The International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) is widely used to screen for inherited bleeding disorders. Adult reference ranges are age- and sex-specific. However, a single reference range (0-2) is currently applied to all individuals under 18 years. Adolescent developmental changes and global differences in healthcare access may influence bleeding scores, necessitating validation in a large international pediatric cohort. We aimed to evaluate age- and sex-specific ranges for ISTH-BAT scores in individuals <18 years using an international dataset. Under the auspices of 2 ISTH Scientific Subcommittees, healthy participants <18 years were recruited from 7 countries across 5 continents. ISTH-BAT assessments were completed by trained investigators using a standard protocol. Participants were stratified by age quartile, sex, country, and World Bank income. Reference ranges were defined using the 2.5th to 97.5th percentile and assessed with 95% CIs. A total of 1168 participants were included (mean age ± SD, 7.7 ± 5.2 years; 50.5% female). The overall ISTH-BAT score reference range was 0 to 2. The overall distribution of scores across age quartiles was not statistically significantly different (P = .065). A significant positive trend in the proportion of participants with scores >0 was observed across increasing age quartiles (linear-by-linear association χ² = 47.3; P < .001). Females -more often than males- had a bleeding score > 0 (P = .02), with significant sex differences observed only in quartile 4 (P = .003). The 2.5th to 97.5th percentile for quartile 4 females was 0 to 3. Scores varied by country and income classification (P ≤ .001), but reference ranges remained stable. We conclude that the ISTH-BAT reference range of 0 to 2 is appropriate for individuals <18 years. For females (12-17 years), 0 to 3 may be considered and interpreted in conjunction with clinical context when guiding referral decisions.

The impact of hemophilia in affected women and girls is insufficiently recognized, resulting in suboptimal evaluation of bleeding symptoms, delay in diagnosis, and missed management opportunities. The aim of this collaborative International Society on Thrombosis and Haemostasis (ISTH) Scientific Subcommittee on Pediatric and Neonatal Thrombosis and Haemostasis, Factor (F)VIII, FIX, and Rare Coagulation Disorders, and Women’s Health Issues in Thrombosis and Haemostasis project is to provide guidance recommendations regarding screening and diagnosis of hemophilia carriers (HC)/women and girls with hemophilia (WGwH) in addition to the previously published revised nomenclature by the Scientific Subcommittee of the ISTH. We provide several guidance recommendations regarding the nomenclature, utilization of the ISTH-Bleeding Assessment Tool as a tool to quantify bleeding phenotype, FVIII/FIX assays for testing, assay discrepancy, genetic testing, and testing during pregnancy and postpartum, to help guide hemophilia providers to streamline the screening and diagnosis of HC/WGwH in a uniform manner. We hope that once the screening and diagnosis of HC/WGwH become a uniform standard practice globally, this will pave the way for global harmonization of terminologies and improved management, bringing gender equity in hemophilia care a step forward.

Background Up to 30% of reproductive-aged women seek medical attention for heavy menstrual bleeding (HMB). Estrogen-containing contraceptives and antifibrinolytics are first-line treatments. Despite evidence for these agents for HMB and for antifibrinolytics in other high-estrogen states (eg, postpartum), many antifibrinolytic monographs warn against use with concurrent estrogen-containing contraception given theoretical thromboembolic risk. Objectives This study aimed to systematically evaluate the literature that explores the combined effect of pharmacologic or high physiologic estrogen and antifibrinolytic agents on thromboembolic risk in women of reproductive age when used for heavy menstrual or postpartum bleeding. Methods A systematic literature search was performed of records until April 2023. Publications written in English describing risk or reported cases of thromboembolism in reproductive-age women prescribed antifibrinolytics with estrogen-containing contraceptives or with a physiologic estrogenic state were included. Results We identified 4302 publications; 55 publications with 199 228 participants were included. Two case reports and one case series described thromboembolism with concomitant estrogen-containing contraceptives and antifibrinolytic use. Four of 5 patients in the case series had other thrombotic risk factors. Fifty-two publications investigated antifibrinolytic use postpartum. Four RCTs of postpartum antifibrinolytic use assessed thromboembolism as a secondary outcome, none of which reported increased risk with antifibrinolytics. One case report suggested possible thrombotic risk wherein the patient had other provoking risk factors. Conclusion We found no strong evidence that intermittent antifibrinolytic use in physiologic estrogenic states is associated with increased reported cases or risk of thromboembolic events. Prospective studies are warranted to assess the thrombotic risk of combined estrogen-containing contraceptives and antifibrinolytics.

