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BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

Background: Depression and anxiety are associated with poor health-related quality of life (HRQoL), lower functioning and decreased treatment adherence. In 2019, 7% adults in the US had moderate/severe symptoms of depression, while Disclosures Roberts: Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding. Kulkarni: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sidonio: Bayer: Consultancy; Catalyst: Consultancy; Genentech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Biomarin: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding. Carpenter: Genentech: Honoraria; Novo Nordisk: Honoraria; Kedrion Pharmaceuticals: Honoraria; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

Prior studies report a greater incidence of second primary malignancy (SPM) among patients with myeloproliferative neoplasms, although the true risk in primary myelofibrosis (PMF) has not been elucidated. We utilized the Surveillance, Epidemiology, and End Results database to evaluate the risk of SPM in PMF patients and analyzed the effects of sociodemographic factors on the risk of SPM. Out of 5273 patients, 385 patients (7.30%) developed SPM. SPM occurred at SIR of 1.95 (95% CI 1.76-2.15) and AER of 149.01 per 10,000 population. A significantly higher incidence of melanoma (SIR 1.76, 95% CI 1.01-2.86), lymphoma (SIR 3.38, 95% CI 2.28-4.83), and leukemia (SIR 27.19, 95% CI 23.09-31.81) was observed. The risk was significantly higher in patients ≤60 years, males, chemotherapy recipients, within 5 years of PMF diagnosis, and for PMF diagnosed after 2009.

von Willebrand disease (VWD) disproportionately affects women because of the potential for heavy menstrual bleeding (HMB), delivery complications, and postpartum hemorrhage (PPH). To systematically synthesize the evidence regarding first-line management of HMB, treatment of women requiring or desiring neuraxial analgesia, and management of PPH. We searched Medline and EMBASE through October 2019 for randomized trials, comparative observational studies, and case series comparing the effects of desmopressin, hormonal therapy, and tranexamic acid (TxA) on HMB; comparing different von Willebrand factor (VWF) levels in women with VWD who were undergoing labor and receiving neuraxial anesthesia; and measuring the effects of TxA on PPH. We conducted duplicate study selection, data abstraction, and appraisal of risk of bias. Whenever possible, we conducted meta-analyses. We assessed the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We included 1 randomized trial, 3 comparative observational studies, and 10 case series. Moderate-certainty evidence showed that desmopressin resulted in a smaller reduction of menstrual blood loss (difference in mean change from baseline, 41.6 [95% confidence interval, 16.6-63.6] points in a pictorial blood assessment chart score) as compared with TxA. There was very-low-certainty evidence about how first-line treatments compare against each other, the effects of different VWF levels in women receiving neuraxial anesthesia, and the effects of postpartum administration of TxA. Most of the evidence relevant to the gynecologic and obstetric management of women with VWD addressed by most guidelines is very low quality. Future studies that address research priorities will be key when updating such guidelines.

Key Points HMB is associated with rare and common variants in genes related to anemias and bleeding disorders.These are the first exome-sequencing results from patients with HMB, as well as their comparison with control exomes., Visual Abstract, Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar “pathogenic” variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar “pathogenic” variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10−6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Background The management of pregnant women with von Willebrand Disease (VWD) is complex as physiological pregnancy-induced increases in plasma von Willebrand Factor (VWF) may be blunted or absent. Women with VWD experience a heightened risk of postpartum haemorrhage (PPH) and special consideration must be given regarding neuraxial anaesthesia (NA) and the need for prophylaxis at time of delivery. These challenges are compounded by a lack of robust evidence to guide clinical decision making. Objectives & Methods To determine the current international clinical practises in the management of pregnancy for women with VWD, the International Society on Thrombosis and Haemostasis (ISTH) conducted an international survey of healthcare providers (HCP). Results 132 respondents from 39 countries were included in the final analysis. Variations in clinical practise were identified in antenatal (monitoring of plasma VWF and ferritin levels), peripartum (optimal plasma VWF target at delivery) and postpartum management (definitions used for PPH and postpartum monitoring). A key area of divergence was suitability for NA for women with type 2 and type 3 VWD, with many respondents advising against the use of NA even with VWF supplementation (29% type 2 VWD, 37% type 3 VWD) but others advising use once plasma VWF activity was was >50 IU/dL (57% type 2 VWD; 50% type 3 VWD). Conclusions This survey highlighted areas of uncertainty surrounding common management issues for pregnant women with VWD. These data underscore the need for international collaborative research efforts focused on peripartum management to improve care for pregnant women with VWD.

