Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. OBJECTIVES: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. METHODS: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs). RESULTS: At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment. CONCLUSION: Hemostatic efficacy was maintained, and safety remained unchanged from previous years.

Increasing optimal coagulation factor dosing in the paediatric emergency department: Update to a quality improvement study.

INTRODUCTION: Prompt, appropriate coagulation factor replacement according to injury and bleeding severity in persons with haemophilia is required to prevent acute and long-term complications. AIMS: Increase proportion of persons with haemophilia A (HA) and B (HB) treated appropriately for an acute injury and bleeding episode at a tertiary children's emergency department (ED) from 65% to 85% and sustain for one year. Secondary aim: increase time interval between patient ED encounters with out-of-range factor dosing. METHODS: Utilizing quality improvement methodology and plan-do-study-analyze cycles, ED encounters for individuals with HA/HB receiving coagulation factor replacement for injuries were audited for in-range coagulation factor dosing. Goal factor dose defined as 50% correction for minor bleeds and 100% correction for major bleeds. Optimal dosing range defined as 90%-120% of the calculated goal dose to account for vial size variability. Interventions targeted communication via the EMR problem list and optimization of physician education. RESULTS: Our previous publication demonstrated 33.3% of ED encounters with out-of-range factor replacement. Following several interventions, the cumulative rate of encounters with out-of-range dosing decreased to 18%. Overall, there was an increase in the mean percent of encounters receiving optimal factor dosing for both HA/HB compared to baseline (82.2% vs. 71.1%), though this was not a statistically significant difference. CONCLUSION: Despite implementation of multiple interventions, out-of-range factor dosing continues to occur. Our team plans to reinstate simulation center education for ED staff and continue education efforts of pharmacists and hematology trainees with the goal of further reducing out-of-range dosing in our ED.

Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1.

BACKGROUND: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL). OBJECTIVES: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1. METHODS: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 1013 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes. RESULTS: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain. CONCLUSION: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA.

Efficacy and safety evaluation of eptacog beta (coagulation factor VIIa [recombinant]-jncw) for the treatment of hemophilia A and B with inhibitors.

INTRODUCTION: Bypassing agents (BPAs) are used to treat acute bleeding episodes, manage bleeding during perioperative care, and prophylactically minimize bleed occurrence in persons with hemophilia A or B with inhibitors (PwHABI). However, the effectiveness of BPAs that have been prescribed for the last several decades can be variable, motivating the development of a new recombinant activated factor VII, eptacog beta. AREAS COVERED: This review covers key eptacog beta findings from phase 1b and phase 3 (PERSEPT) clinical trials, which formed the basis for its regulatory approval to treat PwHABI ages 12 and older. Descriptions of eptacog beta structure and glycosylation profile, mechanism of action, preclinical study results, and cost analyses are also presented. EXPERT OPINION: PwHABI have had only two options for bleed treatment for the past several decades. With its distinct glycosylation profile, eptacog beta offers a novel therapy aiming to improve upon BPAs currently in use, providing an option with more than one dosing regimen and a rapid response that allows most bleeds to be treated with just one dose. This has become particularly important given the use of subcutaneous medications (e.g., emicizumab) for prophylaxis of bleeding. Clinicians should consider eptacog beta as a BPA for all PwHABI.

A regional anticoagulation program improves safety and outcomes for both children and adults.

BACKGROUND: Evidence-based anticoagulation programs usually serve a local, adult patient population. Here we report outcomes for a regional combined pediatric-adult program. AIMS: The aims of this study were: (1) Compare the pre- vs. post-implementation quality of therapy (% time in therapeutic range (%TTR) and compliance). (2) Assess anticoagulant-relevant outcomes (bleeding and thrombotic complications). METHODS: Data were collected for the years 2014-2019. Rosendaal linear interpolation was used to calculate %TTR. Bleeding complications were categorized using ISTH-SSC standard nomenclature and new thrombotic events were reviewed. RESULTS: The patients were divided into a long-term warfarin group (N = 308), 80.2% of whom had cardiac-related therapeutic indications (median age 24y), and a second group (N = 114) comprised of short-term and non-warfarin long-term anticoagulation (median age 16y). Median %TTR for those on long-term warfarin was 78.9%. The incidence of major and clinically relevant non-major bleeding events was 1.65 and 2.43 /100 person-years of warfarin use, respectively. Thromboembolism (TE) incidence was 0.78/100 patient-years of warfarin use. Neither bleeding nor thrombosis was associated with %TTR (p = 0.48). Anticoagulant indication was the only variable associated with bleeding risk (p = 0.005). The second group had no on-therapy TE events but 7.9% experienced bleeding. Complete data were available for a randomly sampled pre-program warfarin group (N = 26). Median %TTR improved from 17.5 to 87% pre- vs. post-implementation. Similarly, compliance (defined as ≥ 1 INR/month) improved by 34.3%. CONCLUSIONS: In conclusion, this program significantly improved and sustained %TTR and compliance. The lack of association between bleeding and thrombosis events and %TTR may be related to the high median %TTR (> 70%) achieved by this approach.

