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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]

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]

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: 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

. 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 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]

SUMMARY Excessive bleeding accounts for a significant incidence of morbidity and mortality resulting from a variety of conditions including congenital and acquired bleeding disorders, trauma, and surgery. A complex network of cellular and plasma components are involved in the process of controlling excessive bleeding, a process known as hemostasis. When excessive bleeding does occur, there are a wide variety of agents with diverse mechanisms of action that can promote hemostasis. These agents include blood products, biologicals such as recombinant proteins, synthetic medications, and topical agents. Historically, non-specific agents such as fresh frozen plasma, cryoprecipitate and antifibrinolytic agents have been the standard therapies for the management of excessive bleeding. These, however, all have significant limitations. Recently, recombinant factor VIIa (rFVIIa) was licensed for use in patients with hemophilia and inhibitors to factors VIII or IX. Since its licensure, it has been used in a wide variety of conditions with excessive bleeding leading to often dramatic results. Another novel agent is factor XIII (FXIII) which is currently in clinical trials. Although data regarding its use in conditions other than FXIII deficiency is lacking, it is expected that FXIII will become another effective agent in the management of excessive bleeding. [ABSTRACT FROM AUTHOR]