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Introduction: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic‐guided (PK) dosing. Aims: In this retrospective study clinical outcomes before and after PK‐guided prophylaxis were examined. Materials and methods: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK‐assessment for product switch (switchers) or to optimize treatment (non‐switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis. Results: The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy‐four (56%) patients were identified as switchers and 58 (44%) patients were classified as non‐switchers. The majority of patients (78.0%) experienced either a decrease in ABR post‐index or maintained 0 ABR during pre‐ and post‐index time periods, with similar proportions identified in both switchers (77.0%) and non‐switchers (79.3%) populations. Non‐switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half‐life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date. Conclusion: PK‐guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product. [ABSTRACT FROM AUTHOR]

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov , NCT03417102. Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5–33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0–2·7]) than in the bypassing agents on-demand group (18·1 [10·6–30·8]), corresponding to a 90·8% (95% CI 80·8–95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. Sanofi. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab has been shown to be safe and effective for prevention of bleeds in patients with severe haemophilia A (SHA), both with and without inhibitors. The subcutaneous administration and long half‐life make emicizumab an attractive option for prophylaxis in infants with SHA, however data to inform treatment decisions in this younger age group are almost absent. Aim: The aim of this report is to share real world experience to illustrate how the availability of emicizumab has shifted the prophylaxis paradigm in the management of infants with SHA. Method: We selected four cases from our own cohort of infants with SHA to outline the rationale for emicizumab prophylaxis in a range of scenarios familiar to paediatric haemophilia treaters. Results: In Case 1 emicizumab was commenced at 7 days following initial treatment of neonatal ICH with a FVIII infusion. In Case 2 emicizumab was commenced at 5 weeks due to parental anxiety regarding the potential for ICH during infancy. Case 3 commenced emicizumab at 15 months in lieu of standard primary prophylaxis. Case 4 switched to emicizumab prophylaxis at 14 months after a period of primary prophylaxis with FVIII concentrates to alleviate parental anxiety regarding future inhibitor development. No patient had any bleeding events after commencement of emicizumab (median follow up 12 months), and no drug‐related adverse effects were observed. Conclusion: Despite the paucity of data in infants with SHA the potential role of emicizumab prophylaxis should be discussed with families when clinically relevant, with decisions tailored to individual need. [ABSTRACT FROM AUTHOR]

Summary: Haemophilia is a serious inherited bleeding disorder resulting from a deficiency of coagulation factor VIII (haemophilia A) or coagulation factor IX (haemophilia B). While effective therapies have been developed to replace the missing factor and restore normal coagulation, they can lead to the development of neutralizing anti‐drug antibodies, termed inhibitors, which significantly worsen morbidity and quality of life. While advancements have been made to improve the management of patients, and particularly for this review, children with inhibitors, there remain significant unmet needs including inhibitor prevention, inhibitor eradication and, when those fail, more effective bleed prevention and a reduction in the treatment burden. This review will discuss current treatment options including the recently licensed bispecific antibody, emicizumab, and provide insights into how I treat children with inhibitors. [ABSTRACT FROM AUTHOR]

The development of inhibitors against factor VIII (FVIII) concentrates represents a significant treatment complication for hemophilia. Immune tolerance induction (ITI) therapy eradicates inhibitors in 60–80% of patients, resulting in a normal FVIII response. This article, based on presentations at the 6th International Coagulation Meeting, held in Barcelona, Spain, in September 2017, provides an overview of management approaches for patients with inhibitors and briefly tabulates four cases of ITI therapy (first-line or rescue ITI therapy in pediatric and adult patients) with successful outcomes. Switching FVIII product from recombinant FVIII to plasma-derived FVIII/VWF concentrate may be helpful in eradicating inhibitors. The rate of decline of inhibitor titer in the initial stages of ITI therapy is a good indicator of the success or failure of therapy, although prognostic biomarkers are needed. The development of the bispecific monoclonal antibody emicizumab, which was recently shown to reduce bleeding in inhibitor patients, offers a potential alternative therapeutic option. However, the benefits of inhibitor eradication, including a wider choice of cheaper therapeutic products for preventing and treating bleeds, suggest that at least one attempt of ITI therapy should be offered to patients who develop inhibitors. [ABSTRACT FROM AUTHOR]

The development of inhibitors against factor VIII (FVIII) concentrates represents a significant treatment complication for hemophilia. Immune tolerance induction (ITI) therapy eradicates inhibitors in 60–80% of patients, resulting in a normal FVIII response. This article, based on presentations at the 6th International Coagulation Meeting, held in Barcelona, Spain, in September 2017, provides an overview of management approaches for patients with inhibitors and briefly tabulates four cases of ITI therapy (first-line or rescue ITI therapy in pediatric and adult patients) with successful outcomes. Switching FVIII product from recombinant FVIII to plasma-derived FVIII/VWF concentrate may be helpful in eradicating inhibitors. The rate of decline of inhibitor titer in the initial stages of ITI therapy is a good indicator of the success or failure of therapy, although prognostic biomarkers are needed. The development of the bispecific monoclonal antibody emicizumab, which was recently shown to reduce bleeding in inhibitor patients, offers a potential alternative therapeutic option. However, the benefits of inhibitor eradication, including a wider choice of cheaper therapeutic products for preventing and treating bleeds, suggest that at least one attempt of ITI therapy should be offered to patients who develop inhibitors. [ABSTRACT FROM AUTHOR]

