Management strategies in persons with inherited haemophilia requiring antithrombotic therapy: A scoping review.

BACKGROUND: Thromboembolic events are increasingly reported in the aging haemophilia population. The purpose of this study was to understand current practices and identify knowledge and research gaps in the management of persons with haemophilia requiring antithrombotic therapy for cardiovascular disorders (CVD) or venous thromboembolism (VTE). METHODS: We searched MEDLINE, EMBASE and Scopus for studies reporting on more than two patients with inherited haemophilia A or B, without inhibitors, requiring antithrombotic therapy for CVD or VTE. Data were extracted by two independent reviewers and analysed using descriptive statistics and narrative synthesis. RESULTS: We included 32 studies reporting on 432 persons with haemophilia. Three themes described the observed practice variation: (1) Difficulty weighing competing bleeding and thrombotic risks; (2) Tensions in providing standards of care and minimizing bleeding risk; (3) Advocacy for individualized strategies and multidisciplinary care. Different management strategies were used to treat persons with haemophilia in the setting of thromboembolic events, such as avoiding or choosing lower intensity antithrombotic therapy, or procedural alternatives to antithrombotic therapy. Initiation or alteration in haemostatic therapies along with antithrombotic therapy were common strategies and reported in 30 studies. However, data on target factor levels and bleeding and thrombotic events were largely missing. DISCUSSION: Our scoping review highlights unmet needs in the management of an aging population of persons with haemophilia with increasing prevalence of CVD and VTE. Management is inconsistent and divergent from those of non-haemophilic patients. Prospective data are needed to inform optimal and evidence-based management strategies of CVD and VTE in persons with haemophilia.

Patient involvement in assessment of postgraduate medical learners: A scoping review.

CONTEXT: Competency-based assessment of learners may benefit from a more holistic, inclusive, approach for determining readiness for unsupervised practice. However, despite movements towards greater patient partnership in health care generally, inclusion of patients in postgraduate medical learners' assessment is largely absent. METHODS: We conducted a scoping review to map the nature, extent and range of literature examining the inclusion (or exclusion) of patients within the assessment of postgraduate medical learners. Guided by Arskey and O'Malley's framework and informed by Levac et al. and Thomas et al., we searched two databases (MEDLINE® and Embase®) from inception until February 2021 using subheadings related to assessment, patients and postgraduate learners. Data analysis examined characteristics regarding the nature and factor influencing patient involvement in assessment. RESULTS: We identified 41 papers spanning four decades. Some literature suggests patients are willing to be engaged in assessment, however choose not to engage when, for example, language barriers may exist. When stratified by specialty or clinical setting, the influence of factors such as gender, race, ethnicity or medical condition seems to remain consistent. Patients may participate in assessment as a stand-alone group or part of a multi-source feedback process. Patients generally provided high ratings but commented on the observed professional behaviours and communication skills in comparison with physicians who focused on medical expertise. CONCLUSION: Factors that influence patient involvement in assessment are multifactorial including patients' willingness themselves, language and reading-comprehension challenges and available resources for training programmes to facilitate the integration of patient assessments. These barriers however are not insurmountable. While understudied, research examining patient involvement in assessment is increasing; however, our review suggests that the extent which the unique insights will be taken up in postgraduate medical education may be dependent on assessment systems readiness and, in particular, physician readiness to partner with patients in this way.

A case of acute pancreatitis-induced microangiopathic hemolytic anemia with thrombocytopenia.

Microangiopathic hemolytic anemia and thrombocytopenia (MAHA-T) is a rare complication of acute pancreatitis (AP). Treatment with therapeutic plasma exchange (TPE) is used at many centers. The natural history of this disease is not well understood. We report a case of acute pancreatitis induced MAHA-T with end organ dysfunction and a normal ADAMTS13 level. Following three TPEs, the patient's clinical status, blood counts and hemolytic markers stabilized. Improvement occurred even after TPE was discontinued. The optimal management of AP-induced MAHA-T is poorly understood. Many centres are reporting good outcomes with the early initiation of TPE. MAHA-T associated with acute pancreatitis is often treated with early initiation of TPE. However, the value of TPE in altering the natural history of the condition is not well understood. Further study is required to understand the role of ADAMTS13 testing to guide treatment, and the role of TPE in management.

Intrinsic Disorder in Tetratricopeptide Repeat Proteins.

