A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation study.

The CYCS gene is highly evolutionarily conserved, with only a few pathogenic variants that cause thrombocytopenia-4 (THC4). Here, we report a novel CYCS variant NM_018947.6: c.59C>T [NP_061820.1:p.(Thr20Ile)] segregating with thrombocytopenia in three generations of a Czech family. The phenotype of the patients corresponds to THC4 with platelets of normal size and morphology and dominant inheritance. Intriguingly, a gradual decline in platelet counts was observed across generations. CRISPR/Cas9-mediated gene editing was used to introduce the new CYCS gene variant into a megakaryoblast cell line (MEG-01). Subsequently, the adhesion, shape, size, ploidy, viability, mitochondrial respiration, cytochrome c protein (CYCS) expression, cell surface antigen expression and caspase activity were analysed in cells carrying the studied variant. Interestingly, the variant decreases the expression of CYCS while increasing mitochondrial respiration and the expression of CD9 cell surface antigen. Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants. Some reports indicate that caspases may be involved in thrombopoiesis; thus, the observed dysregulation of caspase activity might contribute to thrombocytopenia. The findings significantly enhance our understanding of the molecular mechanisms underlying inherited thrombocytopenia and may have implications for diagnosis, prognosis and future targeted therapies.

How much prophylaxis is enough in haemophilia?

INTRODUCTION: Prophylaxis has become standard of care for all persons with haemophilia (PWH) with a severe phenotype. However, 'standard prophylaxis' with either factor or non-factor therapies (currently only emicizumab available) is prohibitively expensive for much of the world. We sought to address the question of 'How much prophylaxis is enough?' and 'Can it be individualized?' and specifically 'Can emicizumab be individualized?'. METHODS: We reviewed the literature on prophylaxis in haemophilia since its inception in the 1950s to the present, the development of more and less intense factor prophylaxis regimens and their outcomes and additionally the published outcomes of prophylaxis with low dose emicizumab. RESULTS: What these experiences collectively show is that low dose emicizumab does result in significant benefits to patients whilst being much less expensive than a "one size fits all" emicizumab prophylaxis approach. We also took note that some non-factor therapies still in development are individualized given that high doses of these can potentially put patients at risk. CONCLUSIONS: Prophylaxis is now clearly accepted as standard of care for PWH with a severe phenotype but now in a very short time a large assortment of different treatment options for prophylaxis have become/are becoming available and the haemophilia community will need to determine how to best use these recognizing that no 'one treatment fits all'.

Moving towards Normalization of haemostasis and health equity: Evolving treatment goals for haemophilia A.

BACKGROUND: Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile. TREATMENT GOALS: The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health-related quality of life impacted by haemophilia and its treatment. CONCLUSION: Capitalizing on the major potential of therapeutic innovations, 'Normalization' of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia-imposed limitations. To achieve this-being supported by the data reviewed in this manuscript-the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community.

Bleeding pattern and consumption of factor VIII concentrate in adult patients with haemophilia A without inhibitors in the Czech Republic between 2013 and 2021 (Czech National Haemophilia Programme registry data).

The manuscript provides an overview of treatment and its changes in adult patients with haemophilia A without inhibitors in the Czech Republic between 2013 and 2021 using data from the registry of the Czech National Haemophilia Programme (CNHP). Over a 9-year period, we focused on the reduction in the annual bleeding rate (ABR), joint bleeding rate (AJBR) and factor VIII consumption when patients with severe haemophilia A switched from on-demand treatment to prophylaxis. The ABR and AJBR include both patient-reported home treatment and treated hospitalisation episodes. All adult patients with severe haemophilia A were categorised into three groups according to the therapeutic regimen. The first group was patients on prophylaxis during the follow-up period, the second group consisted of patients on on-demand treatment, and the third group was patients who received both treatment regimens during follow-up. With an increase in the proportion of patients with severe haemophilia A on prophylaxis from 37 to 74% between 2013 and 2021, the ABR for all patients with severe haemophilia A decreased approximately 6.9-fold, and the AJBR decreased 8.7-fold. Expectedly, the factor consumption increased by approximately 68.5%. In the group of patients with severe haemophilia A who had switched from an on-demand to a prophylactic regimen, the total number of bleeding events decreased 3.5-fold, and the number of joint bleeding episodes decreased 3.9-fold. Factor VIII consumption increased by 78.4%. Our study supports a previously reported positive effect of prophylaxis on bleeding control. We believe that the substantial improvement in ABR justifies the increased treatment costs.

Real-world evidence on efmoroctocog alfa in patients with haemophilia A: A systematic literature review of treatment experience in Europe.

