[Gene therapy of Hemophilia: Recommendations from the German, Austrian, and Swiss Society for Thrombosis and Haemostasis Research (GTH)]. / Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH).

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.

Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr.

Anticoagulant treatment of pediatric cancer-associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. This trial was registered at www.clinicaltrials.gov as #NCT02234843.

Practical considerations and consensus opinion for children's hospital-based inpatient hemostasis and thrombosis (HAT) consultative services: Communication from the ISTH SSC Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis.

Caring for children and adolescents with disorders of hemostasis and thrombosis (HAT) has become more specialized and requires a unique skill set that many providers are not able to obtain in standard pediatric hematology/oncology/bone marrow transplant fellowship training programs. The influx of numerous therapeutic advances and increasing medical complexity has expanded the need for experienced HAT providers and subspecialty collaboration in the inpatient setting due to the nuances in the management of patients with HAT complications and concerns. While there are data highlighting the benefits of an inpatient hemostasis, thrombosis, and anticoagulation management service in adult hospitals, there are limited pediatric data supporting such programs. In this article, we summarize the current practices of various pediatric institutions in the inpatient management of HAT patients and provide a consensus opinion for the development of a pediatric inpatient HAT service at tertiary care referral centers.

Anticoagulant Treatment for Pediatric Infection-Related Cerebral Venous Thrombosis.

BACKGROUND: We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection. METHODS: In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive. RESULTS: Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision. CONCLUSIONS: Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation.

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study.

BACKGROUND: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). OBJECTIVES: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. PATIENTS/METHODS: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. RESULTS: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. CONCLUSIONS: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.

Effects of the ketogenic diet on platelet counts and global coagulation tests in childhood epilepsy.

PURPOSE: Several antiseizure drugs (ASD), especially Valproic acid (VPA), influence platelet counts and coagulation parameters. The ketogenic diet (KD), established in drug-resistant epilepsy, is combined with ASDs. Bruising and prolonged bleeding times during KD have been described, but whether hemostatic changes result from the KD or from concomitant ASDs, remains unclear. Aim of the present study was to evaluate bleeding, platelet counts and global coagulation tests prior to and during KD in childhood epilepsy. METHOD: Consecutive children treated with KD were systematically observed for bleeding. Serial measurements of platelet counts and global coagulation tests (APTT, PT and fibrinogen) were obtained at baseline and during KD (at 1, 3, 6 and 12 months). Children with KD monotherapy, concomitant VPA, or other ASDs were compared. RESULTS: Among 162 children receiving KD, we observed neither bleeding in daily life nor perioperative bleeding in those undergoing surgery (n = 25). Most children had normal platelet counts and coagulation parameters. Only a few had transient mild thrombocytopenia and mildly prolonged APTT values, not indicative of a bleeding risk. Even KD combined with VPA did not cause relevant coagulopathy. Unexpectedly, we found mild thrombocytosis in 24 % of patients prior to KD, which was most pronounced in yet untreated epilepsy. Thrombocytosis steadily resolved during KD. CONCLUSIONS: During KD treatment of childhood epilepsy, we observed neither bleeding symptoms nor laboratory results indicating a bleeding risk. Unexpectedly, mild thrombocytosis was present in 24 % at baseline, normalising during KD. Thrombocytosis may reflect the underlying inflammatory process of untreated epilepsy and requires further study.

Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.

Epidemiology and outcomes of clinically unsuspected venous thromboembolism in children: A systematic review.

BACKGROUND: Clinically unsuspected venous thromboembolic events (uVTE) detected during routine imaging pose a management challenge due to limited knowledge about their clinical significance. Unsuspected VTE are often referred as "asymptomatic," "incidental," or "clinically silent/occult" VTE. OBJECTIVE: To understand the epidemiology, management, and outcomes of uVTE in children. METHODS: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search criteria included controlled vocabulary and keywords for VTE, incidental findings, and children (ages ≤ 21 years). RESULTS: Among 10 875 articles, 51 studies (8354 children with 758 uVTE) were selected. The studies were heterogeneous, I2 96%; P < .0001. Unsuspected VTE were diagnosed in two settings: first, asymptomatic VTE (aVTE) diagnosed through surveillance imaging for VTE (46 studies; n = 5894; aVTE: 715, pooled frequency: 19%, 95% confidence interval [CI]: 13%-24%); second, incidental VTE (iVTE) diagnosed during imaging performed for indications without primary suspicion for VTE (6 studies; n = 2460; iVTE: 43). The majority (94%) of aVTE were associated with central venous lines (CVL). Non-CVL settings included post-spinal surgery, post-splenectomy, trauma, nephrotic syndrome, and newborns. In general, aVTE were reported to have a benign clinical course, were mostly transient, and resolved without intervention and with few immediate or long-term functional complications. Incidental VTE were primarily detected in children with cancer and ranged from tumor-associated thrombi to pulmonary embolism (PE) with insufficient evidence to draw meaningful conclusions about their management. CONCLUSION: Clinically uVTE were predominantly diagnosed with CVL and their outcomes were generally favorable implying limited benefit of routine surveillance and thromboprophylaxis. Prospective research is needed to clarify the optimal management of iVTE.