Among the realm of repeat containing proteins that commonly serve as "scaffolds" promoting protein-protein interactions, there is a family of proteins containing between 2 and 20 tetratricopeptide repeats (TPRs), which are functional motifs consisting of 34 amino acids. The most distinguishing feature of TPR domains is their ability to stack continuously one upon the other, with these stacked repeats being able to affect interaction with binding partners either sequentially or in combination. It is known that many repeat-containing proteins are characterized by high levels of intrinsic disorder, and that many protein tandem repeats can be intrinsically disordered. Furthermore, it seems that TPR-containing proteins share many characteristics with hybrid proteins containing ordered domains and intrinsically disordered protein regions. However, there has not been a systematic analysis of the intrinsic disorder status of TPR proteins. To fill this gap, we analyzed 166 human TPR proteins to determine the degree to which proteins containing TPR motifs are affected by intrinsic disorder. Our analysis revealed that these proteins are characterized by different levels of intrinsic disorder and contain functional disordered regions that are utilized for protein-protein interactions and often serve as targets of various posttranslational modifications.

Scurvy, an old story in a new time: The hematologist's experience.

BACKGROUND: Scurvy is a rare entity in developed countries and the diagnosis may often be delayed resulting in unnecessary investigations and/or potentially severe complications. A recent increase in the number of patients diagnosed with scurvy in our hematology clinics indicated the need to review the literature on the diagnosis and optimal management of similar patients. METHODS: We conducted a retrospective chart review of patients referred to hematology at our tertiary care centre between 2010 and 2018, who were ultimately diagnosed with scurvy. Data collected from electronic medical records included baseline characteristics, clinical features on presentation, bloodwork results from initial consultation, treatment plan as well as response to treatment. FINDINGS: Twenty-two adults patient had a diagnosis of scurvy with a mean vitamin C level of 6 µmol/L. Iron deficiency anemia (54%) and gastrointestinal disorders (54%) were the most common comorbidities noted in our cohort. Proton-pump inhibitors use was noted in 54% of patients. Bleeding (45%) and bruising (45%) were the most commonly reported clinical features. Eleven patients received oral supplementation, five had intravenous (IV) vitamin C and six were not treated. Two patients required a transition from oral to IV supplementation. Vitamin C dosing ranged between 250 and 2000 mg and the frequency varied from daily for oral therapy to every few weeks or months for IV. INTERPRETATION: Awareness of scurvy and its associated risk factors and clinical presentation is important in the evaluation of a patient with bleeding tendency. Treatment plan should be individualized, and a careful review of patients' diet, medial history and medications is warranted.

Predictors of diagnostic delays and loss to follow-up in women with von Willebrand disease: a single-center retrospective cohort study.

Background: Women with von Willebrand disease (VWD) often face diagnostic delays, leading to increased bleeds, stress, and healthcare use. The factors influencing these delays and their effects on gynecologic outcomes are not well understood. Objectives: This study aimed to 1) identify the prevalence and predictors of diagnostic delays and loss to follow-up in women with VWD and 2) determine how these delays affect severe gynecologic bleeding, emergency visits, transfusions, and hysterectomies. Methods: We conducted a single-center retrospective cohort study and included women aged ≥18 years diagnosed with VWD. Delayed diagnosis was defined as ≥3 bleeding events prior to VWD diagnosis, excluding easy bruising due to its subjectivity. Loss to follow-up was defined as ≥5 years since the last hematology visit. We used logistic regression for analysis. Results: Among 178 diagnosed women (median age, 27 years), 71 (40%) experienced ≥3 bleeding events before diagnosis. The median time from the first bleeding event to VWD diagnosis was 14.2 years. Severe bleeding events significantly predicted diagnostic delays (adjusted odds ratio, 3.1; 95% CI, 1.5-6.2). Fifty-four (30%) women were lost to follow-up, with remote era of initial bleed and VWD type identified as significant predictors. Delays were associated with increased risks of hysterectomies (odds ratio, 2.7; 95% CI, 1.2-6.3) and other gynecologic procedures. Conclusion: Delayed diagnosis and loss to follow-up in VWD are common even in a specialized Hemophilia Treatment Centre. Such delays lead to more severe bleeding and increased gynecologic interventions. Prompt diagnosis is paramount for better patient outcomes and reduced healthcare utilization.

Bleeding disorders and postpartum hemorrhage by mode of delivery: a retrospective cohort study.