INTRODUCTION: The real-world effectiveness of the efmoroctocog alfa (recombinant FVIII Fc fusion protein, a rFVIIIFc) has been investigated in numerous studies, however, currently, there exists no comprehensive collection of the existing real-world evidence (RWE) on the performance of prophylactic use of rFVIIIFc. AIM: The aims of this systematic literature study were to identify, review, evaluate and collate the RWE of prophylactic rFVIIIFc for patients with haemophilia A reported in Europe. METHODS: We searched Medline and Embase from 2014 to February 2022 to identify publications reporting the effectiveness of rFVIIIFc in patients with haemophilia A. The outcomes of interest were annualised bleeding rates (ABR, AjBR, AsBR), injection frequency, factor consumption, adherence, development of inhibitors and quality-of-life measures. RESULTS: 46 eligible publications (eight full-text articles) were included. rFVIIIFc showed a low ABR in patients with haemophilia A. Studies assessing treatment switching from a standard half-life (SHL) treatment to rFVIIIFc found that the ABR and consumption were reduced in most patients. Studies assessing rFVIIIFc effectiveness reported a median ABR between 0.0 and 2.0 with median injections per week ranging between 1.8 and 2.4 and median doses between 60 and 105 IU/kg/week. Of the studies assessing inhibitor development, only one study reported an incidence of a low titre inhibitor, and no patients developed clinically significant inhibitors. CONCLUSION: rFVIIIFc prophylaxis treatment results in a low ABR across studies in patients with haemophilia A in a European real-world setting, which correlates with findings from clinical trials assessing the efficacy of rFVIIIFc in patients with haemophilia A.

Dilemmas on emicizumab in children with haemophilia A: A survey of strategies from PedNet centres.

INTRODUCTION: Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres. AIM: We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia. METHODS: An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors. RESULTS: All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protocol. CONCLUSION: Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI.

Capnometry during neonatal transport-Mini review.

AIM: The aim of this review was to give an overview of available data on end-tidal CO2 (etCO2 ) monitoring, also called capnometry, during neonatal transport. METHODS: Pubmed/MEDLINE database was searched using research question (capno* OR etCO2 OR detCO2 OR (['end tidal' OR 'end-tidal'] AND [CO2 OR 'carbon dioxide']) AND (neonat* OR infant* OR newborn*) AND transport*). All articles relevant to the topic were reviewed and summarised. RESULTS: The lack of studies relevant to neonatal transport prompted us to extend the search to capnometry in a neonatal intensive care setting. The published studies are showing conflicting results. The different study populations, technologies used to measure etCO2 , types of etCO2 sampling and the diverse sites of blood gas tests make the data unsuitable for systematic comparison. CONCLUSION: Further research to obtain more data on capnometry during neonatal transport will be necessary to define precisely under what circumstances can end-tidal monitoring of CO2 be reliably used in neonates during transport and also how to interpret the measured values.

Control Centre for Intensive Care as a Tool for Effective Coordination, Real-Time Monitoring, and Strategic Planning During the COVID-19 Pandemic.

In the Czech Republic, the strategic data-based and organizational support for individual regions and for providers of acute care at the nationwide level is coordinated by the Ministry of Health. At the beginning of the COVID-19 pandemic, the country needed to very quickly implement a system for the monitoring, reporting, and overall management of hospital capacities. The aim of this viewpoint is to describe the purpose and basic functions of a web-based application named "Control Centre for Intensive Care," which was developed and made available to meet the needs of systematic online technical support for the management of intensive inpatient care across the Czech Republic during the first wave of the pandemic in spring 2020. Two tools of key importance are described in the context of national methodology: one module for regular online updates and overall monitoring of currently free capacities of intensive care in real time, and a second module for online entering and overall record-keeping of requirements on medications for COVID-19 patients. A total of 134 intensive care providers and 927 users from hospitals across all 14 regions of the Czech Republic were registered in the central Control Centre for Intensive Care database as of March 31, 2021. This web-based application enabled continuous monitoring and decision-making during the mass surge of critical care from autumn 2020 to spring 2021. The Control Center for Intensive Care has become an indispensable part of a set of online tools that are employed on a regular basis for crisis management at the time of the COVID-19 pandemic.

Prophylaxis in children with haemophilia in an evolving treatment landscape.

INTRODUCTION: For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab. AIM: To review key factors that determine the choice of prophylaxis in young children. METHODS: Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis. RESULTS: The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen. CONCLUSIONS: In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration.

Czech and Slovak Diamond-Blackfan Anemia (DBA) Registry update: Clinical data and novel causative genetic lesions.