Fibrinogen is a glycoprotein with a crucial role in blood coagulation. Upon enzymatic cleavage by thrombin, fibrinogen is converted from its soluble form to insoluble fibrin which is key structural protein of a clot. It also participates in platelet aggregation by binding to GPIIb/IIIa. Genetic alterations can lead to either complete or partial, quantitative or qualitative defects of fibrinogen. Inherited afibrinogenemia is a rare bleeding disorder with autosomal recessive inheritance due to a complete absence of fibrinogen. The primary aim of this study was to determine whether 70 mg/kg of human fibrinogen concentrate (HFC) is an adequate dose in subjects with inherited afibrinogenemia to reach normal levels of plasmatic fibrinogen (1.5‐2 g/L). Secondary aims included assessing changes in thromboelastography (TEG) and thrombin generation assay (TGA) before and after a dose of HFC. Four patients were included, and each underwent pre‐and post (one time‐point) HFC dose laboratory testing. Two patients needed dose adjustments to reach a normal post‐dose fibrinogen level. In addition, we noted that the TEG parameter maximum amplitude (MA) improved in accordance with correction of the fibrinogen levels. TGA results were normal in all subjects. Our results suggest that individualized dosing based on fibrinogen levels may be necessary. [ABSTRACT FROM AUTHOR]

The incidence of pediatric venous thromboembolism (VTE) has been increasing significantly over the past decade in part as a result of increased recognition of this serious disorder but more so because of the increased use of central venous catheters and other technological advancements involved in the care of ill children. Management of pediatric VTE is a complex undertaking, considering that the vast majority of children who develop this complication have serious underlying medical disorders. Although the incidence is rising, in comparison with adults, this remains a relatively rare disorder, and as such, large-scale clinical trials have not been completed, rendering management decisions to be based on extrapolation from adult data and the experience of the treating physician. Clearly, both are fraught with problems. Thus, day-to-day management remains more art than science until such time that the results from clinical trials (many of which are under way) become available. This edition of "How I Treat" describes the author's experience in managing 3 common scenarios that one may encounter in pediatric thrombosis and suggests a logical approach to such situations. Furthermore, the author provides 3 algorithms to help guide management decisions. [ABSTRACT FROM AUTHOR]

Thrombotic complications are increasing at a steady and significant rate in children resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the standard agents (heparin, low molecular weight heparin, and vitamin K antagonists) and alternative agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the standard and alternative anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. Clearly, the standard anticoagulants all have significant shortcomings including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The alternative anticoagulants have properties which overcome these shortcomings and prospective clinical trial data are presented supporting the current and future use of these agents in place of the standard anticoagulants. [ABSTRACT FROM AUTHOR]

This guidance document has been prepared on behalf of the International Council for Standardisation in Hematology. The aim of the document is to provide guidance and recommendations on the measurement of factor VIII (FVIII) and factor IX (FIX) inhibitors. After an introduction on the clinical background and relevance of factor VIII and factor IX inhibitor testing, the following aspects of laboratory testing are included: screening for inhibitors, assay principle, sample requirements, testing requirements and interpretation, quality assurance, interferences and recent developments. This guidance document focusses on recommendations for a standardised procedure for the laboratory measurement of FVIII and FIX type I inhibitors. The recommendations are based on published data in peer‐reviewed literature and expert opinion. [ABSTRACT FROM AUTHOR]

Introduction Paradigm™4 was an international extension trial investigating the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in haemophilia B patients (FIX activity ≤ 2%; aged 13–70 years) who had previously participated in phase III pivotal (paradigm™2) or surgery (paradigm™3) trials. Methods Patients chose to continue treatment with nonacog beta pegol in either one of two once-weekly prophylaxis arms (10 IU/kg or 40 IU/kg), or an on-demand arm (40 IU/kg for mild/moderate bleeds; 80 IU/kg for severe bleeds). The primary objective was to evaluate immunogenicity; key secondary objectives included assessing safety and haemostatic efficacy in the treatment and prevention of bleeds. Results Seventy-one patients received prophylaxis or on-demand treatment. No patient developed an inhibitor and no safety concerns were identified. The success rate for the treatment of reported bleeds was 94.6%; most (87.9%) resolved with one injection. The median annualised bleeding rate for patients on prophylaxis was 1.36 (interquartile range [IQR] 0.00–2.23) and 1.00 (IQR 0.00–2.03) for the 10 and 40 IU/kg treatment arms, respectively. The mean FIX activity trough achieved for 10 and 40 IU once weekly was 9.8% and 21.3%, respectively. Fourteen patients on prophylaxis underwent 23 minor surgical procedures; haemostatic perioperative outcomes for all of those evaluated were ‘excellent’ or ‘good’. Conclusions Nonacog beta pegol showed a favourable tolerability profile (with no safety issues identified) with good prophylactic protection and control of bleeding in previously treated adult and adolescent haemophilia B patients. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The recent proliferation of deep vein thrombosis in children has been attributed to the increased use of central venous catheters, specifically tunneled lines and peripherally inserted central catheters. A formal comparison of the incidence rate for deep vein thrombosis between tunneled lines and peripherally inserted central catheters has not been undertaken. Methods: Children <18years of age who were admitted to Children’s Hospital Los Angeles from July, 2005 to July, 2012 were eligible for inclusion. Data were extracted from the hospital discharge database which includes data on all procedures and up to 20 diagnoses per admission. Diagnoses and procedures were identified by International Classification of Disease, Ninth Revision coding. Patients were excluded if they received more than one central line. Data collected included type of central line, deep vein thrombosis event, and underlying medical illnesses classified according to chronic complex conditions. Results: Over the seven year study period there was an overall rate of 73 deep vein thromboses per 10,000 hospital discharges. Of the 6915 eligible subjects, 181 had a deep vein thrombosis for an overall incidence rate of 2.6%. There were 152 thrombi (2.6%) in subjects with peripherally inserted central catheters and 29 thrombi (3.1%) in subjects with tunneled lines [OR=.83 (0.55, 1.29), p=0.38]. Conclusion: Despite the relative ease and simplicity of use of peripherally inserted central catheters leading to a substantial rise in their use, this study demonstrates that such lines pose a substantial risk for venous thrombosis and no difference in incidence was detected between such lines and tunneled lines. [Copyright &y& Elsevier]