Background: Pregnant persons with bleeding disorders and their potentially affected newborns are at a higher risk of peripartum bleeding complications. The safest mode of delivery for persons with bleeding disorders remains debated, leading to uncertainties in decision-making between the patient and her multidisciplinary team. Objectives: This study aimed to describe maternal outcomes for pregnant persons with bleeding disorders by mode of delivery and to examine whether postpartum hemorrhage (PPH) and neonatal hemorrhagic manifestations are associated with the mode of delivery. Methods: We collected retrospective data on pregnant persons with bleeding disorders who delivered at a single center from 2010 to 2021. Descriptive statistics, Fisher exact test, and odds ratios were used for analysis. Results: A total of 82 pregnancies in 56 subjects were included. Hemophilia A and von Willebrand disease represented the largest cohort, at 30% (17/56) each. Overall rates of primary and secondary PPH were 7.3% (6/82) and 17.4% (12/69), respectively. We did not find a statistically significant difference between mode of delivery and PPH. Upon comparing vaginal and cesarian deliveries, we found an odds ratio of 0.7 (95% CI, 0.1-3.4) for primary PPH and 2.6 (95% CI, 0.4-16.4) for secondary PPH. One male newborn with severe hemophilia A was treated for a suspected intracranial hemorrhage. Conclusion: In our cohort, high rates of PPH remained an important complication for pregnant persons with bleeding disorders. There was no significant difference in PPH based on modes of delivery. The small sample size likely limited the power of our study, and consequently, future larger studies are needed.

Having a Bad Day Is Not an Option: Learner Perspectives on Learner Handover.

PURPOSE: Learner handover is the sharing of learner-related information between supervisors involved in their education. The practice allows learners to build upon previous assessments and can support the growth-oriented focus of competency-based medical education. However, learner handover also carries the risk of biasing future assessments and breaching learner confidentiality. Little is known about learner handover's educational impact, and what is known is largely informed by faculty and institutional perspectives. The purpose of this study was to explore learner handover from the learner perspective. METHOD: Constructivist grounded theory was used to explore learners' perspectives and beliefs around learner handover. Twenty-nine semistructured interviews were completed with medical students and residents from the University of Ottawa and University of California, San Francisco. Interviews took place between April and December 2020. Using the constant comparative approach, themes were identified through an iterative process. RESULTS: Learners were generally unaware of specific learner handover practices, although most recognized circumstances where both formal and informal handovers may occur. Learners appreciated the potential for learner handover to tailor education, guide entrustment and supervision decisions, and support patient safety, but worried about its potential to bias future assessments and breach confidentiality. Furthermore, learners were concerned that information-sharing may be more akin to gossip rather than focused on their educational needs and feared unfair scrutiny and irreversible long-term career consequences from one shared mediocre performance. Altogether, these concerns fueled an overwhelming pressure to perform. CONCLUSIONS: While learners recognized the rationale for learner handover, they feared the possible inadvertent short- and long-term impact on their training and future careers. Designing policies that support transparency and build awareness around learner handover may mitigate unintended consequences that can threaten learning and the learner-supervisor relationship, ensuring learner handover benefits the learner as intended.

Thrombin generation, bleeding and hemostasis in humans: Protocol for a scoping review of the literature.

INTRODUCTION: Hemostasis and bleeding are difficult to measure. Thrombin generation assays (TGAs) can measure both procoagulant and anticoagulant contributions to coagulation. TGAs might prove useful for the study of bleeding disorders. There has been much progress in TGA methodology over the past two decades, but its clinical significance is uncertain. We will undertake a scoping review of the literature to synthesize available information on the application of TGAs towards the study of bleeding and hemostasis, TGA methodologies being used and to summarize available literature on associations between TGA parameters, bleeding and hemostatic outcomes. METHODS AND ANALYSIS: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched in collaboration with an information specialist. Title/abstract and full-text screening will be carried out independently and in duplicate; eligible study types will include randomized controlled trials, non-randomized studies, systematic reviews, and case series reporting TGA results and bleeding/hemostatic outcomes among humans. Mapping the information identified will be carried out with results presented using qualitative data analytical techniques. ETHICS AND DISSEMINATION: This scoping review will use published, publicly available information. Research ethics approval will not be required. We will disseminate our findings using conference presentations, peer-reviewed publications, social media, and engagement with knowledge users. This review will outline knowledge gaps concerning TGAs, better delineate its applicability as a clinically relevant assay for bleeding. and seek to identify ongoing barriers to its widespread adoption in clinical research, and eventually, in the clinical setting. TRAIL REGULATIONS: Registration ID with Open Science Framework: osf.io/zp4ge.

Knowledge gaps in bleeding disorders: Results from an objective structured oral examination in internal medicine residency training.