Diamond-Blackfan anemia (DBA) is a rare congenital erythroid aplasia, underlied by haploinsufficient mutations in genes coding for ribosomal proteins (RP) in approximately 70% of cases. DBA is frequently associated with somatic malformations, endocrine dysfunction and with an increased predisposition to cancer. Here we present clinical and genetic characteristics of 62 patients from 52 families enrolled in the Czech and Slovak DBA Registry. Whole exome sequencing (WES) and array comparative genomic hybridization (aCGH) were employed to identify causative mutations in newly diagnosed patients and in cases with previously unrecognized molecular pathology. RP mutation detection rate was 81% (50/62 patients). This included 8 novel point mutations and 4 large deletions encompassing some of the RP genes. Malignant or predisposing condition developed in 8/62 patients (13%): myelodysplastic syndrome in 3 patients; breast cancer in 2 patients; colorectal cancer plus ocular tumor, diffuse large B-cell lymphoma and multiple myeloma each in one case. These patients exclusively harbored RPL5, RPL11 or RPS19 mutations. Array CGH is beneficial for detection of novel mutations in DBA due to its capacity to detect larger chromosomal aberrations. Despite the importance of genotype-phenotype correlation in DBA, phenotypic differences among family members harboring an identical mutation were observed.

Social support and resilience in persons with severe haemophilia: An interpretative phenomenological analysis.

INTRODUCTION: Haemophilia is a hereditary haemorrhagic disorder characterized by deficiency or dysfunction of coagulation factors. Recurrent joint and muscle bleeds lead to progressive musculoskeletal damage. Haemophilia affects patients physically but also socially and psychologically. Traumatic experiences, chronic stress and illnesses can lead to mental disorders, but many persons with haemophilia maintain a highly positive outlook. AIM: To explore qualitatively which coping mechanisms persons with haemophilia use and in what way they help them to live with their diagnosis. METHODS: We recruited five adults with haemophilia and conducted semi-structured face-to-face interviews. Transcripts were analysed using interpretative phenomenological analysis (IPA). RESULTS: Two core themes emerged from the analysis: social support as an external factor and resilience as an internal factor of coping with the disease. Persons with haemophilia usually need help with health-related complications, and this affects the social support they require. Their wider support network tends to involve family and friends but also healthcare professionals and other specialists. This network provides practical help but also functions as an important psychological protective factor. An unexpected finding was that persons with haemophilia want not only to receive support but are also keen to offer support to others. CONCLUSION: These findings can help identify persons who provide most support to people suffering from haemophilia. Haemophilic centres should include in their teams psychologists and social workers and offer individual and group therapy to their clients, group meetings for friends and families of persons with haemophilia, provide learning resources to teachers aiming to incorporate children with haemophilia in their peer group, and organize Balint groups for physicians, psychologists and other healthcare professionals.

Postauthorization safety surveillance study of antihaemophilic factor (recombinant) reconstituted in 2 mL sterile water for injection in children with haemophilia A.

INTRODUCTION: Antihaemophilic factor (recombinant) (rAHF; ADVATE® ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. AIM: To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII < 1%) or moderately severe (FVIII 1%-2%) haemophilia A. METHODS: This was a prospective, non-interventional, postauthorization safety surveillance study (NCT02093741). Eligible patients were previously treated with rAHF and had a negative inhibitor test result during ≤10 exposure days prior to study entry. RESULTS: Of 65 patients enrolled (0-11 years of age), 54 and 11 had severe and moderately severe haemophilia A, respectively; 56 patients received prophylaxis, and 11 had ≤50 exposure days, of which 4 had ≤4 exposure days. No patients reported local hypersensitivity reactions, treatment-related adverse events or developed inhibitors. Investigators rated overall effectiveness of rAHF 2 mL prophylaxis as excellent or good. Ninety-four bleeding events in 34 patients were treated. Haemostatic effectiveness was rated as excellent or good for 75.8% of bleeds; 86.2% of bleeds required 1 or 2 infusions. CONCLUSION: In children with severe/moderately severe haemophilia A, no hypersensitivity reactions were reported with rAHF 2 mL treatment, and the safety and effectiveness are consistent with data previously reported for rAHF 5 mL.

The second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany.

The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016.

Partnering to change the world for people with haemophilia: 6(th) Haemophilia Global Summit, Prague, Czech Republic, 24-26(th) September 2015.

The 6(th) Haemophilia Global Summit was held in Prague, Czech Republic, in September 2015. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and aimed to share optimal management strategies for haemophilia at all life stages, explore recent potential advances in the management of haemophilia A and B and discuss challenges in haemophilia care. In this supplement from the meeting, Dan Hart reviews the lessons that can be learnt from cost-constrained environments with regard to improving care for people with haemophilia globally. Sébastien Lobet discusses the importance of physical activity for optimising care and Roseline d'Oiron and Jan Blatný consider the role of real-world data in understanding the effect of treatment in a clinical setting over the long term and the true impact of treatment on the day-to-day life of the patient. Gili Kenet addresses the current challenges relating to the optimal management of prophylaxis, and Gerry Dolan and Cedric Hermans discuss the value of pharmacokinetic (PK) parameters in informing treatment decisions. Cedric Hermans and Valérie Libotte explore the importance of considering social and occupational development factors as an integral part of haemophilia care, and Jan Astermark reviews key strategies to predict and prevent inhibitor development.