Hemophilia A and B predominantly attracts clinical attention in males due to X‐linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients. Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD. Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 12 recommendations and outlined future research priorities. Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.

Background Bleeding disorders (BD) are under-recognized in adolescents with heavy menstrual bleeding (HMB). Objectives The lack of clinical guidelines and variable symptomatic management of HMB created the imperative to standardize HMB care to identify and manage BD in adolescents. Methods We convened an international working group (WG), utilized the results of a literature review to define knowledge gaps in HMB care, and used the collective clinical experience of the WG to develop care considerations for adolescents with BD and HMB. We then solicited input on the appropriateness of HMB care considerations from expert stakeholders representing hematology, adolescent medicine, and obstetrics-gynecology. We conducted an expert panel online, using the ExpertLens platform. During a 3-round online modified-Delphi process, the expert panel rated the appropriateness of 21 care considerations using a 9-point scale to designate care as appropriate (7-9), uncertain (4-6), or inappropriate (1-3) covering screening for BD, the laboratory work-up, and management of adolescents with BD that present with HMB. We used the RAND/UCLA appropriateness method to determine the existence of consensus among the interdisciplinary panel of experts. Results Thirty-nine experts participated in the panel. The experts rated fifteen HMB care considerations as appropriate, six as uncertain, and none as inappropriate. Conclusions The HMB care statements represent the first set of HMB care considerations in adolescents with BD, developed with broad expert input on appropriateness. Although likely to be of interest to a range of clinicians who routinely manage adolescents with HMB, additional research is required in many key areas.

Increased awareness of von Willebrand Disease (VWD) has led to more frequent diagnostic laboratory testing, which insurers often dictate be performed at a facility with off-site laboratory processing, instead of a coagulation facility with onsite processing. Off-site processing is more prone to preanalytical variables causing falsely low levels of von Willebrand Factor (VWF) due to the additional transport required. Our aim was to determine the percentage of discordance between off-site and onsite specimen processing for VWD in this multicenter, retrospective study. We enrolled females aged 12 to 50 years who had off-site specimen processing for VWF assays, and repeat testing performed at a consulting institution with onsite coagulation phlebotomy and processing. A total of 263 females from 17 institutions were included in the analysis. There were 251 subjects with both off-site and onsite VWF antigen (VWF:Ag) processing with 96 (38IU/dL) being low off-site and 56 (22IU/dL) low onsite; 223 subjects had VWF ristocetin co-factor (VWF:RCo), 122 (55IU/dL) were low off-site and 71 (32IU/dL) were low onsite. Similarly, 229 subjects had a Factor VIII (FVIII) assay, and 67 (29IU/dL) were low off-site with less than half, 29 (13IU/dL) confirmed low with onsite processing. Higher proportions of patients demonstrated low VWF:Ag, VWF:RCo, and/or FVIII with off-site processing compared to onsite (McNemar's test P-value

The aim of this study is to compare the patient-reported bleeding outcomes and complication rates with the use of the 52-mg levonorgestrel-releasing intrauterine system (52-LNG-IUS) for treatment of heavy menstrual bleeding (HMB) among adolescents with and without a diagnosed inherited bleeding disorder (BD) within the first 12 months after insertion.Retrospective chart review was conducted of adolescents ages 14-21 years, with and without an inherited BD, who underwent 52-LNG-IUS insertion between September 2013 and February 2020 for the treatment of HMB.One hundred forty-four 52-LNG-IUS insertions among 139 subjects were evaluated. Fifty-nine (41%) of these were among adolescents with a diagnosed inherited BD, and 85 (59%) were among those without a BD. Among subjects with follow-up, documentation of patient-reported bleeding outcome, and a retained IUS (92/144), both groups subjectively reported improvement in bleeding outcome, with 91.7% (33/36) of those with a BD and 94.6% (53/56) of those without a BD reporting that bleeding outcome was better than prior to IUS insertion (p = .675). There was no statistically significant difference in the rate of spontaneous expulsion (p = .233), with the rate of expulsion in the first 12 months after placement among those with a BD of 13.7% (7/51) and 6.8% for those without a BD (5/72).Adolescents with HMB both with and without an inherited BD benefit from the 52-LNG-IUS for the treatment of HMB. Rates of spontaneous IUS expulsion are not statistically different regardless of the presence of a BD and are similar to rates found in other studies of intrauterine device use in adolescents.