Hemophilia is a bleeding disorder that afflicts about 1 in 5000 males. Treatment relies upon replacement of the deficient factor, and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically. However, these assays are limited in their ability to fully evaluate the patient's clot-forming capability. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors and in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. In this article we review the existing literature and discuss several controversial issues surrounding the assays. Last, a vision of future clinical uses of these assays is briefly described. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Hemophilia patients with inhibitors have frequent bleeding episodes and often develop hemophilic arthropathy which is in contradistinction to non-inhibitor patients for whom prophylaxis prevents joint disease. Recently, two prospective trials have demonstrated that secondary prophylaxis with bypassing agents in inhibitor patients offers benefit by reducing bleeding episodes. This report describes the clinical experience of secondary prophylaxis in a large population of inhibitor patients. Patients/Methods: This retrospective, observational study was performed by abstracting data from medical records of patients in whom secondary prophylaxis with rFVIIa was prescribed. Data were collected by professional medical record abstractors and included patient demographics, dosing regimens, bleeding events, and healthcare resource utilization. Data analysis was descriptive and included sensitivity analyses. Results: Data from 86 patients from 14 countries were collected. The primary outcome measure (% reduction in bleeding) was 46% (95% CI, -54.0 to −38.2) in patients with at least one bleeding episodes prior to starting prophylaxis and 52% (95% CI, -60.7 to −43.3) in patients with at least one bleeding episode per month prior to starting prophylaxis. A variety of subanalyses were performed, including among age and bleed location; the results for pediatric patients, adults, target and non-target joint bleeds categorizations were similar to the overall primary outcome. Conclusions: The results in this large observational study are similar to those from the previously reported prospective study of prophylaxis with rFVIIa in inhibitor positive patients, although this study represents a more typical inhibitor population who utilized prophylaxis in the clinical setting. As such, prophylaxis should be considered a potentially effective therapy in hemophilia patients with inhibitors. [Copyright &y& Elsevier]

. Haemophilia is a life-long genetic disorder most often diagnosed in early childhood which results in bleeding into deep tissues and can result in arthropathy and, rarely, other serious complications. As a result of the natural physical and cognitive development in children, combined with the manner in which haemophilia is treated, there is a continuous process of changes in the approach to patient management, which collectively are called transitional issues. It is important to point out that while some traditional definitions of transition are limited to the stage when an adolescent becomes an adult and how the mode and delivery of care change during this time, a broader definition incorporating all the changes that occur from birth through adulthood will be described in this article. As such, transition should be thought of as a continuous process, though for the sake of clarity and practicality, we will divide the process into several phases. The transition issues to be discussed will be divided into medical issues and psychosocial issues, though there is clearly overlap between the two. A well-developed transition plan from birth to adulthood for patients with haemophilia facilitates the necessary change from total dependence on caregivers to complete independence by the time one reaches 18 years of age. [ABSTRACT FROM AUTHOR]

Abstract: Thromboembolic complications are increasing in children and the use of anticoagulation has seen a dramatic increase. The most widely used agents in children, heparin, low molecular weight heparin, and warfarin all have limitations which are exaggerated in children. This has led to the study of newer agents with improved pharmacologic properties such as bivalirudin, argatroban, and fondaparinux. In addition, clinical trials are under way to assess several new oral anticoagulants that are in late phase studies or already licensed in adults. Based on the completed studies in children, several recommendations for the use of currently available agents (bivalirudin, argatroban, and fondaparinux) are suggested for clinical use today. Additional studies need to be conducted for the above agents which will lead to their expanded use in selected indications. Furthermore, new regulatory requirements are leading to a number of studies in the newer anticoagulants that are yet to be licensed in adults for treatment of venous thromboembolism. Pediatric thrombosis is entering a fruitful era of research in the area of anticoagulation management which is sure to lead to significant changes in how children are treated in the next 10years. [ABSTRACT FROM AUTHOR]

The most serious current complication of factor replacement therapy for hemophilia patients is the development of neutralizing antibodies to the factor termed inhibitors. Patients with high-titer inhibitors frequently develop serious bleeding complications which do not respond to standard factor replacement therapy. Therefore, they must be treated with the so-called bypassing agents, recombinant factor VIIa and activated prothrombin complex concentrates, neither of which is as effective as standard factor replacement in patients without inhibitors. Immune tolerance therapy aimed at eradicating inhibitors is successful in a majority of patients; however, a sizable minority will have life-long inhibitors and often develop debilitating joint disease. The ultimate goal is to develop strategies aimed at preventing inhibitor development though these have not been realized yet. Until this is achieved, additional novel approaches are needed to improve the treatment of bleeding episodes and to better treat arthropathy once it develops. Finally, there is no laboratory monitoring device which can predict the clinical response of patients to bypassing agents. Thus another goal of current research is to develop such a tool which will enable the individualization of bypassing agent. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We investigated the anticoagulant effects of argatroban, a direct thrombin inhibitor, versus heparin in extracorporeal membrane oxygenation (ECMO) circuits. Three sham circuits were prepared according to our hospital's standard practice and run for six hours simultaneously. Two circuits were anticoagulated with argatroban (one with heparin in the wet prime and one without). One circuit had heparin in the initial prime and was then anticoagulated with heparin. We measured thrombin generation (prothrombin fragment 1 + 2, D-dimer and thrombin - antithrombin complexes), activated clotting times (ACTs) and partial thromboplastin times (aPTTs), and monitored thrombus formation using thromboelastography. ACTs were >1000 s in each circuit throughout assessment. No clot initiation was detected by thromboelastography. Thrombin generation was decreased in circuits anticoagulated with argatroban versus heparin, despite aPTTs being less prolonged. These results suggest that argatroban may be more efficacious than heparin for anticoagulation in ECMO. Additional studies are warranted to further evaluate argatroban in this setting. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia treatment centres (HTCs) and healthcare providers (HCPs) will need to adapt to a new treatment paradigm with the emergence of adeno‐associated virus (AAV)‐based gene therapy for the treatment of haemophilia in adults. Aim: This review examines the upcoming patient and institutional journeys, along with practical aspects of preparedness for clinical delivery of gene therapy by HTCs. Methods: Based on our clinical experience and examination of published literature, we explored the parallel journeys for patients and treatment centres to navigate before, during, and after administration of gene therapy. Results: The patient journey includes: information gathering; decision making; comprehensive patient assessment; preparation for the infusion itself; short‐ and long‐term monitoring; lifestyle modifications; and the possible need for immunosuppressive treatment. Informed decision‐making may require patient education with extensive discussions and an understanding that not all people with haemophilia will choose or be eligible for gene therapy, although eligibility criteria continue to evolve. The institutional journey includes: consideration of biosafety procedures; planning for product procurement, handling, storage, and administration; development of detailed protocols and guidance documents; contingency planning for immunosuppressive and haemostatic management; consideration of clinical capabilities and staff training needs; coordination of efforts by the full multidisciplinary team; and collaboration between referring, dosing, and follow‐up treatment centres. Documented protocols and guidance documents are pivotal for this complex therapy to ensure safe handling, optimal delivery, and post‐infusion management and follow‐up. Conclusion: Successful implementation of this new treatment modality will require communication and collaboration among multiple stakeholders. [ABSTRACT FROM AUTHOR]