Mild Hemophilia in a Competitive High School Soccer Player: A Case Report.

In this report, we discuss the case of a now 23-year-old athlete who was diagnosed with mild hemophilia, successfully played varsity soccer throughout high school, and continued to play intramural and club soccer while in college. A prophylactic protocol was developed by the athlete's hematologist to allow his safe participation in contact sports. Similar prophylactic protocols have been discussed by Maffet et al that successfully allowed an athlete to participate in high-level basketball. However, significant barriers still exist for an athlete with hemophilia who wants to engage in contact sports. We discussed how athletes with adequate support networks can participate in contact sports. Decisions need to be made on a case-by-case basis and involve the athlete, family, team, and medical personnel.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities to transform the care of people with hemophilia.

BACKGROUND: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. RESEARCH DESIGN AND METHODS: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk. RESULTS: WG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial. CONCLUSIONS: Collaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.

Hemophilia is the best known of the inherited bleeding disorders (BD). This is a rare condition that causes disproportionate bleeding, often into joints and vital organs. Factor replacement, injecting recombinant or plasma-based clotting factor products directly into the vein, became commonplace to control the disorder in the 1990s and 2000s. Prophylaxis, or injecting replacement factor every few days into people with hemophilia (PWH), has revolutionized patients' lives. In the last few years, other advances in new therapies have entered this space, such as non-factor replacement therapies and gene therapy. With many more research advances on the horizon, the National Hemophilia Foundation (NHF) initiated a State of the Science Research Summit in 2020. This event was attended by over 880 interested parties to help design an agenda of research priorities for inherited BDs for the next decade, based on community consultations. NHF formed multiple Working Groups (WG), each exploring a theme resulting from the community consultations, and presenting their results at the Summit. Led by 2 hematologists who manage and treat PWH daily, the 21-community member WG1 assigned to hemophilia A and B divided into 7 subgroups to identify and organize research priorities for different topic areas. The outcomes focused on prioritizing patients' needs, technological advances, and research in the areas of greatest potential for PWH and those who care for them. The results are a roadmap for the future execution of a research plan that truly serves the community.

Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

Achieving access to haemophilia care in low-income and lower-middle-income countries: expanded Humanitarian Aid Program of the World Federation of Hemophilia after 5 years.

Highly effective treatment of haemophilia A and B is primarily available to 15% of the world's population, in high-income countries. In low-income countries (LICs) and lower-middle-income countries (LMICs), morbidity and mortality are high because of greatly reduced access to diagnosis, care, and treatment. We report the challenges and impact after the first 5 years (mid-2015-2020) of the expanded World Federation of Hemophilia (WFH) Humanitarian Aid Program (HAP). WFH HAP donated coagulation products were used to treat more than 250 000 acute bleeding episodes, manage approximately 4000 surgeries, and establish bleeding preventive prophylaxis in about 2000 patients in 73 countries. Health-care providers worldwide learned optimal management of patients with complex needs through virtual and in-person training. In response to the programme, some governments increased investment in haemophilia care, including independent purchases of small amounts of treatment products. With unparalleled scope and complexity, and substantial benefits to people with haemophilia and society in general, the WFH HAP is an exemplar of partnership between for-profit and not-for-profit organisations advancing health-care equity in LICs and LMICs, which could be replicated by other organisations supporting people with different monogenic diseases.

Moderate-intensity aerobic exercise vs desmopressin in adolescent males with mild hemophilia A: a randomized trial.

