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.

Introduction Limited studies have reported data on the real-world clinical use of extended half-life (EHL) IX products in children and adolescents with haemophilia B, also referred to as people with haemophilia B (PWHB). Aim To examine the real-life experience with EHL factor IX products in PWHB regarding the clinical experience with standard half-life products (SHL). Methods A retrospective review of medical records of PWHB who have been prescribed EHL IX factor concentrates was conducted. Results Fourteen male PWHB were enrolled in the study, all with severe bleeding phenotypes being on prophylaxis (1–6 years old: n = 3, 7–12 years old: n = 5 and 13–18 years old: n = 6). Four of them were previously untreated patients; nine out of fourteen children (64%) had severe, four had moderate, and one child had mild haemophilia B. Median length of follow-up was 45 months (range 16–84 months). Children who transitioned from SHL prophylaxis to EHL prophylaxis experienced changes in their treatment outcomes. The median dosing interval increased from 3.5 days to 7 days, mean trough levels rose from 4.3% to 15.3% among children with severe haemophilia B, and the mean annual bleeding rate (ABR) decreased from 1.8 to 1 (p = 0.3, Wilcoxon test). Significant differences were found in EHL vs. SHL use regarding (a) the factor IX consumption for prophylaxis and bleeds (p = 0.046, t-test), with the EHL consumption (45.6 IU/kg/week) being significantly lower than the SHL consumption (70.3 IU/kg/week), and (b) the factor IX consumption only for prophylaxis (p = 0.022, t-test), with the EHL consumption (37.0 IU/kg/week) being significantly lower than the SHL consumption (66.0 IU/kg/week). There was no inhibitor development. Conclusion This study demonstrates the successful use of EHL prophylaxis in PWHB.

Background: Pediatric thrombosis (PT) represents a rare condition that can manifest from neonatal life to adolescence, encompassing life-threatening complications. Its pathogenesis is attributed to immature hemostasis in conjunction with environmental and genetic factors, predominantly including those resulting in increased levels of plasminogen activator inhibitor 1 (PAI-1), the principal inhibitor of fibrinolysis, subject to upstream regulation by ACE (angiotensin-converting enzyme). Although the implication of microRNAs (miRNAs), epigenetic modulators of gene-expression, is demonstrated in adult-thrombosis, evidence is lacking in the pediatric setting. Here, we investigated the involvement of two miRNA-regulators of PAI-1 in PT, in relation to clinical and genetic parameters that induce PAI-1 fluctuations. Methods: Following bioinformatic target-prediction, miRNA expression was assessed by quantitative real-time PCR, in serum-samples of 19 pediatric patients with thrombosis (1-18 months post-incident), and 19 controls. Patients were genotyped for the PAI-1-4G/5G and ACE-I/D polymorphisms by PCR-based assays. Genotypic and thrombosis-related clinical data were analyzed in relation to miRNA-expression. Results: Two miRNAs (miR-145-5p, miR-34a-5p) were identified to target PAI-1 mRNA, with miR-34a additionally targeting ACE mRNA. The expression of miR-34a was significantly decreased in patients compared to controls (p=0.029), while no difference was observed for miR-145. Within patients, miR-34a demonstrated a peak 1-3 months post-thrombosis and was diminished upon treatment-completion (p=0.031), followed by a slight long-term increase. MiR-34a expression differed significantly by thrombosis site (p=0.019), while a significant synergistic interaction between site and onset-type (provoked/unprovoked) was detected (p=0.016). Finally, an epistatic modification was observed in cerebral cases, since double homozygosity (4G/4G+D/D) led to miR-34a diminishing, with DD carriership reversing the 4G4G-induced upregulation of miR-34a (p=0.006). Conclusions: Our findings suggest that in pediatric thrombosis, downregulation of miR-34a is indicative of impaired fibrinolytic capacity, attributed to deficient regulation of the inhibitory ACE/PAI-1 axis.

Thoracic outlet syndrome (TOS) is underdiagnosed in children/adolescents. We describe three cases of children/adolescents with TOS diagnosed within one year in our Haemostasis and Thrombosis Unit: 1) a 14-year-old girl with sudden onset of left arm oedema- thrombosis of the left subclavian vein and filling defect in both subclavian veins due to an elongated C7 transverse process, 2) a 13-year-old swimming champion with sudden onset of right arm oedema and 3) an eight-year-old girl with left arm discomfort (already on anticoagulation due to cerebral sinovenous thrombosis) and complete outflow interruption of the left subclavian vein. All three girls have been on anticoagulation for 18, 6 and 4 months respectively without symptoms. Conclusion: These three cases underline physicians TOS awareness concluding in diagnosing in children/ adolescents and demonstrate a clinically satisfying outcome of pediatric TOS with initially conservative treatment, surgery planning and continuing follow-up.

Pediatric thrombosis (PT) represents a rare condition that can manifest from neonatal life to adolescence, encompassing life-threatening complications. Its pathogenesis is attributed to immature hemostasis in conjunction with environmental and genetic factors, predominantly including those resulting in increased levels of plasminogen activator inhibitor 1 (PAI-1), the principal inhibitor of fibrinolysis, which is subject to upstream regulation by angiotensin-converting enzyme (ACE). Although the implication of microRNAs (miRNAs), epigenetic modulators of gene expression, has been demonstrated in adult thrombosis, evidence is lacking in the pediatric setting. Here, we investigated the involvement of two miRNA regulators of PAI-1 (SERPINE1 gene) in PT, in relation to clinical and genetic parameters that induce PAI-1 fluctuations. Following bioinformatic target-prediction, miRNA expression was assessed by quantitative real-time PCR in serum-samples of 19 pediatric patients with thrombosis (1–18 months post-incident), and 19 healthy controls. Patients were genotyped for the SERPINE1-4G/5G and ACE-I/D polymorphisms by PCR-based assays. Genotypic and thrombosis-related clinical data were analyzed in relation to miRNA-expression. Two miRNAs (miR-145-5p, miR-34a-5p) were identified to target SERPINE1 mRNA, with miR-34a additionally targeting the mRNA of ACE. The expression of miR-34a was significantly decreased in patients compared to controls (p = 0.029), while no difference was observed in miR-145 expression. Within patients, miR-34a expression demonstrated a peak 1–3 months post-thrombosis and was diminished upon treatment completion (p = 0.031), followed by a slight long-term increase. MiR-34a levels differed significantly by thrombosis site (p = 0.019), while a significant synergistic interaction between site and onset type (provoked/unprovoked) was detected (p = 0.016). Finally, an epistatic modification was observed in cerebral cases, since double homozygosity (4G/4G + D/D) led to a miR-34 decrease, with D/D carriership reversing the 4G/4G-induced upregulation of miR-34a (p = 0.006). Our findings suggest that in pediatric thrombosis, downregulation of miR-34a is indicative of impaired fibrinolytic capacity, attributed to deficient regulation of the inhibitory ACE/PAI-1 axis.