Neuraxial anesthesia is used for pain management in surgical and nonsurgical settings. Spinal/epidural hematomas likely occur in between 1:10 000 and 1:200 000 procedures. Risk is believed to be greater in patients with bleeding disorders/thrombocytopenia, and there are no existing comprehensive recommendations to guide neuraxial anesthesia in these patients. The study’s objective was to develop recommendations to advise clinicians on treatment thresholds for neuraxial anesthesia in patients with platelet disorders/coagulation defects. A 4-round electronic modified Delphi consensus study was conducted. A steering committee generated the original Delphi statements and refined them based on panelist feedback. Consensus was achieved if ≥70% of participants agreed/strongly agreed or disagreed/strongly disagreed with a statement. This project was endorsed by the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on von Willebrand Factor. Forty-five experts participated (42% response rate) with an essentially equal number of hematologists and anesthesiologists. Thirty consensus statements were developed for 11 disorders ranging from various causes of thrombocytopenia, inherited platelet function disorders, and single or multiple coagulation defects in obstetrical and nonobstetrical patients. Risk of sampling bias is present due to a predominantly North American sample, attrition (common in Delphi studies), and steering committee participation in the Delphi rounds. This is the first set of consensus recommendations for neuraxial anesthesia in adult patients with an array of platelet disorders/coagulation defects. These recommendations, based on the best available evidence and expert opinion, provide a decision framework for clinicians when faced with this challenging scenario.

Abstract: Inherited bleeding disorders are a heterogenous group of conditions characterized by the presence of abnormal bleeding. Currently, the diagnostic odyssey for patients with a suspected bleeding disorder is lengthy, costly, resource intensive, emotionally draining, and often futile, because up to half of patients will remain without a clear diagnosis. Genetic testing has been suggested as a possible remedy for these diagnostic challenges and is increasingly incorporated into clinical care. In this review, we outline 3 factors that contributed to the translation of genetic advances into improved diagnostic outcomes. These include the early success experienced with hemophilia, advances in genetic sequencing technology, and significant investment by the hemostasis scientific community. We also identify 3 areas for improvement to facilitate ongoing translation, highlighting the need to optimize integration of genetic and genomic testing into diagnostic pathways and improve variant classification through ongoing research and curation efforts, and reconsider whether incidental and secondary findings represent a disadvantage or an opportunity.

ABSTRACT:von Willebrand disease (VWD) is the most common inherited bleeding disorder, resulting from a deficiency and/or dysfunction of von Willebrand factor (VWF). Since its first description 100 years ago, the diagnosis of VWD has evolved due to advancements in laboratory diagnostic tests and clinical guidelines and recommendations. There are 3 established diagnostic criteria for VWD: a personal history of excessive mucocutaneous bleeding, a family history of bleeding, and reduced VWF levels. Over the years, the diagnosis of VWD has been challenging, due to a lack of consensus and barriers to achieving an accurate and timely diagnosis. In 2021 evidence-based clinical practice guidelines were developed. These guidelines have provided clarity and consensus but there continues to be opposing views and challenges. Additionally, there remain barriers to achieving a diagnosis of VWD that need to be addressed.

Background and Clinical Significance: Acquired hemophilia A (AHA) and acquired von Willebrand syndrome (AVWS) are rare bleeding disorders that do not often present concurrently. Here, we report a coexisting AHA and AVWS case due to underlying autoantibodies to factor VIII (FVIII) and von Willebrand factor (VWF). Case Presentation: A patient with gastrointestinal bleeding and prolonged aPTT was diagnosed with AHA and AVWS. The patient was started on immunosuppression with prednisone, cyclophosphamide, and intravenous immunoglobulin, alongside recombinant porcine FVIII replacement, susoctocog alfa. AVWS reduced the half-life of susoctocog alfa, requiring more frequent dosing and laboratory monitoring until AVWS resolved. The patient had two further relapses; the most recent was treated with Rituximab, following which remission has been maintained. Conclusions: Given the potential therapeutic implications, VWF testing should be considered as part of the diagnostic workup for AHA.

ABSTRACT:Previous reports have highlighted that some patients with low von Willebrand factor (VWF) with significant bleeding were diagnosed based on an isolated but persistent reduction in plasma VWF activity levels in the 30 to 50 IU/dL range. These patients had plasma VWF antigen (VWF:Ag) levels >50 IU/dL and thus had qualitative low VWF (low VWF-QL) rather than quantitative low VWF. Although the clinical importance of functional VWF defects in type 2 von Willebrand disease (VWD) is well recognized, the translational implications of mild functional defects in patients with low VWF-QL have not been defined. To address this clinically important question, we combined low VWF data sets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for ∼50% of our combined low VWF cohort. Importantly, our findings demonstrated that many of these patients with mild isolated functional VWF defects in the 30 to 50 IU/dL range had significant bleeding phenotypes, although their plasma VWF:Ag levels were within the normal range. In addition, we further showed that low VWF-QL is a distinct clinicopathological entity compared to type 2 VWD. Finally, our studies highlighted that low VWF-QL is predominantly caused by abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.