Background Pediatric hospital-acquired venous thromboembolism (HA-VTE) rates have increased dramatically. To achieve generalizable knowledge in the derivation and validation of HA-VTE risk factors and risk prediction models and inform future risk-stratified prevention strategies, multi-institutional studies are needed. Objectives This paper presents an investigator-initiated, multicenter pediatric case-cohort study designed to identify risk factors for HA-VTE to create a HA-VTE risk prediction model. Methods A registry, which houses pertinent variables from HA-VTE subjects and non-HA-VTE controls, was created for the Children's Hospital-Acquired Thrombosis (CHAT) study. Specific variables from the registry associated with HA-VTE risk will be identified using multivariable regression to create a pediatric HA-VTE risk prediction model to be prospectively validated. Results Seven large pediatric institutions have entered over 600 HA-VTE subjects aged 0–21 years of age into the registry. Subjects showed a male predominance (57%), a median age of three years (IQR 0.3–13) and were most likely admitted to an intensive care unit (57%) at VTE diagnosis. Median time to HA-VTE was 10 days after admission. The most prevalent risk factors include central venous catheters (80%), surgery (43%), systemic steroids (31%), congenital heart disease (27%), infection (14%) and cancer (13%). Conclusions CHAT, with its creation of a risk prediction model with prospective validation using the CHAT registry, is a novel study design and will be the first step in identifying safe and effective strategies to decrease HA-VTE in children by helping define the highest risk population for initial, or more aggressive, thromboprophylaxis efforts. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A. Breakthrough bleeding still occurs in patients on emicizumab and can be managed with recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC). Thrombotic events were reported when patients on emicizumab received concomitant aPCC at relatively high doses. We studied the effect of infusing various doses of aPCC to patients on emicizumab. Material and methods: Nine patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Patients were infused with varying doses of aPCC in vivo. Samples were tested with thrombin generation (TG) assay. Results: In the current in vivo arm of the study four out of nine patients reached the highest dose, 75 U/kg of aPCC and six out of nine patients were actually eligible for the highest dose. In the previous in vitro arm of the study seven out of eight patients reached the normal plasma with spiking aPCC at a very low concentration equivalent to 5 U/kg. Conclusion: The in vitro portion of the study demonstrated that clinically relevant concentrations of aPCC resulted in excessive TG, however, in vivo administration of aPCC to the same patients demonstrated that most of the patients had normal TG at the approved doses of aPCC. In the management of breakthrough bleeding clinicians should heed the boxed warning for concomitant use of emicizumab and aPCC, however, should also be aware that low doses of aPCC may not result in sufficient TG. [ABSTRACT FROM AUTHOR]

The incidence of pediatric hospital-acquired venous thromboembolism (HA-VTE) has increased over time. Congenital heart disease (CHD) as a co-morbidity has been demonstrated to significantly increase HA-VTE risk among hospitalized children. To identify specific risks factors for the development of HA-VTE in hospitalized children with CHD. This retrospective case-control study included hospitalized participants aged 0–21 years within the Children's Hospital Acquired Thrombosis (CHAT) Consortium Registry with a co-morbidity of CHD. Participants with HA-VTE and non-VTE controls with a past medical history of CHD were selected from the CHAT Registry and data regarding multiple clinical variables were extracted. These variables were then analyzed to assess their association with HA-VTE development. Three hundred and thirty-three participants with a co-morbidity of CHD were identified, comprising 275 HA-VTE cases and 58 controls. Median age for HA-VTE cases was 0.4 (IQR = 0–2.6) years compared to 3.4 (IQR = 0.7–6.5) for controls. Male participants were predominant in both groups (57.5 % HA-VTE cases vs 51.7 % controls). Multivariable analysis identified prior recent hospitalization (OR = 4.12, 95%CI = 1.66–10.24), intensive care unit (ICU) admission (OR = 3.29, 95 % CI = 1.15–9.40), and CVC placement (OR = 9.14, 95 % CI = 3.38–24.72) as significant risk factors for HA-VTE in subjects with CHD. ICU admission, CVC placement, and prior hospitalization were identified as statistically significant predictors associated with HA-VTE development in hospitalized children with history of CHD. Prospective studies are needed to validate these results and help develop strategies to mitigate HA-VTE development in these patients. [ABSTRACT FROM AUTHOR]

Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight-based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents. [ABSTRACT FROM AUTHOR]

Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight-based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents. [ABSTRACT FROM AUTHOR]

