.94; 1 trial; 103 participants; low-certainty evidence). The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on-demand therapy (moderate-certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering. A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient-reported outcomes. No case of treatment-related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes. None of the included studies evaluated marstacimab. AUTHORS' CONCLUSIONS: Evidence from RCTs shows that prophylaxis using non-clotting factor therapies compared with on-demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non-serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long-term joint outcomes, and assessment of economic outcomes will improve evidence-based decision-making for the use of these therapies in bleed prevention.

Use of nonacog beta pegol during surgery in persons with hemophilia B: a case series.

Background: Hemophilia B is a coagulation disorder that puts patients at an increased risk of bleeding. Factor (F) IX replacement therapy is traditionally used in such cases to maintain hemostasis. Nonacog beta pegol (N9-GP; Refixia) is a glycoPEGylated, extended half-life, recombinant FIX product that has demonstrated safety and efficacy when used to manage persons with hemophilia B. Key clinical question: Given the limited real-world evidence, we aimed to explore the role of N9-GP in maintaining hemostasis in persons with hemophilia B undergoing surgery. Clinical approach: In this case series, we report real-world clinical experience with N9-GP to maintain hemostasis in persons with hemophilia B undergoing major and minor surgeries. Conclusion: The majority of cases presented in this case series had an excellent or very good hemostatic response, with no reported surgical complications related to the use of N9-GP.

Inhibitors in hemophilia: association with surgery plans and outcomes in a retrospective cohort study.

Background: The development of antibodies (inhibitors) to clotting factors compromises the management of hemophilia A and B, resulting in resistance to clotting factor replacement and, in many cases, the need for bypassing agents to achieve hemostasis. Objectives: To evaluate the association between the presence of inhibitors and achievement of perioperative hemostasis, development of complications, and presurgical plan deviations. Methods: We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center surgical database (1998-2019). Associations between perioperative outcomes and inhibitor status were assessed while controlling for patient and procedural characteristics. Results: A total of 1492 surgeries were performed in 539 persons with hemophilia, with 72 procedures performed in 20 patients with inhibitors (15 with hemophilia A; 5 with hemophilia B). High-responding inhibitors (>5 BU/mL) were present in 27 procedures, low-responding inhibitors (≤5 BU/mL) were present in in 13 procedures, and 32 procedures were performed in patients with historically persistent inhibitors. Adjusting for age, diagnosis, surgery setting, hemostatic agent, data collection period, and surgery type (major/minor), inhibitors were associated with a higher risk of inadequate perioperative hemostasis (33.4% vs 8.6%; adjusted relative risk [adjRR], 3.78; 95% CI, 1.89-7.56; P < .001). Reported complications include hemorrhage, fever, pain, thrombosis, and infections. Complications were not statistically different based on inhibitor status (31.7% vs 14.6%; adjRR, 1.25; 95% CI, 0.63-2.49; P = .526). Presurgical plan deviations (eg, hemostatic medication dose adjustments, procedure rescheduling, and changes in the length of postoperative hospitalization) occurred more frequently in surgeries involving inhibitors (70.8 vs 39.5%; adjRR, 1.47; 95% CI, 1.12-1.93; P = .005). Conclusion: Inhibitors are associated with higher risks of adverse perioperative outcomes. Strategies to address inhibitor development should be prioritized to avoid undesirable perioperative outcomes.

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B.

BACKGROUND: The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. OBJECTIVES: To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect.   AUTHORS' CONCLUSIONS: There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI.  When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons.  Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.

Potential Risk Factors Contributing to Development of Venous Thromboembolism for Total Knee Replacements Patients Prophylaxed With Rivaroxaban: A Retrospective Case-Control Study.

Rivaroxaban after total knee arthroplasty (TKA) is used to prevent postoperative venous thromboembolism (VTE); however, despite thromboprophylaxis, some patients still develop postoperative VTE. To determine whether tourniquet time, time to initiate rivaroxaban (TTIRIV), or Body Mass Index (BMI) was associated with postoperative VTE. A retrospective case-control study was conducted. Those patients that developed VTE despite prophylaxis (cases) were compared to controls (no VTE). A univariate analysis was conducted (p < 0.05 statistically significant). Seven VTE cases were identified from 234 TKA-patients. Patients with and without VTE had BMI of 40.1 ± 9.1 and 32.8 ± 7.5, respectively (p = 0.064). TTIRIV in VTE and control group was 28.2 ± 4.7 hours and 26.4 ± 4.2 hours, respectively (p = 0.39). Mean tourniquet time in VTE and control group was 65.0 ± 8.7 minutes and 49 ± 8.8 minutes, respectively (p = 0.0007). Statistically significant differences in tourniquet times were noted between VTE and non-VTE group but not for TTIRIV and BMI. Prolonged tourniquet use could pose a potential risk factor for postoperative VTE. Thromboprophylaxis management may need to be adjusted, based on patient-specific factors that could include increasing doses of oral anticoagulants and/or mechanical prophylaxis. However, further large-scale studies are required to establish pathophysiology.