Purpose of review To summarize the recent literature related to female hemophilia A carriers with respect to prevalence in the population, the impact of baseline factor VIII levels and other influences on bleeding phenotype, and clinical management needs. Recent findings Many female hemophilia A carriers are at risk for abnormal bleeding, yet they are underrecognized by healthcare providers and their bleeding symptoms are underreported. Low FVIII levels are consistently associated with clinically significant bleeding and correlate well with skewed X chromosome inactivation (XCI). Most interestingly, bleeding tendency is also observed in some hemophilia A carriers with normal factor VIII levels and requires further investigation. Well controlled studies investigating peripartum and periprocedural FVIII levels and adequate hemostatic treatment are necessary to inform management guidelines. Summary Prevalence and bleeding tendency of hemophilia A carriers remain underreported, despite a significant proportion having low FVIII levels. Skewed XCI may explain low FVIII but does not explain the bleeding risk encountered in a larger proportion of hemophilia A carriers with random XCI and borderline/normal FVIII.

Although rare clotting factor deficiencies primarily referred to as rare bleeding disorders (RBD), including factors II, V, VII, and X, make up ∼5% of all inherited bleeding disorders worldwide, each of these clotting factors play a critical role in the coagulation cascade. Incomplete bleeding evaluation or misinterpretation of laboratory studies can result in delayed diagnoses that ultimately affect patient outcomes. Bleeding manifestations can range from mild to severe, but the most common are mucocutaneous bleeding. The ideal treatment in RBD is dedicated single-factor concentrates that can be used for acute bleeding events, surgical management, and prophylaxis.

Heavy menstrual bleeding is common in adolescents. The frequency and predictors of bleeding disorders in adolescents, especially with anovulatory bleeding, are unknown. Adolescents referred for heavy menstrual bleeding underwent an evaluation of menstrual bleeding patterns, and bleeding disorders determined a priori. The primary outcome was the diagnosis of a bleeding disorder. Two groups were compared: anovulatory and ovulatory bleeding. Multivariable logistic regression analysis of baseline characteristics and predictors was performed. Kaplan Meier curves were constructed for the time from the first bleed to bleeding disorder diagnosis. In 200 adolescents, a bleeding disorder was diagnosed in 33% (n=67): low von Willebrand factor levels in 16%, von Willebrand disease in 11%, and qualitative platelet dysfunction in 4.5%. The prevalence of bleeding disorder was similar between ovulatory and anovulatory groups (31% vs. 36%; P=0.45). Predictors of bleeding disorder included: younger age at first bleed (OR: 0.83; 95%CI: 0.73, 0.96), Hispanic ethnicity (OR: 2.48; 95%CI: 1.13, 5.05), non-presentation to emergency department for heavy bleeding (OR: 0.14; 95%CI: 0.05, 0.38), and International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool score ≥4 (OR: 8.27; 95%CI: 2.60, 26.44). Time from onset of the first bleed to diagnosis was two years in the anovulatory, and six years in the ovulatory cohort (log-rank test, P

Both apixaban and rivaroxaban have been approved for use in acute venous thromboembolism (VTE). Although indirect comparison through network meta-analyses of randomized trials have been performed to compare the efficacy and safety of these agents, further comparison between these agents was lacking until recently. We sought to systematically review and carry out a meta-analysis of studies to further compare apixaban with rivaroxaban from multiple studies done in the real-world settings. Studies comparing rivaroxaban with apixaban in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, and the Cochrane library up to May 2019. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 24 041 patients, recurrent VTE within 6 months occurred in 56 of 4897 patients (1.14%) in the apixaban group and 258 of 19 144 patients (1.35%) in the rivaroxaban group (RR, 0.89; 95% confidence interval [CI], 0.67-1.19; P = .45). Clinically relevant major bleeding occurred in 85 of 11 559 patients (0.74%) in the apixaban group and 350 of 33 909 patients (1.03%) in the rivaroxaban group (RR, 0.73; 95% CI, 0.58-0.93; P = .01). Clinically relevant nonmajor bleeding occurred in 169 of 3417 patients (4.95%) in the apixaban group and 1094 of 12 475 patients (8.77%) in the rivaroxaban group (RR, 0.59; 95% CI, 0.50-0.70; P < .01). Apixaban shows equivalent efficacy in prevention of recurrent VTE but decreased risk of major and minor bleeding events compared with rivaroxaban.