Introduction: Challenges with personalised prophylaxis in haemophilia remain, including designing unique dosing schedules that require continual adjustments and monitoring using complex sampling procedures. Aim: To assess long‐term efficacy and pharmacokinetic outcomes with fixed‐dose N8‐GP prophylaxis. Methods: Descriptive analyses were performed on data from the pathfinder 2 and pathfinder 5 trials of patients with severe haemophilia A. Bleed frequency and reoccurrence were assessed in relation to several clinical criteria of interest. Bleed risk relative to time since last dose was assessed using calculated annualised bleeding rate (ABR). Long‐term ABR and mean factor VIII (FVIII) trough levels were assessed in patients who received consistent N8‐GP prophylaxis every 4 days (Q4D). Results: During pathfinder 2, 117/136 patients with study‐drug exposure of ≥600 days experienced bleeding episodes; 8.6% of bleeds were reoccurring bleeds; bleed reoccurrence decreased over time. For patients who received consistent Q4D prophylaxis across the trial (n = 61), mean ABR decreased from 3.5 bleeds/year (Year 1) to 1.6 bleeds/year (Year 6); mean FVIII trough levels stabilised at approximately 5% (Year 6). Across patients who received prophylaxis at some point during pathfinder 2 (n = 177), 125/126 (99%) reoccurring bleeds were joint bleeds. For patients receiving Q4D prophylaxis, bleeding risk generally increased as the time since the last prophylaxis dose increased. A similar reduction in ABR and stabilisation of trough level was observed in pathfinder 5. Conclusion: Long‐term exposure (> 5 years) to fixed‐dose N8‐GP prophylaxis resulted in a protective haemostatic effect, with reduction in bleed frequency and reoccurrence, and stabilisation of FVIII trough level over time. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The thromboelastograph is a point-of-care, global hemostasis assay that measures the dynamics of clot formation, including physical properties, over time and is licensed for use in monitoring coagulation during complex surgical procedures. It has more recently been used as a research tool to investigate various bleeding and clotting disorders. Although attempts have been made to use thromboelastography to detect hypercoagulable states, thus far a consistent, reliable approach has not been discovered. The objective of this study was to develop a novel approach utilizing thromboelastography that is sensitive for detecting hypercoagulability. Materials and Methods: Healthy, adult volunteers provided blood samples that were subjected to pre-analytic modifications from standard thromboelastography methods with the goal of prolonging clot initiation and propagation times. The methods which resulted in the desired changes in a consistent and reliable manner utilized corn trypsin inhibitor, a contact pathway inhibitor, on unactivated blood samples. To demonstrate that these methods are sensitive to detecting hypercoagulability, increasing concentrations of recombinant human thrombin were added as a surrogate for hypercoagulability. Results: Our methods were able to consistently and statistically significantly change the baseline TEG parameters of R time, K time, and angle in the desired fashion. Additionally, these methods were able to detect increasing concentrations of thrombin. Conclusions: We describe a novel approach in which thromboelastography is highly sensitive to detecting increasing concentrations of thrombin in vitro. Further studies are underway to determine if these methods will be sensitive for detecting hypercoagulable states in vivo. [Copyright &y& Elsevier]

Introduction: Emicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with haemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to predict the approximate FVIII level in severe haemophilia A patients with inhibitors on emicizumab using global haemostasis assays. Materials and methods: Patients with moderate and mild HA in the non‐bleeding state and healthy controls had FVIII levels and thrombin generation assessed. Linear regression was utilized to model the FVIII levels as a function of the thrombin generation assay parameters and to make a calibration curve of FVIII levels versus peak thrombin and endogenous thrombin potential. Patients with severe haemophilia A with inhibitors on emicizumab had thrombin generation performed in the same manner and their peak thrombin and endogenous thrombin potential results were placed on the calibration curve to calculate their FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT). Results: All patients with severe HA with inhibitors on emicizumab had F8EmT >10%, suggesting they had been converted to a mild haemophilia phenotype. The patient's weight was inversely correlated to their F8EmT. Conclusion: The results from this study suggest that the F8EmT in patients with severe HA on emicizumab falls within the range of mild haemophilia which is consistent with the data noted in the emicizumab clinical trials and in vivo studies in animals. [ABSTRACT FROM AUTHOR]

Introduction: Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders. Methods: The subgroup decided to focus on haemophilia, the prototypal congenital bleeding disorder and the one with the largest available body of evidence. MEDLINE, EMBASE and PsycINFO, The Cochrane Review, CINAHL, and Web of Science were searched for systematic and narrative reviews on outcomes used in haemophilia clinical trials. Three different clinical goals were identified as typical objectives of future research. Results: Out of 1322 unique citations, 24 reviews published in the period 2002–2019 were included. We identified 113 outcome measures, categorized in 6 domains: health‐related quality of life (HRQoL), comorbidities and mortality, overall physical functioning and participation, bleeding and hemostasis, joint health, and costs and resource use. Three different clinical goals were identified as typical objectives of future research: Episodic 'on demand' replacement therapy, prevention of bleeding (Prophylaxis), and long‐term and overall impact of bleeding. For each of these scenarios, specific outcomes were recommended. Conclusions: Primary outcomes for clinical trials assessing the efficacy of hemostatic treatment in achieving control, prevention and limiting long‐term consequences of bleeding in inherited bleeding disorders are suggested, and their strength and limitations discussed. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A with and without inhibitors. Management of breakthrough bleeding in patients with inhibitors on emicizumab involves episodic treatment with bypassing agents (BPA), activated prothrombin complex concentrate (aPCC) or recombinant activated factor VII (rFVIIa). Thrombotic events and thrombotic microangiopathy were reported when patients on emicizumab received concomitant aPCC at relatively high doses yet such events were not reported with rFVIIa. We studied the effect of spiking various concentrations of BPA on plasma taken from patients on emicizumab. Material and Methods: Eleven patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Blood samples drawn from patients were spiked in vitro with varying concentrations of aPCC and rFVIIa. All samples were tested utilizing global haemostasis assays, thromboelastography and thrombin generation assay. Results: Thrombin generation increased with higher concentrations of spiked BPA with a normalized endogenous thrombin potential at a concentration of 0.05 IU/ml and 4 mcg/ml for aPCC and rFVIIa, respectively. Concentrations of aPCC in the range of licensed dosing led to excessive thrombin generation. Thromboelastography was not sufficiently sensitive. Conclusion: Due to the known thrombotic complications when emicizumab is used in conjunction with aPCC, there has been a large‐scale abandonment of the use of aPCC in patients on emicizumab. However, it is possible that aPCC can be used safely with emicizumab albeit with lower doses than are typically prescribed. It would be important to test this hypothesis in a clinical study. [ABSTRACT FROM AUTHOR]