Persons with mild hemophilia A (HA) may use intranasal desmopressin prior to sports participation. Desmopressin is expensive and can cause vomiting, headache, palpitation, and occasionally seizures. Our group has previously documented a 2.3-fold increase in factor VIII activity (FVIII:C) in adolescents with mild HA after moderate-intensity aerobic exercise. Herein, we report principal findings of a randomized trial of intranasal desmopressin vs a standardized, moderate-intensity aerobic exercise regimen in adolescents with mild HA. Our primary objective was to compare the change in FVIII:C associated with these 2 interventions. We also examined changes in hemostatic parameters arising from their sequential administration. The study was conducted simultaneously at the Hospital for Sick Children, Canada, and Nationwide Children's Hospital, USA. Thirty-two eligible male adolescents (mean age ± standard deviation: 16.1 ± 2.6 years) with mild HA (mean baseline FVIII:C: 27.9% ± 18.4%) were randomized to 1 of 4 study arms (desmopressin followed by exercise, desmopressin alone, exercise followed by desmopressin, and exercise alone). Blood work was obtained at baseline and at 3 subsequent time-points. Participants randomized to exercise cycled on an ergometer for approximately 12 minutes, with the final 3 minutes at 85% of their predicted maximum heart rate. Standard weight-based dosing of desmopressin was used. Mean immediate increase in FVIII:C was 1.7-fold with exercise compared with 1.9-fold with desmopressin (noninferiority, P = .04). Exercise-induced improvement in hemostatic parameters including FVIII:C was brief compared with more sustained improvements seen with desmopressin. More than 60% of participants randomized to receive both exercise and desmopressin achieved normal (>50%) FVIII:C, 75 and 135 minutes into the study protocol.

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 µg/kg initial dose regimen (IDR) and 60% in the 225 µg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 µg/kg IDR and 98% for the 225 µg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 µg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

Andexanet Alfa Versus Prothrombin Complex Concentrates/Blood Products as Apixaban/Rivaroxaban Reversal Agents: A Survey Among Pediatric Hematologists.

Direct oral factor Xa inhibitors (DXIs) are approved for use in adult patients with non-valvular heart disease for stroke prevention, and the treatment/prevention of venous thromboembolism (VTE). Recent pediatric clinical trials have demonstrated safety and efficacy of direct oral anticoagulants (DOACs) in the treatment of VTE. However, there is a lack of evidence regarding the use of andexanet alfa and prothrombin complex concentrates (PCC) for anticoagulation reversal of DXIs in the pediatric population. To better understand current DXI reversal strategies in this age group, a 10-question survey was conducted among pediatric hematology members of the Hemostasis and Thrombosis Research Society. Seventeen percent completed the survey (27 of 163 pediatric hematology members) with 74% (n = 20) reporting their use of DXIs for the treatment and prevention of VTE. Forty-four percent (n = 12) would choose andexanet alfa as first-line treatment for life-threatening bleeding while 52% (n = 14) would use PCC first with one individual choosing recombinant factor VII for DXI reversal. Clinical studies of andexanet alfa and PCC for the management of DXI-associated life-threatening bleeding require further investigation in the pediatric population.

Drive-Through Anticoagulation Clinic During the COVID-19 Pandemic.

An innovative approach to anticoagulation management during the COVID-19 pandemic was used at our center that allowed patients to stay in their vehicle while our anticoagulation advanced practice registered nurse obtained blood for point-of-care international normalized ratio (INR) testing while education and counseling were completed. A significant improvement in the median percentage of INR within the therapeutic range was observed among the patients who used the drive-through clinic. A small group of patients improved compliance to anticoagulation monitoring. Clinical care models, such as this clinic approach may improve patient compliance and adherence to anticoagulation beyond the pandemic needs.

A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE).

INTRODUCTION: High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding. AIM: To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA). METHODS: SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria. RESULTS: Fifty-four patients aged 11-58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding. CONCLUSION: These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding.

Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders.

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.

Adherence of Mobile App-Based Surveys and Comparison With Traditional Surveys: eCohort Study.

BACKGROUND: eCohort studies offer an efficient approach for data collection. However, eCohort studies are challenged by volunteer bias and low adherence. We designed an eCohort embedded in the Framingham Heart Study (eFHS) to address these challenges and to compare the digital data to traditional data collection. OBJECTIVE: The aim of this study was to evaluate adherence of the eFHS app-based surveys deployed at baseline (time of enrollment in the eCohort) and every 3 months up to 1 year, and to compare baseline digital surveys with surveys collected at the research center. METHODS: We defined adherence rates as the proportion of participants who completed at least one survey at a given 3-month period and computed adherence rates for each 3-month period. To evaluate agreement, we compared several baseline measures obtained in the eFHS app survey to those obtained at the in-person research center exam using the concordance correlation coefficient (CCC). RESULTS: Among the 1948 eFHS participants (mean age 53, SD 9 years; 57% women), we found high adherence to baseline surveys (89%) and a decrease in adherence over time (58% at 3 months, 52% at 6 months, 41% at 9 months, and 40% at 12 months). eFHS participants who returned surveys were more likely to be women (adjusted odds ratio [aOR] 1.58, 95% CI 1.18-2.11) and less likely to be smokers (aOR 0.53, 95% CI 0.32-0.90). Compared to in-person exam data, we observed moderate agreement for baseline app-based surveys of the Physical Activity Index (mean difference 2.27, CCC=0.56), and high agreement for average drinks per week (mean difference 0.54, CCC=0.82) and depressive symptoms scores (mean difference 0.03, CCC=0.77). CONCLUSIONS: We observed that eFHS participants had a high survey return at baseline and each 3-month survey period over the 12 months of follow up. We observed moderate to high agreement between digital and research center measures for several types of surveys, including physical activity, depressive symptoms, and alcohol use. Thus, this digital data collection mechanism is a promising tool to collect data related to cardiovascular disease and its risk factors.