Background Randomized clinical trials comparing the efficacy and safety of direct oral anticoagulants (DOAC) with vitamin K antagonist (VKA) or low molecular weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) generally exclude patients who are morbidly obese (body mass index ≥ 40 kg/m2 or weight ≥ 120 kg). Recently, smaller studies have compared DOACs with warfarin or low molecular weight heparin (LMWH) in morbidly obese patients with VTE. We aim to systematically review and do a meta-analysis of the studies that directly compared DOACs with VKAs or LMWH in morbidly obese patients. Methods Studies comparing DOAC with warfarin or LMWH in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, clinicaltrials.gov, and the Cochrane Library up to March 2020. The primary efficacy outcome was recurrent VTE and the primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) guidelines. Study-specific odds ratios (OR) were calculated and combined using a random-effects model meta-analysis. Result Five studies were identified. Recurrent VTE occurred in 95 of 3207 (2.96%) patients in the DOAC group and 81 of 3181 (2.54%) patients in the VKA and LMWH group (OR: 1.17; 95% CI 0.87 to 1.59, p=.30). Major bleeding occurred in 63 of 3316 (1.89%) patients in the DOAC group, and 83 of 3259(2.54%) patients in the VKA or LMWH group (OR: 0.74; 95% CI: 0.53 to 1.03, p=.08). Sensitivity analysis comparing factor Xa inhibitors apixaban and rivaroxaban to warfarin also yielded consistent findings. Conclusion DOACs showed similar efficacy and safety in the prevention of recurrent VTE risk and major bleeding events in morbidly obese patients when compared to warfarin/LMWH. Our study underscores the need for further modifications of therapy to reduce the high VTE recurrence rate irrespective of whether the patient is on a DOAC or VKA. This might be possible through a very large multi-institutional randomized clinical trial.

Introduction Reproductive tract bleeding (RTB) is an important outcome in menstruating females on anticoagulant therapy (AC). The diagnosis and management of AC-RTB in adolescent and young adult (AYA) females is unknown. Aims The aim of this study was to survey the contemporary patterns of diagnosis and management of AC-RTB in AYA females. Methods SurveyMonkey® questions were sent to members of 1) Pediatric and Neonatal Thrombosis Hemostasis Subcommittee and Women's Health Subcommittee of the International Society on Thrombosis and Haemostasis and 2) Hemostasis and Thrombosis Research Society. Results are reported using descriptive statistics. Results Response rate was 33% (251 out of 753). AC-RTB was infrequently reported. Menstrual history was not routinely reviewed prior to initiation of AC. Respondents indicated a differential risk of AC-RTB, most frequently with Rivaroxaban. Respondents continued hormonal therapy (HT) if an AYA female was on it at the start of AC. When AC-RTB occurred, management strategies were variable with initiation of HT or antifibrinolytic therapy being the most frequent. The timing of AC-RTB after the thrombotic event influenced the respondents' choice of therapy. Differences were seen in the management strategies between US and non-US participants, with more US respondents initiating HT while more non-US respondents modifying the AC regimen. Respondents uniformly reported complications with AC-RTB and with its treatment. Conclusion This survey highlights the need to review menstrual history at the start of and during AC and for future research into choosing the optimal AC in AYA females. The results can inform the design of future studies.

Introduction In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning. Aim Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC-treated prevalence and incidence). Methods During the period 2012-2019, de-identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC-treated prevalence by VWD type and sex. Data from patients born 1995-1999 were used to estimate HTC-treated incidence rates. Results During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age-adjusted HTC-treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC-treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3. Conclusion Prevalence and incidence of HTC-treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis.