Inferior vena cava syndrome in neonates: An evidence-based systematic review of the literature.

Neonatal inferior vena cava syndrome (IVCS), though uncommon, is associated with significant morbidity and mortality. Information on risk factors, diagnosis, treatment, and outcomes is limited. This review comprised 61 neonates across 33 reports. Thrombosis occurred in 98% and 42% involved a central venous catheter. Diagnosis was mainly established by ultrasound in 82%. Therapeutically, heparin was employed in 36% and thrombolysis in 18% of the cases. The overall mortality was 23%. An algorithm of clinical signs, investigation, and management is presented. Well-designed prospective studies are needed to establish a concrete investigational approach to neonatal IVCS and institute safe, evidence-based treatment.

Engagement of Nuclear Coactivator 7 by 3-Hydroxyanthranilic Acid Enhances Activation of Aryl Hydrocarbon Receptor in Immunoregulatory Dendritic Cells.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first step in the kynurenine pathway of tryptophan (Trp) degradation that produces several biologically active Trp metabolites. L-kynurenine (Kyn), the first byproduct by IDO1, promotes immunoregulatory effects via activation of the Aryl hydrocarbon Receptor (AhR) in dendritic cells (DCs) and T lymphocytes. We here identified the nuclear coactivator 7 (NCOA7) as a molecular target of 3-hydroxyanthranilic acid (3-HAA), a Trp metabolite produced downstream of Kyn along the kynurenine pathway. In cells overexpressing NCOA7 and AhR, the presence of 3-HAA increased the association of the two molecules and enhanced Kyn-driven, AhR-dependent gene transcription. Physiologically, conventional (cDCs) but not plasmacytoid DCs or other immune cells expressed high levels of NCOA7. In cocultures of CD4+ T cells with cDCs, the co-addition of Kyn and 3-HAA significantly increased the induction of Foxp3+ regulatory T cells and the production of immunosuppressive transforming growth factor ß in an NCOA7-dependent fashion. Thus, the co-presence of NCOA7 and the Trp metabolite 3-HAA can selectively enhance the activation of ubiquitary AhR in cDCs and consequent immunoregulatory effects. Because NCOA7 is often overexpressed and/or mutated in tumor microenvironments, our current data may provide evidence for a new immune check-point mechanism based on Trp metabolism and AhR.

Amino acid metabolism as drug target in autoimmune diseases.

In mammals, amino acid metabolism has evolved to control immune responses. Autoimmune diseases are heterogeneous conditions that involve the breakdown of tolerogenic circuitries and consequent activation of autoreactive immune cells. Therefore, critical enzymes along amino acid degradative pathways may be hijacked to keep in check autoimmunity. We examined here current knowledge of indoleamine 2,3-dioxygenase 1 (IDO1) and arginase 1 (ARG1), the main enzymes catabolizing tryptophan and arginine, respectively, in organ-specific and systemic autoimmune diseases as well as in the development of autoantibodies to therapeutic proteins. At variance with neoplastic contexts, in which it is known to act as a pure immunosuppressive molecule, ARG1 exhibited a protective or pathogenetic profile, depending on the disease. In contrast, in several autoimmune conditions, the bulk of data indicated that drugs capable of potentiating IDO1 expression and activity may represent valuable therapeutic tools and that IDO1-based immunotherapeutic protocols could be more effective if tailored to the genetic profile of individual patients.

S1P promotes migration, differentiation and immune regulatory activity in amniotic-fluid-derived stem cells.

Stem cells have high potential for cell therapy in regenerative medicine. We previously isolated stem cell types from human amniotic fluid, derived from prenatal amniocentesis. One type, characterized by a fast doubling time, was designated as fast human amniotic stem cells (fHASCs). These cells exhibited high differentiation potential and immunoregulatory properties. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that influences stem-cell pluripotency, differentiation, mobility, and regulates immune functions. In this study, we investigated the influence of S1P on fHASC migration, proliferation, differentiation and immune regulatory functions. We found that fHASC stimulation with S1P potentiated their migratory and proliferative activity in vitro. Notably, short fHASC exposure to S1P enhanced their differentiation towards multiple lineages, including adipocytes, osteocytes and endothelial cells, an effect that was associated with downregulation of the main transcription factors involved in the maintenance of a stem-cell undifferentiated state. A specific crosstalk between S1P and tumor growth factor ß1 (TGF-ß1) has recently been demonstrated. We found that fHASC exposure to S1P in combination with TGF-ß1 promoted the expression of the immune regulatory pathway of indoleamine 2,3-dioxygenase 1 (IDO1). In addition, human peripheral blood mononuclear cells, co-cultured with fHASCs treated with S1P and TGF-ß1, expanded regulatory T-cells, via a mechanism requiring IDO1. Overall, this study demonstrates that S1P potentiates several properties in fHASCs, an effect that may be critical for exploiting the therapeutic potential of fHASCs and might explain the specific effects of S1P on stem cells during pregnancy.

The Proteasome Inhibitor Bortezomib Controls Indoleamine 2,3-Dioxygenase 1 Breakdown and Restores Immune Regulation in Autoimmune Diabetes.