Screening urinalysis demonstrates that haematuria is a frequent finding in persons with haemophilia treated at a paediatric haemophilia treatment centre.

INTRODUCTION: Haematuria is a recognized complication of haemophilia A and B (HA, HB). Adult persons with haemophilia (PWH) have a higher prevalence of renal disease than the general population. There is limited literature investigating the prevalence of haematuria in paediatric PWH. AIM: Our paediatric haemophilia treatment centre (HTC) had previously used quality improvement methods to increase the frequency of screening urinalyses at annual comprehensive visits. We retrospectively reviewed the data collected to determine the prevalence of haematuria and explore for associations in those with haematuria. METHODS: Retrospective chart review to identify the frequency of haematuria on screening urinalysis in all male PWH ≥2 years old. Haematuria was defined as ≥3 red blood cells (RBCs) per high power field. Univariate logistic regression was performed to evaluate for associations with haematuria. RESULTS: A total of 93 patients met eligibility criteria. Sixty-seven with HA (11 mild, 17 moderate, 39 severe) and 26 with HB (three mild, 16 moderate, seven severe). Forty-two of ninety-three (45%) patients were identified as having haematuria (median RBCs 7, mean RBCs 332). Of those with haematuria, 76% were identified by screening UA, as opposed to clinical symptoms, and 52% had recurrent haematuria. Older age and HA were associated with an increased likelihood of haematuria. CONCLUSIONS: Our study demonstrated that the prevalence of haematuria was high in PWH treated at our paediatric HTC. Future investigation is needed to determine the population-wide prevalence of haematuria in paediatric PWH and its impact on renal function.

Optimizing patient flow in a multidisciplinary haemophilia clinic using quality improvement methodology.

INTRODUCTION: Multidisciplinary clinics in academic settings are often inefficient and can lead to lengthy clinic visits for patients and staff. AIM: We aimed to use quality improvement (QI) methodology and a multidisciplinary approach to optimize outpatient comprehensive haemophilia clinic flow. METHODS: At baseline, a multidisciplinary QI team created a key driver diagram to identify drivers of haemophilia clinic flow. Identified drivers included patient needs/scheduling, provider flow and laboratory/research requirements. From December 2016 to August 2017, value stream mapping (VSM) was used to identify barriers to clinic flow, and plan-do-study-act cycles were used to address these barriers. Interventions included (a) standardizing the order in which providers saw patients to enable time-sensitive laboratories, (b) improving HTC team meeting functionality, (c) optimizing a visual management board and implementing a flow coordinator, (d) initiating a team huddle prior to clinic start and (e) modifying the clinic appointment template. Timely laboratory draw was used as a surrogate marker of clinic flow, and VSM utilization percentage was used as an objective measure of efficiency. RESULTS: We did not demonstrate a statistically significant improvement in timed laboratory draws; however, clinic utilization percentage increased by 30%, which resulted in adding point-of-care musculoskeletal ultrasound services without lengthening clinic duration. CONCLUSION: Quality improvement methodology is an effective means of improving clinic utilization in a multidisciplinary clinic.

Fibrinogen Columbus II: A novel c.1075G>T mutation in the FGG gene causing hypodysfibrinogenemia and thrombosis in an adolescent male.

Hypodysfibrinogenemia, the least frequently reported congenital fibrinogen disorder is characterized by low circulating levels of a dysfunctional protein, and is associated with phenotypic features of both hypo- and dysfibrinogenemia. Herein, we report an adolescent male with unprovoked venous thromboembolism and hypodysfibrinogenemia. Patient had recurrent, progressive thrombosis despite therapeutic anticoagulation with both low molecular weight heparin and warfarin. He had clinical and radiological improvement after transition to a direct thrombin inhibitor. Sequencing of the FGG gene identified a novel heterozygous mutation, c.1075G>T. Structural visualization of the identified variant was pursued and suggested that the mutation likely destabilizes the Ca2+ -binding site of fibrinogen resulting in pathogenicity.