Hemophilia A (HA) is a serious inherited bleeding disorder resulting from a deficiency of coagulation factor VIII (FVIII). Replacement therapy with intravenous infusion of FVIII can be associated with treatment failure in approximately one-third of patients secondary to the development of neutralizing alloantibodies (inhibitor). Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that binds factor IXa and factor X and mimics FVIII. It has been licensed in many countries for the treatment of patients with HA with and without inhibitors with a favorable efficacy and safety profile. A 7-year-old child with severe HA and FVIII inhibitors, refractory to immune tolerance therapy, developed hematuria with nephroticrange proteinuria after the first dose of emicizumab and subsequently also after a second dose 6 weeks later, which was associated with mild and transient leukopenia. Renal biopsy revealed a pattern of a full-house lupus nephritis. The patient fully and spontaneously recovered between 2 weeks after symptoms onset. In this report, we provide insights on a new and so far unreported renal complication associated to emicizumab treatment. Although emicizumab offers significant benefits for patient with HA, clinicians should be aware of this rare and potential serious renal adverse effect. [ABSTRACT FROM AUTHOR]

Introduction: Persons with haemophilia A (PwHA) with factor (F)VIII inhibitors, including children, have impaired health‐related quality of life (HRQoL). The HAVEN 2 study (NCT027955767) of paediatric PwHA with FVIII inhibitors demonstrated that subcutaneous emicizumab prophylaxis resulted in low annualizedbleed rates. Aim: We assessed the impact of emicizumab prophylaxis on the HRQoL of children and their caregivers participating in HAVEN 2. Methods: Children aged 8‐11 years self‐reported HRQoL using the Haemophilia‐Specific Quality of Life Assessment Instrument for Children and Adolescents Short Form (Haemo‐QoL SF II). Caregivers of children aged 0‐11 years completed the Adapted Inhibitor‐Specific Quality of Life Assessment with Aspects of Caregiver Burden. All scores were transformed to a 0‐100 scale, where lower scores reflect a better HRQoL. The number of missed days from school/day care and hospitalizations was also recorded. Results: In HAVEN 2 (n = 88), the median age was 6.5 years (range: 1‐15 years); 85 participants were aged < 12 years and included in this analysis, and 34 participants were aged 8‐11 years, thereby eligible to complete the Haemo‐QoL SF II questionnaire. The mean (standard deviation, n) baseline Haemo‐QoL SF II 'Total' score was 30.2 (14.9, 30), indicating moderate impairment; with emicizumab, mean score decreased by −9.62 (7.73, 17) points to 23.0 (13.93, 20) by Week 49. The most improved domains were 'Sports & School' and 'Physical Health'. Caregivers reported similar improvements. Conclusion: Prophylactic emicizumab is accompanied by substantial and sustained improvements in HRQoL of paediatric PwHA with FVIII inhibitors and their caregivers. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half‐life treatment for severe haemophilia A were demonstrated in the Phase 3 A‐LONG and Kids A‐LONG studies. Eligible subjects who completed A‐LONG and Kids A‐LONG could enrol in ASPIRE (NCT01454739), an open‐label extension study. Aim: To report the long‐term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results: A total of 150 subjects from A‐LONG and 61 subjects from Kids A‐LONG enrolled in ASPIRE. Most subjects received the IP regimen (A‐LONG: n = 110; Kids A‐LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A‐LONG and Kids A‐LONG was 3.9 (0.1‐5.3) years and 3.2 (0.3‐3.9) years, respectively. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 0‐5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended‐dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. Conclusion: ASPIRE results, which include up to 5 years of follow‐up data, confirm earlier reports on the consistent and well‐characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A. [ABSTRACT FROM AUTHOR]

Introduction: As a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed. Aim: The Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors. Discussion and Conclusions: Despite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further. [ABSTRACT FROM AUTHOR]

Highlights from the article: The other seven patients had at least one bleed treated with 2 or more doses of Rebleeding) and the second bleed was treated with 6 doses, Bleeds, the ability to treat most bleeds with 1 dose with Table 1 OD treatment of bleeds by the number of N9-GP doses.

Introduction: Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health‐related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis. Aim: Describe health‐related outcomes in PwHA with inhibitors in HAVEN 1. Methods: PwHA with inhibitors aged ≥12 years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n = 35) or no prophylaxis (Arm B; n = 18); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n = 49). Health‐related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem‐A‐QoL), Haemophilia‐specific Quality of Life Questionnaire for Children Short Form (Haemo‐QoL SF), EuroQol 5‐Dimensions 5‐Levels (EQ‐5D‐5L) index utility score (IUS) and visual analogue scale (EQ‐VAS) and work/school days. Days hospitalized also recorded. Results: At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem‐A‐QoL "Total" score (14.0 [5.6, 22.5]; P = 0.002) and "Physical Health" (21.6 [7.9, 35.2]; P = 0.003); EQ‐VAS (−9.7 [−17.6, −1.82]; P = 0.017); and IUS (−0.16 [−0.25, −0.07]; P = 0.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire‐specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. Conclusions: In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health‐related outcomes. [ABSTRACT FROM AUTHOR]