Bortezomib (BTZ) is a first-in-class proteasome inhibitor approved for the therapy of multiple myeloma that also displays unique regulatory activities on immune cells. The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan metabolizing enzyme exerting potent immunoregulatory effects when expressed in dendritic cells (DCs), the most potent antigen-presenting cells capable of promoting either immunity or tolerance. We previously demonstrated that, in inflammatory conditions, IDO1 is subjected to proteasomal degradation in DCs, turning these cells from immunoregulatory to immunostimulatory. In non-obese diabetic (NOD) mice, an experimental model of autoimmune diabetes, we also identified an IDO1 defect such that the DCs do not develop tolerance toward pancreatic islet autoantigens. We found that BTZ rescues IDO1 protein expression in vitro in a particular subset of DCs, i.e., plasmacytoid DCs (pDCs) from NOD mice. When administered in vivo to prediabetic mice, the drug prevented diabetes onset through IDO1- and pDC-dependent mechanisms. Although the drug showed no therapeutic activity when administered alone to overtly diabetic mice, its combination with otherwise suboptimal dosages of autoimmune-preventive anti-CD3 antibody resulted in disease reversal in 70% diabetic mice, a therapeutic effect similar to that afforded by full-dosage anti-CD3. Thus, our data indicate a potential for BTZ in the immunotherapy of autoimmune diabetes and further underline the importance of IDO1-mediated immune regulation in such disease.

Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors.

BACKGROUND: In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors. OBJECTIVES: To determine the clinical effectiveness of recombinant factor VIIa concentrate compared to plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Coagulopathies Trials Register: 23 September 2015. SELECTION CRITERIA: Randomised and quasi-randomised controlled clinical trials comparing recombinant factor VIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant factor VIII or factor IX concentrate; non-activated prothrombin complex concentrates; activated prothrombin complex concentrates) in people with haemophilia. Comparisons with animal-derived products were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials (eligibility and risk of bias) and extracted data. No combined meta-analyses were performed due to the unavailability of outcomes and comparisons common to the included trials. MAIN RESULTS: A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. AUTHORS' CONCLUSIONS: Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.

Stem cells from human amniotic fluid exert immunoregulatory function via secreted indoleamine 2,3-dioxygenase1.

Although human amniotic fluid does contain different populations of foetal-derived stem cells, scanty information is available on the stemness and the potential immunomodulatory activity of in vitro expanded, amniotic fluid stem cells. By means of a methodology unrequiring immune selection, we isolated and characterized different stem cell types from second-trimester human amniotic fluid samples (human amniotic fluid stem cells, HASCs). Of those populations, one was characterized by a fast doubling time, and cells were thus designated as fHASCs. Cells maintained their original phenotype under prolonged in vitro passaging, and they were able to originate embryoid bodies. Moreover, fHASCs exhibited regulatory properties when treated with interferon (IFN)-γ, including induction of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). On coculture with human peripheral blood mononuclear cells, IFN-γ-treated fHASCs caused significantly decreased T-cell proliferation and increased frequency in CD4(+)  CD25(+)  FOXP3(+) regulatory T cells. Both effects required an intact IDO1 function and were cell contact-independent. An unprecedented finding in our study was that purified vesicles from IFN-γ-treated fHASCs abundantly expressed the functional IDO1 protein, and those vesicles were endowed with an fHASC-like regulatory function. In vivo, fHASCs were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. This was concurrent with the expansion of CD4(+)  CD25(+)  Foxp3(+) T cells in graft-draining lymph nodes from recipient mice. Thus fHASCs, or vesicles thereof, may represent a novel opportunity for immunoregulatory maneuvers both in vitro and in vivo.

High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance.

BACKGROUND: The natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI. METHODS: A retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time. RESULTS: The cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance. CONCLUSIONS: Spontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases.

Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors.

BACKGROUND: In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-FVIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII "by-passing" agents and used for treatment of bleeding in people with inhibitors. OBJECTIVES: To determine the clinical effectiveness of recombinant FVIIa concentrate in comparison to plasma-derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Trials Register: 07 July 2010. SELECTION CRITERIA: Randomised (RCTs) and quasi-randomised controlled clinical trials comparing recombinant FVIIa concentrate (rFVIIa) to human plasma-derived concentrates (high-dose human or recombinant FVIII or FIX concentrate; prothrombin complex concentrates (PCCs); activated prothrombin complex concentrate (aPCC)) in persons with haemophilia. Comparisons with animal derived products were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials (eligibility and risk of bias) and extracted data. No meta-analysis was performed due to unavailability of outcomes and comparisons common to the included studies. MAIN RESULTS: A total of ten trials were identified, two of which (total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that (rFVIIa and aPCC appeared to have a similar haemostatic effect in both studies, without increasing thromboembolic risk. AUTHORS' CONCLUSIONS: Although the main conclusion should be the need for further randomised controlled trials, we conclude that both rFVIIa and aPCC can be used to treat bleeding in haemophiliacs with inhibitors.