BACKGROUND:Studies on pulmonary embolism (PE) rule-out strategies traditionally recruited patients in the ED. This method is increasingly impractical given excessive pressures experienced in EDs. Attempting to reach patients after leaving the ED may be more feasible. The aim of this study was to assess the feasibility of recruiting and following patients for an ED PE testing study by telephone. METHODS:This was a prospective pilot study conducted in one ED and one urgent care centre in Ontario, Canada. Adult patients tested for PE using Adjust-Unlikely (a simple decision rule combining Gestalt with age-adjusted D-dimer) were called for consent after leaving the ED. Patients were followed for 90 days by medical record review plus telephone, text or email to identify subsequent venous thromboembolism testing. Venous thromboembolism events were independently adjudicated. Feasibility outcomes were recruitment rate, missed eligible rate and follow-up rate. Progression criteria were a recruitment rate of at least five participants per site, per week, a missed eligible rate of no more than two patients per site, per week, and a follow-up rate of at least 90% of enrolled patients. RESULTS:684 patients were tested for PE between 24 March and 10 June 2023. A total of 210 patients were excluded. From 474 eligible patients, 200 were recruited. Median age was 58 years, 72.2% were female, and 3.5% were diagnosed with PE on index visit. Median recruitment rate was 7 participants per site, per week (first-third quartile (Q1-Q3), 4-14) and median missed eligible rate was 6 patients per site, per week (Q1-Q3, 3-8). After 90 days, 2 participants withdrew and 191/198 (96.5%, 95% CI 92.9, 98.3%) were contacted in follow-up. 143/198 (72.2%, 95% CI 65.6, 78.0%) participants did not require pulmonary imaging because PE was excluded by Adjust-Unlikely. 1/143 (0.7%, 95% CI 0.1, 3.9%) of these participants was diagnosed with PE in the segmental pulmonary arteries during follow-up. CONCLUSIONS:Telephone recruitment did not meet predefined feasibility thresholds as the missed eligible rate was high. However, the recruitment rate was higher than in previous studies, and there was minimal loss to follow-up.

Background: While bleeding around pregnancy is well described in von Willebrand disease (VWD), the risk of pregnancy loss is less certain. Objectives: We aimed to describe the frequency of pregnancy loss in females with VWD compared with those with a similar mucocutaneous bleeding phenotype and no VWD or compared with nonbleeding disorder controls. Methods: Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014 and 2023. The VWD group was defined as having von Willebrand factor (VWF) antigen and VWF activity levels, each <0.50 IU/mL on >= 2 occasions, and a condensed MCMDM-1 score of >= 4. The non-VWD mucocutaneous bleeding disorder group had VWF levels >= 0.50 IU/mL on >= 2 occasions and an MCMDM-1 score >= 4. A nonbleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic. Results: There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with >= 1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%; 82/145; -11.2%; 97.5% CI, -24.2%, 1.8%), and the nonbleeding disorder control group (37.2%; 51/137; 8.1%; 97.5% CI, -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group vs the non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared with the literature. Conclusion: There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and nonbleeding disorder controls.

In many patients referred with signi ficant bleeding phenotype, laboratory testing fails to de fine any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses signi ficant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a signi ficant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical signi ficance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.

INTRODUCTION:Treatment options are expanding for von Willebrand disease (VWD). A core outcome set (COS)-a minimum set of agreed-upon outcomes to be used in every clinical trial for a given condition-provides guidance on which outcomes are most important to measure to ensure necessary data is collected for a variety of stakeholders and enable comparison across products and trials. AIM:coreVWD aimed to develop a COS for trials for prophylaxis and perioperative treatments for VWD. METHODS:A modified Delphi consensus process was used to condense/prioritize a long list of potential outcomes. Over three Delphi rounds, a multi-stakeholder panel (patients, clinicians, pharmaceutical company representatives, HTA organizations, payer, and government organization representatives) rated each outcome from 1 (not important to include in a COS) to 9 (essential to include). Outcomes were eliminated or retained based on pre-determined criteria; a special provision to elevate patient priorities was included. An in-person consensus meeting was held after Delphi round 2. RESULTS:Thirty-nine panellists participated. The final COS for prophylaxis treatment included 18 outcomes, seven of which are part of a special subset selected for women, girls and people with the potential to menstruate. There were 11 outcomes in the final perioperative branch COS. Six outcomes overlapped both COS. CONCLUSIONS:The coreVWD COS represents a consensus list of outcomes for clinical trials for both factor and non-factor VWD therapies. These outcomes will be useful across the lifecycle of a product, from clinical development through regulatory and market access phases and into patient-provider decision-making.