Teenagers and Adolescents with Hemophilia-Need for a Specific Approach.

Adolescents with hemophilia are a patient population with special requirements, having to manage their condition alongside the typical challenges of adolescence. Given the psychosocial impact of hemophilia and a desire to fit in with non-hemophilic peers, they may perceive treatment as more of a burden than a benefit. This can result in low adherence and a high risk of hemophilia-related complications. Hemophilia management has changed over time. To best inform shared decision-making with adolescent patients and their families, healthcare professionals must consider all the currently available evidence, highlighting treatment benefits as appropriate. They should also appreciate the requirements of all adolescents affected by hemophilia, including individuals with non-severe disease and girls/women. We discuss specific issues relating to the management of adolescents with hemophilia: prevention and management of bleeds, treatment adherence, joint health and physical activity, and other health-related issues. A multidisciplinary approach is advocated, and the potential role of digital technology in helping to equip patients with self-management skills to fully engage with treatment is considered. Currently, available hemophilia management generally enables adolescents with hemophilia to lead normal lives, participating in physical activities while maintaining good joint health. However, more work is required to help address both actual and perceived limitations.

Rationale for the Potential Use of Recombinant Activated Factor VII in Severe Post-Partum Hemorrhage.

Severe post-partum hemorrhage (PPH) is a major cause of maternal mortality worldwide. Recombinant activated factor VII (rFVIIa) has recently been approved by the European Medicines Agency for the treatment of severe PPH if uterotonics fail to achieve hemostasis. Although large randomized controlled trials are lacking, accumulated evidence from smaller studies and international registries supports the efficacy of rFVIIa alongside extended standard treatment to control severe PPH. Because rFVIIa neither substitutes the activity of a missing coagulation factor nor bypasses a coagulation defect in this population, it is not immediately evident how it exerts its beneficial effect. Here, we discuss possible mechanistic explanations for the efficacy of rFVIIa and the published evidence in patients with severe PPH. Recombinant FVIIa may not primarily increase systemic thrombin generation, but may promote local thrombin generation through binding to activated platelets at the site of vascular wall injury. This explanation may also address safety concerns that have been raised over the administration of a procoagulant molecule in a background of increased thromboembolic risk due to both pregnancy-related hemostatic changes and the hemorrhagic state. However, the available safety data for this and other indications are reassuring and the rates of thromboembolic events do not appear to be increased in women with severe PPH treated with rFVIIa. We recommend that the administration of rFVIIa be considered before dilutional coagulopathy develops and used to support the current standard treatment in certain patients with severe PPH.

Determinants of bleeding before and during immune tolerance in 222 boys with severe hemophilia A and inhibitors >5 BU.

ABSTRACT: Prevention of bleeding and its consequences is the main goal of hemophilia treatment and determines treatment choices for patients who develop inhibitors. To assess bleeding before and during immune tolerance induction (ITI) and its association with ITI regimen and inhibitor titer, we selected and analyzed data on patients receiving high-titer inhibitors from the international prospective PedNet cohort study. In total, 222 patients with severe hemophilia A and inhibitor titers of >5 Bethesda units (BU) were followed from the first positive to the first negative inhibitor result (median overall follow-up, 1.7 years). Mean annual (joint) bleeding rates (AJBR) and 95% confidence intervals (CIs) were compared according to treatment and inhibitor titer using multivariable negative binomial regression. Before ITI, 115 patients showed an ABR of 6.1 (5.0-7.4) and an AJBR 2.6 (2.1-3.2). Bleeding was independent of inhibitor titer. During ITI, 202 patients had an ABR of 4.4 (3.9-5.1) and an AJBR of 1.7 (1.5-2.0). AJBR during ITI increased with inhibitor titer (hazard ratio [HR] for ≥200 BU vs 5 to 39 BU [4.9; CI, 3.2-7.4]) and decreased with daily ITI infusions (HR, 0.4; CI, 0.3-0.6) or activated prothrombin complex concentrate prophylaxis (HR, 0.4; CI, 0.2-0.8), whereas ITI dose and recombinant activated factor VII prophylaxis did not independently affect bleeding. These data provide evidence for a protective effect of repeated FVIII infusions (ITI) on bleeding in patients who have developed inhibitors; these data should be used to plan ITI and/or serve as a comparator for prophylaxis with nonreplacement therapy.

Future needs for continuing innovation in hemophilia: improving outcomes for individuals of all severities, including women and those in resource-constrained regions.

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting 'normal,' making the most of available resources, and considering treatment affordability. Ultimately, all PwH-men and women, of all ages and severities, and worldwide-should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this.

Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage.

Background: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03-0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06-5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03-1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.