Study Objective Heavy menstrual bleeding (HMB) may be the sentinel event for identifying a patient with a bleeding disorder (BD). The levonorgestrel intrauterine system (LNG IUS) has been proposed as a treatment for HMB in adolescents with and without BDs; however, no standard protocols for LNG IUS insertion in these populations exist. Providers were surveyed regarding the use of the LNG IUS in adolescents with HMB, with and without BD. Design, Setting, Participants, Interventions, and Main Outcome Measures An institutional review board−approved survey assessing provider attitudes, LNG IUS insertion practices, and patient outcomes in adolescents with HMB, with and without BD, was electronically distributed to 3523 providers in the fields of hematology, adolescent medicine, and obstetrics and gynecology. Descriptive analysis was performed. Results A total of 312 respondents across all 3 specialties completed the survey. Nearly 100% of respondents considered the LNG IUS safe and effective treatment for adolescents with HMB, both with and without BD. Additionally, 66% of providers chose LNG IUS as the ideal treatment for HMB in patients with BD. Differences were noted in clinical setting for LNG IUS insertion, peri-procedural medication use, and post-procedure follow-up among specialties. Providers across all specialties reported low complication rates related to IUS insertion and use in both patient groups. Conclusion Providers considered the LNG IUS safe and effective treatment for HMB in adolescents with and without a diagnosed BD. Practice patterns regarding LNG IUS insertion in this population vary. Further research is necessary to explore IUS outcomes in adolescent patients with HMB, with and without BD, and to inform evidence-based protocols for LNG IUS insertion.

Heavy menstrual bleeding (HMB) can be the first manifestation of an undiagnosed bleeding disorder (BD). Identifying a BD can be challenging in the adolescent age group. The utility of bleeding assessment tools (BAT) remains elusive in this population.We evaluated the ability of the International Society on Thrombosis and Haemostasis-BAT (ISTH-BAT) in predicting a BD in adolescents referred for HMB to a multidisciplinary hematology clinic.Two hundred adolescents with HMB underwent a standardized evaluation for BD. The clinical characteristics, laboratory data, and bleeding scores (BS) assessed using ISTH-BAT were prospectively collected. Comparisons were made between patients based on the diagnosis of BD receiver operating characteristic (ROC) curve analyses of ISTH-BAT were performed to assess its value for predicting BD.Overall, 33% (n = 67) of adolescents were diagnosed with a BD. The mean ISTH-BAT BS was higher in BD as compared to those without (4.1 versus 3.1, P .0001), but the mean menorrhagia-specific scores did not differ (2.9 in both groups). The ISTH-BAT demonstrated a modest discriminative ability as a screening tool to identify BD in girls with HMB with an area under the curve (AUC) of 0.71. The ROC analysis demonstrated that with increasing BS, the sensitivity decreased, but the specificity increased. At BS = 3, sensitivity was 88%, specificity 31%, and accuracy 50%; at BS = 5, sensitivity was 37%, specificity 94%, and accuracy was 75%. There was no change thereafter.In adolescents with HMB, an ISTH-BAT BS of4 instead of the established cut-off of2 in children is highly specific in predicting a BD.

With licensure of extended half-life (EHL) factor products and the changing landscape of available hemophilia products, patients and providers have options for less treatment-intense prophylaxis. The impact of these products in clinical practice to date remains understudied. We aimed to quantify the use of EHL products in prophylaxis in the US using the ATHN-dataset, a database of 145 ATHN-affiliated hemophilia treatment centers (HTCs). Further, we aimed to quantify the impact of EHL on key hemophilia indicators including annualized bleed rates (ABRs), hemophilia joint health scores (HJHS) and quality of life (QOL) metrics. The use of EHL vs standard half-life (SHL) products in severe hemophilia was compared between June 2018 and March 2019 using the ATHN-dataset. A cohort of patients was also recruited from seven participating HTCs in order to compare ABR, HJHS and QOL between product classes. By March 2019 the number of individuals with severe Hemophilia A (SHA) receiving EHLs remained relatively stable (28.4%), whereas the number of prescribed non-factor products increased to 7.1%, with a diminishing majority of patients (64.0%) continuing to receive SHLs. The majority of patients with severe hemophilia B (SHB) received treatment with EHLs including 57.5% by March 2019. There was a trend toward lower ABR with use of EHLs in SHA and SHB, although this did not result in improved HJHS nor QOL. EHL use in the United States in severe hemophilia continues to increase, although at a slower rate in SHA with the availability of non-factor therapy. The impact of the EHL therapies in clinical practice should continue to be examined prospectively.

Adolescent pregnancies are a global problem affecting all incomes with variable rates across regions. According to the World Health Organization, approximately 12 million girls aged 15–19 years and at least 777,000 girls under 15 years give birth each year in developing regions. Knowing that complications during pregnancy and childbirth are the leading cause of death for 15–19-year-old girls globally. These complications include in addition to preeclampsia, infections, preterm delivery and neonatal conditions, bleeding, and clotting consequences. While management of bleeding in pregnant adolescents is difficult, a multidisciplinary early approach is highly recommended.