INTRODUCTION:It is widely acknowledged that haemophilia affects women and girls, yet current testing recommendations for factor level and genetic testing vary and do not universally incorporate updated research. Canadian parents have expressed frustration at inconsistent recommendations and reported instances where delayed testing led to missed diagnosis and preventable bleeding. AIM:Study aim was to explore and describe the practice of haemophilia-related testing of young girls in Canada. METHODS:A mixed methods study was carried out with two populations: (1) Nurses working in haemophilia care completed a survey regarding the current testing recommendations of their Haemophilia Treatment Centre (HTC), (2) Parents of obligate or potential haemophilia carriers completed a structured interview with questions about their family experience of haemophilia and testing decisions for daughters. RESULTS:Twenty-six survey responses were received and showed wide variation in the usual recommendations of Canadian HTCs. Different factor level testing recommendations may be given to obligate and potential carriers despite no difference in bleeding risk. Only a minority of HTCs currently recommend an early baseline factor level (< 10 years) to obligate carriers (27%) or potential carriers (15%). For genetic testing of potential carriers, 70% of HTC would approve a family request for genetic testing of a minor with specific conditions. The majority of parents interviewed felt dissatisfied with their testing experience (58%) and highlighted many issues related to delayed testing recommendations. CONCLUSION:Updated, nationally affirmed testing recommendations are needed that align with research on bleeding in women and girls affected by haemophilia.

The history of hemophilia is well documented, yet reports focus heavily on the male perspective and severe forms of the disease. Although hemophilia was initially believed to only affect men with women seen as silent carriers, it is now universally acknowledged that women and girls can also be affected. In this narrative review, we tracked the progression of beliefs about women and hemophilia as documented in the literature from pre-1800s to the present time. We present a timeline of evolving beliefs and testing practices and identified 9 distinct time periods when key shifts occurred related to various scientific discoveries. Our review highlights how women affected by hemophilia experienced complete dismissal of their health issues despite evidence of bleeding symptoms as early as the 1900s. We identified 1990 as a major timepoint for shifting beliefs when large scale acknowledgment that hemophilia also affects women is documented and systematic testing for bleeding risk is first suggested. Women evolve from being seen as unaffected genetic transmitters only, to being recognized as a population affected by hemophilia in unique ways requiring timely testing and effective treatment. Yet, despite this clear progress, recent publications continue to document many persistent issues such as delayed diagnosis, untreated symptoms, and barriers to care. Ongoing research and advocacy efforts are required to improve knowledge translation until real-world outcomes are seen in screening, diagnosis, treatment, and prevention of bleeding.

BACKGROUND:Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with an individual's quality of life. Many individuals with HMB are inadequately managed by health care providers. OBJECTIVES:This systematic review aims to provide a comprehensive summary of the etiologies and diagnosis of HMB while calculating the prevalence of underlying causes among premenopausal patients and quantifying the test accuracy of diagnostic strategies. METHODS:MEDLINE, EMBASE, the Cochrane Library, and Web of Science were searched since inception to include studies investigating the prevalence of underlying etiology and diagnostic accuracy of investigations for HMB. The primary outcome was the prevalence of the causes of HMB, secondary outcome included the prevalence of etiology by age. Meta-analyses were conducted via random-effects model. RESULTS:In total, 53 studies were included. Forty-five studies included data on the prevalence of underlying HMB etiology, totaling 41 541 patients. The overall prevalence of bleeding disorders was 30% (95% CI, 14-46); von Willebrand disease, 8% (95% CI, 7-10); platelet function defect, 9% (95% CI, 7-12); abnormal thyroid, 3% (95% CI, 0-6); and polycystic ovarian syndrome, 8% (95% CI, 4-12). Subgroup analysis showed bleeding disorders were prevalent in 16% (95% CI, -8 to 41) of adults with HMB but in 39% (95% CI 18-60) of adolescents with HMB. CONCLUSION:Many diagnoses were associated with bleeding disorders and, therefore, warrant investigation when assessing a patient with HMB of unknown etiology. The causes are likely age dependent and should be considered when diagnosing HMB.

There is signi fi cant ongoing debate regarding type 1 von Willebrand disease (VWD) de fi ntion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with signi fi cant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age ( beta = 0.00; 95% con fi dence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our fi ndings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classi fi cation criteria.