[Treatment of haemophilia in Austria]. / Hämophiliebehandlung in Österreich.

This guideline which is endorsed by the Austrian Society of Haemophilia, the Austrian Society of Paediatrics, and the Austrian Society of Haematology & Medical Oncology is intended to give a clear and practical guidance for diagnosing and treating haemophilia in Austria. In the treatment of haemophilia there are few controlled interventional trials, and recommendations usually have a rather low level of evidence.The main basis for this paper are the new international guidelines by the World Federation of Hemophilia, published in 2013. These were adapted according to the local situation and experience.Covered topics are diagnostics, control visits, pharmacological treatment options, prophylaxis and treatment in children and adults, possible problems arising in haemophilia carriers and special aspects like home therapy, options for venous catheters, management of various traumas, bleedings and interventions, including dental procedures, and last not least inhibitors and their treatment.

Anticoagulation in children undergoing cardiac surgery.

Advances in medical and surgical care have resulted in improved survival of patients with congenital heart disease (CHD). Parallel to these progresses, an increasing number of immediate and long-term complications have been recognized. One important complication in CHD is the development of thrombosis. Children with a single functional cardiac ventricle usually require sequential steps of surgery: the initial Blalock-Taussig shunts (BTS) during the neonatal period, followed by the Glenn shunt, and finally, the Fontan shunt, the "definitive palliative" procedure. Surgery mostly involves cardiopulmonary bypass (CPB), which also affects the coagulation system and causes an inflammatory response. This article will review surgical procedures, such as BTS, Glenn shunt, and Fontan shunt, prosthetic mechanical valves, and CPB, and their risk of thrombotic complications. There is insufficient evidence and no consensus for optimal anticoagulant prophylaxis or treatment in children with CHD. Current recommendations are mostly based on adult data.

Special schooling in children with congenital heart disease: a risk factor for being disadvantaged in the world of employment.

The objective of this study was to evaluate type of schooling in children with congenital heart disease (CHD) who were inpatients at a tertiary pediatric cardiology center. This retrospective cohort study included 227 consecutive children with CHD (male, 125; female, 102) who had been inpatients from 1996 to 2005. Data on type of schooling had been documented by the in-hospital teacher at the time of admission. Medical data were obtained by reviewing medical charts. The primary endpoint was the percentage of children requiring special schooling, which was related to the respective percentage in the Austrian pediatric background population. Furthermore, the influence of clinical and demographic covariables was assessed. Fifteen percent (vs. 3.6% in the background population) of the study cohort required special schooling; 86% of them had a history of cardiac surgery. Cardiopulmonary bypass surgery in the first year of life showed a trend for an association with an increased frequency of special schooling. There were no significant associations with the Aristotle Basic Score (a measure for procedure complexity in CHD), gender, or first language. In conclusion, the need for special schooling is increased in children with CHD.

Ventricular interaction in children after repair of tetralogy of Fallot: a longitudinal echocardiographic study.

AIMS: Progressive right ventricular (RV) dilation due to pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) may impair left ventricular (LV) filling. Our aim was to analyse long-term time courses of M-mode LV and RV measurements and to relate these to the degree of PR. METHODS AND RESULTS: Retrospective longitudinal cohort of children (n = 88) after repair of TOF followed by serial echocardiography over 9 years. LV and RV diameters were expressed by z-scores based on normal paediatric reference values. Time courses of LV and RV diameter z-scores, degree of PR, and influence of co-variables were analysed using mixed regression models. LV diameter z-scores were significantly lowered before repair, increased after surgery, but fell again over time; thus, mean LV diameters were significantly lower than normal population means at all times. LV diameter z-scores correlated negatively with RV dilation and degree of PR. Notably, they were significantly higher in patients with previous shunts. After pulmonary valve replacement, LV diameter z-scores recovered to normal, whereas RV diameter z-scores remained abnormal. CONCLUSION: Our results confirm progressive adverse RV-LV interaction in the long-term post-operative follow-up of TOF. The use of z-scores facilitated the analysis of time courses of LV and RV diameters.

Monitoring survival and function of transfused platelets in Bernard-Soulier syndrome by flow cytometry and a cone and plate(let) analyzer (Impact-R).

BACKGROUND: Bernard-Soulier syndrome (BSS) patients may repeatedly require transfusion of platelets (PLTs). The hemostatic competence of transfused PLTs requires monitoring. STUDY DESIGN AND METHODS: Flow cytometry and a cone and plate(let) analyzer (Impact-R, DiaMed) were used to monitor survival and function of transfused PLTs in a 7-year-old girl with BSS undergoing surgery. Flow cytometry was applied to differentiate autologous PLTs from transfused PLTs by staining for CD42b. The Impact, which measures PLT adhesion and aggregation in response to high shear stress, was used to evaluate PLT function. RESULTS: Transfused PLTs were detectable by flow cytometry for 1 week after transfusion. While the patient's PLTs did not respond to high shear stress before transfusion, a normal response was documented by the Impact on the day after transfusion and 1 week thereafter. CONCLUSION: Transfused PLTs were detectable by flow cytometry, and their functional activity was demonstrated by the Impact.