B Learning Objectives: b The current standard of care for parenteral treatment of venous thromboembolism (VTE) in the acute setting is anticoagulation with unfractionated heparin. Secondary outcomes were titrations required to reach therapeutic goal and titrations per drug run. Choice of drug had no effect on number of titrations to reach therapeutic goal and overall number of titrations per drug run. [Extracted from the article]

Introduction: Prophylaxis with replacement factor IX (FIX) reduces bleeding frequency and improves quality of life in haemophilia B patients. With prophylaxis, the likelihood of bleeding is lowered with increasing trough levels. New products with extended half‐life (EHL) can maintain high factor activity levels over prolonged periods, compared with standard FIX products. Aim: To evaluate the safety, efficacy and pharmacokinetics of the new recombinant FIX EHL product, nonacog beta pegol (N9‐GP), using pooled data, with a focus on—but not limited to—prophylaxis at 40 IU/kg. Methods: N9‐GP has been investigated in males with congenital haemophilia B and FIX activity ≤2% in the paradigm™ clinical trial programme. This analysis includes pooled data from five completed paradigm™ trials conducted in previously treated adults, adolescents and children, focusing on results of prophylaxis with 40 IU/kg once‐weekly intravenous dosing. Results: In total, 115 previously treated patients were exposed to N9‐GP. Of 54 patients (47%) treated with N9‐GP 40 IU/kg once‐weekly prophylaxis, 72% experienced no spontaneous bleeds over 1 year. In all patients receiving 40 IU/kg once‐weekly, median overall annualized bleeding rate (ABR) was 1.03 (interquartile range 0.00; 2.89); median spontaneous ABR was 0.00 (0.00; 0.80). No patients developed inhibitors. Estimated mean steady‐state trough levels with N9‐GP 40 IU/kg once‐weekly were ≥15% overall; 27.3% in adolescents and adults. Conclusion: N9‐GP 40 IU/kg once‐weekly was well tolerated and effective in preventing bleeding, maintaining mean FIX activity levels ≥15% across all age groups. N9‐GP may provide a new treatment option for preventing bleeding in haemophilia B patients. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily. Methods: EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18 years. A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months. Conclusions: EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials. Trial registration: Clinicaltrials.gov NCT02234843, registered on 9 September 2014. [ABSTRACT FROM AUTHOR]

Introduction Acute lymphoblastic leukemia (ALL) therapy confers risk for venous thromboembolism (VTE) and associated acute and long-term morbidity. Obesity increases VTE risk in the general population but its impact on ALL therapy-associated VTE is unknown. Methods In a retrospective cohort of children treated for ALL between 2008 and 2016 ( n  = 294), we analyzed obesity at diagnosis (body mass index [BMI] ≥95%) and subsequent development of VTE. A subset participated in two concurrent prospective ALL trials studying body composition via dual-energy X-ray absorptiometry (DXA) ( n  = 35) and hypercoagulability via thromboelastography (TEG) ( n  = 46). Secondary analyses explored whether precise measurement of body fat and/or global hemostasis ex vivo by TEG could further delineate VTE risk in the obese. Results Overall, we found 27/294 (9.2%) patients developed symptomatic VTE during therapy, 19/27 (70%) occurred during Induction. Study-defined “serious” VTE developed in 4/294 (1.4%) of patients. Obesity but not overweight was strongly predictive of symptomatic VTE (obesity odds ratio = 3.8, 95% confidence interval 1.5–9.6, p  = 0.008). In the DXA subset, only 2/35 patients developed symptomatic VTE. However, within those prospectively screened during Induction, 30% (14/46) developed VTE; eight (17%) of these were asymptomatic and found only via screening. Conclusions In this pediatric ALL cohort, obesity conferred more than a three-fold increased risk for symptomatic VTE. In a subgroup of patients who underwent active screening, up to a third were noted to have VTE (symptomatic and asymptomatic). TEG did not predict VTE. Additional studies are necessary to validate these findings and to further refine a risk-stratified approach to thrombo-prevention during ALL therapy. [ABSTRACT FROM AUTHOR]

Background: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.Methods: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.Results: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.Conclusions: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .). [ABSTRACT FROM AUTHOR]

Background Recent epidemiological evidence suggests sickle cell disease (SCD) and sickle cell trait (SCT) is a risk factor for venous thromboembolism. The increased in-vivo markers of thrombin generation support the notion that such patients are in a chronic hypercoagulable state. In an attempt to better understand the underlying mechanism, global hemostatic assays including thrombin generation assay (TGA) and thromboelastography (TEG) have been utilized by several groups, but thus far, have shown inconsistent results either due to small sample size or technical differences. Objectives Global hemostatic characterization of children with SCD or SCT by using TGA and modified TEG methods. Materials and Methods In this pilot study, we obtained TGA, TEG and other hemostatic data on specimens from 13 patients with SCD, 14 with SCT and 12 race-matched healthy controls (NC). Results R time and K time with modified TEG methods were significantly shorter in SCD when compared to SCT and NC. Alpha and MA did not show any significant differences between the groups. There was no difference seen between SCT and NC. TGA profiles did not show any difference between the three groups. As expected the in-vivo markers of thrombin generation and activation of fibrinolysis including D dimer and thrombin-antithrombin complexes were significantly higher in SCD subjects as compared to SCT and NC. Conclusion The modified TEG methods are able to detect the activated coagulation system for the SCD population but a larger and more homogenous SCT cohort needs to be studied for more conclusive results. [ABSTRACT FROM AUTHOR]

Deficiency of antithrombin ( AT), protein C ( PC) or protein S ( PS) constitutes a major risk factor for venous thromboembolism ( VTE). Individuals at high risk for recurrence who benefit from screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non-central-venous-catheter-associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46-17·2) and female gender (2·6/1·1-6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6-10) in AT-deficient children, 1·3% (0·3-3·8) in patients with PC deficiency, 0·7% (0·08-2·4) in the PS-deficient cohort and 0·9% (0·4-1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of plasma-derived von Willebrand factor-containing FVIII concentrates for treating haemophilia. It discusses how the early pd-VWF-FVIII products had resulted in developing human immunodeficiency virus (HIV), how a level of safety had to be maintained for viral transmission.