BACKGROUND: Empirical evidence for physicians' knowledge gaps in bleeding disorders is limited to self-reported surveys, yet often cited as a leading cause of diagnostic and management delays. OBJECTIVES: Our aim was to assess internal medicine (IM) residents' competence, based on their training level, in evaluating a patient with a bleeding disorder, and knowledge gaps in their clinical approach. METHODS: Content experts developed patient case presenting with abnormal bleeding, bruising, and an isolated prolonged PTT. We administered the hemostasis case as part of an objective structured clinical examination (OSCE). We performed a descriptive analysis. One-way anova was conducted to compare the effect of training level on performance. Item difficulty level for the hemostasis case was also determined. RESULTS: Sixty-seven IM residents participated in the OSCE. The hemostasis case had the highest failure rate at 41.8% with a mean score for the station of 57.96% (SD 13.04). Senior residents scored significantly higher than junior residents on this case (F(2,64) = 4.604, p = .014, ηp2  = 0.126). The item difficulty analysis demonstrated challenges in in eliciting a history of bleeding provoked by challenges, examining the bleeding site, interpreting the mixing study, requesting appropriate follow-up tests, making the diagnosis and providing acute management for a bleeding patient. Only 49.3% of residents requested a hematology consultation. CONCLUSIONS: We demonstrated important knowledge gaps in IM residents' approach to the bleeding patient. Innovative strategies for hemostasis education should be a priority to address physician-related factors in the diagnostic and management delays of patients with bleeding disorders.

A Faculty Development Workshop for Planning and Implementing Interactive Virtual Case-Based Teaching.

Introduction: The virtual learning environment has become increasingly important due to physical distance requirements put in place during the COVID-19 pandemic. The transition to a virtual format has been challenging for case-based teaching sessions, which involve substantial audience participation. We developed a faculty development workshop aimed at teaching health professions educators how to use various interactive virtual tools within videoconferencing platforms to facilitate virtual case-based sessions. Methods: Two 90-minute workshops were piloted as a faculty development initiative. The facilitators demonstrated interactive teaching tools that could be used within virtual case-based sessions. Then, participants discussed how to incorporate these tools into case-based teaching sessions of different class sizes in small-group breakout sessions. Participants completed an online survey following each workshop to evaluate the sessions. Results: A total of 18 and 26 subjects participated in the first and second workshops, respectively. Survey response rates were 100% (n = 18) and 65% (n = 17) for the first and second workshops, respectively. Both groups provided overall high ratings and reported that the workshop was clear, organized, and relevant. Participants were more familiar and comfortable with the use of various interactive tools for online teaching. Discussion: Distance online teaching will be increasingly required for an undetermined time. Faculty development efforts are crucial to facilitate effective interactive teaching sessions that engage learners and maximize learning. This virtual teaching workshop is a simple and straightforward way to introduce a more interactive format to virtual case-based teaching in the health professions.

Intrinsic Disorder in Human Proteins Encoded by Core Duplicon Gene Families.

Segmental duplications (i.e., highly homologous DNA fragments greater than 1 kb in length that are present within a genome at more than one site) are typically found in genome regions that are prone to rearrangements. A noticeable fraction of the human genome (∼5%) includes segmental duplications (or duplicons) that are assumed to play a number of vital roles in human evolution, human-specific adaptation, and genomic instability. Despite their importance for crucial events such as synaptogenesis, neuronal migration, and neocortical expansion, these segmental duplications continue to be rather poorly characterized. Of particular interest are the core duplicon gene (CDG) families, which are replicates sharing common "core" DNA among the randomly attached pieces and which expand along single chromosomes and might harbor newly acquired protein domains. Another important feature of proteins encoded by CDG families is their multifunctionality. Although it seems that these proteins might possess many characteristic features of intrinsically disordered proteins, to the best of our knowledge, a systematic investigation of the intrinsic disorder predisposition of the proteins encoded by core duplicon gene families has not been conducted yet. To fill this gap and to determine the degree to which these proteins might be affected by intrinsic disorder, we analyzed a set of human proteins encoded by the members of 10 core duplicon gene families, such as NBPF, RGPD, GUSBP, PMS2P, SPATA31, TRIM51, GOLGA8, NPIP, TBC1D3, and LRRC37. Our analysis revealed that the vast majority of these proteins are highly disordered, with their disordered regions often being utilized as means for the protein-protein interactions and/or targeted for numerous posttranslational modifications of different nature.