Surfactant application during extracorporeal membrane oxygenation improves lung volume and pulmonary mechanics in children with respiratory failure.

INTRODUCTION: This study was performed to determine whether surfactant application during extracorporeal membrane oxygenation (ECMO) improves lung volume, pulmonary mechanics, and chest radiographic findings in children with respiratory failure or after cardiac surgery. METHODS: This was a retrospective chart review study in a pediatric intensive care unit (PICU). Seven patients received surfactant before weaning from ECMO was started (group S). They were compared to six patients treated with ECMO who did not receive surfactant (group C). These control patients were matched based on age, weight, and underlying diagnosis. Demographic data, ventilator settings, tidal volume, compliance of respiratory system (calculated from tidal volume/(peak inspiratory pressure - positive end-expiratory pressure), and ECMO flow were extracted. Chest radiographs were scored by two blinded and independent radiologists. Changes over time were compared between groups by repeated-measures analysis of variance (time*group interaction). Values are given as percentages of baseline values. RESULTS: The groups did not differ with regard to demographic data, duration of ECMO, ventilator settings, PICU and hospital days. After application of surfactant, mean tidal volume almost doubled in group S (from 100% before to 186.2%; p = 0.0053). No change was found in group C (100% versus 98.7%). Mean compliance increased significantly (p = 0.0067) in group S (from 100% to 176.1%) compared to group C (100% versus 97.6%). Radiographic scores tended to decrease in group S within 48 h following surfactant application. ECMO flow tended to decrease in group S within 10 h following surfactant application but not in group C. Mortality was not affected by treatment. CONCLUSION: Surfactant application may be of benefit in children with respiratory failure treated with ECMO, but these findings need confirmation from prospective studies.

Developmental hemostasis: pro- and anticoagulant systems during childhood.

An understanding of developmental hemostasis is pivotal for optimal prevention, diagnosis, and treatment of hemostatic problems during childhood. The development of microassays in the early 1980s enabled researchers to delineate age-dependent features of the coagulation system and to establish reference ranges for healthy children of all age groups, from premature infants to adolescents. Based on the results from these studies, the hemostatic system in the young can be described as evolving, and yet functional, since healthy fetuses, infants, and children do not suffer hemorrhagic nor thromboembolic complications spontaneously or in the presence of minor challenges. Plasma concentrations of most pro- and anticoagulant proteins are decreased throughout childhood but provide an effective hemostatic balance on a lower level compared with adults. The current article describes the development of pro- and anticoagulant systems throughout childhood.

Central venous line-related thrombosis in children: association with central venous line location and insertion technique.

Venous thromboembolic events (VTEs) in children are associated with central venous lines (CVLs). The study objective was to assess whether CVL location and insertion technique are associated with the incidence of VTE in children. We hypothesized that VTE would be more frequent with (1). CVL location on the left body side, (2). CVL location in the subclavian vein rather than the jugular vein, and (3). CVL insertion by percutaneous technique rather than venous cut-down. This was a prospective, multicenter cohort study in children with acute lymphoblastic leukemia who had a CVL placed in the upper venous system during induction chemotherapy. Characteristics of CVL were documented prospectively. All children had outcome assessment for VTE by objective radiographic tests, including bilateral venography, ultrasound, echocardiography, and cranial magnetic resonance imaging. Among 85 children, 29 (34%) had VTE; 28 VTEs appeared in the upper venous system, and 1 was sinovenous thrombosis. Left-sided CVL (odds ratio [OR], 2.5; 95% confidence interval, 1.0-6.4; P =.048), subclavian CVL (OR, 3.1; 95% CI, 1.2-8.5; P =.025), and percutaneous CVL insertion (OR, 3.5; 95% CI, 1.3-9.2; P =.011) were associated with an increased incidence of VTE. Interaction occurred between CVL vein location and insertion technique. Subclavian vein CVL inserted percutaneously had an increased incidence (54%) of VTE compared with any other combination (P =.07). For CVL in the upper venous system, CVL placement on the right side and in the jugular vein may reduce the risk for CVL-related VTE. If subclavian vein placement is necessary, CVL insertion by venous cut-down appears preferable over percutaneous insertion.

Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase.

Deep vein thrombosis (DVT) in children occurs primarily in the upper body venous system. This prospective diagnostic study compared bilateral venography and ultrasound for detection of DVT in the upper venous system in 66 children with acute lymphoblastic leukemia. Results were interpreted by central blinded adjudication. Deep venous thrombosis occurred in 29% (19/66) patients. While 15/19 DVT were detected by venography (sensitivity 79%), only 7/19 were detected by ultrasound (sensitivity 37%). The 12 DVT detected by venography but not by ultrasound were located in the subclavian vein or more central veins. Three of 4 DVT detected by ultrasound but not by venography were in the jugular vein. We conclude that ultrasound is insensitive for DVT in the central upper venous system but may be more sensitive than venography in the jugular veins. A combination of both venography and ultrasound is required for screening for DVT in the upper venous system.