Haemophilia A and B are hereditary haemorrhagic disorders characterised by deficiency or dysfunction of coagulation protein factors VIII and IX, respectively. Recurrent joint and muscle bleeds lead to severe and progressive musculoskeletal damage. Existing treatment relies on replacement therapy with clotting factors, either at the time of bleeding (ie, on demand) or as part of a prophylactic schedule. The major complication of such therapy is the development of neutralising antibodies (ie, inhibitors), which is most frequent in haemophilia A. Treatment might improve considerably with the availability of new modified drugs, which might overcome existing prophylaxis limitations by reducing dosing frequency and thereby rendering therapy less distressing for the patient. Subcutaneous administration of some new therapies would also simplify prophylaxis in children with poor venous access. Gene therapy has the potential for a definitive cure, and important results have been obtained in haemophilia B. Despite improvements in haemophilia care, the availability of clotting factor concentrates for all affected individuals worldwide remains the biggest challenge. [ABSTRACT FROM AUTHOR]

. Haemostasis management in people with haemophilia can present a range of challenges to physicians. Specific challenges that may be encountered relate to regimens for immune tolerance induction, use of central venous access devices, optimizing care of paediatric patients with inhibitors and improving outcomes in acquired haemophilia. There are also challenges related to performing surgery, and the establishment of specialist centres is valuable with regard to this. These challenges are considered in the light of available data, and with perspectives gained from the experience of experts treating patients around the world. Sharing this knowledge may help to improve patient management. [ABSTRACT FROM AUTHOR]

The aim of this study was to estimate the impact of antiphospholipid (aPL) antibodies on the risk of incident thromboembolism (TE; arterial and venous) in children via meta-analysis of published observational studies. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1966 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, TE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using either fixed-effects or random-effects models. Of 504, 16 pediatric studies met the inclusion criteria. In total 1403 patients and 1667 population-based controls ≤18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. Thus, data from arterial and venous TE were analyzed together. In addition, meta-regression analysis did not reveal statistically significant differences between site of TE, age at first TE, country, or publication year. A statistically significant association with a first TE was demonstrated for persistent aPL antibodies, with an overall summary ORs/CI of 5.9/3.6–9.7 (arterial 6.6/3.5–12.4; deep vein thrombosis 4.9/2.2–10.9). The present meta-analysis indicates that detection of persistent aPL is clinically meaningful in children with, or at risk for, TE and underscores the importance of pediatric thrombophilia screening programs. [ABSTRACT FROM AUTHOR]

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of argatroban in pediatric patients and derive dosing recommendations. An open-label multicenter trial was conducted in pediatric patients (n = 18 from birth to 16 years). A population modeling approach was used to characterize pharmacokinetics and pharmacodynamics of argatroban in pediatric patients. Simulations were performed to derive a dosing regimen for pediatric patients. The estimated clearance of argatroban in pediatric patients was 2-fold lower than that in healthy adults. Body weight was significant predictor of argatroban clearance. The clearance in a typical 20-kg pediatric patient was 3.1 L/h. In 4 patients with elevated serum bilirubin levels, the estimated clearance was 0.6 L/h. Effect on activated plasma thromboplastin time (aPTT) was found to be concentration dependent. Simulations suggested that a starting dose of 0.75 µg/kg/min in pediatric patients was comparable in performance to 2.0 µg/kg/min approved in adults for attaining target aPTT and risk for bleeding. A dose increment step size of 0.25 µg/kg/min was suitable for titration. The PK/PD of argatroban was reasonably characterized in pediatrics. Plasma concentration—aPTT relationship was used to derive a safe starting dose and titration scheme for the first time in pediatric patients and was incorporated into the US prescribing information for argatroban. [ABSTRACT FROM PUBLISHER]

Abstract: The hepatitis C virus (HCV) genotype is the most important factor in predicting the outcome of chronic hepatitis C treatment. Therefore, convenient and accurate HCV genotyping methods for routine laboratory testing are needed. In this study, to identify the HCV genotypes, an oligonucleotide DNA chip was designed using 15 probes from the 5′-untranslated region. Reverse transcription was combined with asymmetric polymerase chain reaction (PCR) to obtain an amplified product for hybridization without the need for a denaturation step. In addition, a biotin-labeled PCR product and streptavidin-Cy3 conjugate were cohybridized simultaneously. Clinical sera from Korean and French patients (n =112) were used to compare the chip results with those obtained by direct sequencing. The DNA chip showed 100% accuracy for the commercial panels and had a lower detection limit of 2.8×102 IU/ml. Agreement levels between the chip and sequencing results at the genotype and subgenotype levels were 100% and 94.6% (106/112), respectively. By the combined reverse transcription-asymmetric PCR and cohybridization methods, the DNA chip reduced assay time and was convenient to use. This DNA chip may be useful for identifying HCV genotypes in clinical laboratories. [Copyright &y& Elsevier]

B Learning Objectives: b Heparin resistance is a common problem encountered in the ICU yet currently lacks standard definitions and characterization. Since standard clinical practice states patients with anti-Xa < 0.3 I.U./mL are subtherapeutic, we also considered all patients who never reached this threshold despite a minimum of 3 heparin titrations as heparin resistant. By defining heparin resistance as any patient who failed to achieve anti-Xa greater than 0.3 I.U./mL despite 3 or more heparin titrations OR required greater than 45 units/kg/hr of heparin, we identified 36 patients (15%) as heparin resistant. [Extracted from the article]