Adolescent pregnancy is a significant global health concern, with more than 21 million girls aged 15–19 and two million under age 15 becoming pregnant each year in developing countries. Pregnancy occurs in approximately 13% of the US adolescent population and 25% of the world adolescent population. The physical effects of pregnancy on adolescents are significant. Pregnancy and complications related to childbirth are the leading cause of death for adolescent girls aged 15–19 worldwide. Adolescents with preexisting hematologic disorders of thrombosis or coagulation, like their adult counterparts, are at increased risk of adverse maternal and fetal outcome during pregnancy and in the postpartum period. In this chapter, we review physiology of thrombosis in pregnancy and clinical considerations for diagnosis and management of pregnant adolescents with hematologic disorders.

Background Anticoagulated patients are particularly vulnerable to ADEs when they experience changes in medical acuity, pharmacotherapy, or care setting, and resources guiding care transitions are lacking. The New York State Anticoagulation Coalition convened a task force to develop a consensus list of requisite data elements (RDEs) that should accompany all anticoagulated patients undergoing care transitions. Methods A multidisciplinary panel of 15 anticoagulation experts voluntarily completed an iterative Delphi process. Resources were disseminated and deliberated via remote technology, with consensus achieved via blinded electronic polling. Results The panel reached consensus on a list of 15 RDEs for anticoagulation communication at discharge (the ACDC List). Consensus was rapidly achieved by the full panel on 13 elements, while 3 (2 of which were combined into 1 element) required multiple iterations and achieved consensus with votes from 8 available panelists. The elements encompassed a range of factors, including drug use and indications, previous exposure and duration of therapy, recent drug exposure and laboratory results and expectations for subsequent administration, therapy goals, patient education and comprehension, and expectations for clinical management. Twelve of the elements are applicable to any anticoagulant, and 3 are specific to warfarin. Conclusion The ACDC List identifies specific pieces of clinical information that a panel of anticoagulant experts agree should be communicated to downstream providers for all anticoagulated patients undergoing care transitions. Additional study is needed to objectively evaluate the ability of existing care systems to communicate the elements and to assess possible relationships between communication of the elements and clinical outcomes.

Background: Bleeding is a major cause of morbidity in patients with continuous flow left ventricular assist devices (LVADs). We sought to identify clinical predictors of bleeding within the first year of LVAD implantation. Methods: A prospective study was performed on 30 patients with HeartMate II implantation at the University of Rochester Medical Center, Rochester, New York, United States. Blood was collected within 1 week before implantation, and at 1, 3, and 30 ± 10 days after implantation. Blood samples were analyzed for prothrombin time (PT), international normalized ratio (INR), von Willebrand factor (vWF) activity, vWF antigen, vWF multimers, collagen binding assay, factor VIII, and epinephrine closure time. The first bleeding event within 1 year of implantation was recorded. Results: There were 17 (57%) patients with a bleeding event. The cumulative incidence of bleeding was 50% at 304 days. Age at the time of LVAD implantation was associated with higher risk of bleeding (hazard ratio (HR) = 1.05, 95% confidence interval (CI) = 1.01–1.10, p = 0.013). Higher baseline INR was also associated with increased risk of bleeding after adjusting for age at the time of implant (HR = 6.58, 95% CI = 1.21–35.70, p = 0.028). The bleeders and non-bleeders had similar hemostatic markers at all four time points. Prior to LVAD, mean epinephrine closure time was similar between bleeders and non-bleeders. However, post LVAD measurement of epinephrine, closure time was frequently limited by platelet clumping. Conclusion: Older age and baseline INR are associated with higher risk of bleeding in LVAD patients. Platelet clumping may suggest underlying platelet dysfunction and associated high risk of bleeding

Introduction It is well established that von Willebrand factor (VWF) levels increase with age among healthy adults. Recently, there is emerging research demonstrating this may also occur in patients with von Willebrand disease (VWD), particularly type 1 VWD, and may be related to comorbidities. Despite increasing VWF levels, it remains unclear as to whether or not this alters bleeding phenotype. It is also unclear why this occurs most commonly in patients with type 1 VWD, but VWF mutation status may play a role. Older patients commonly undergo invasive procedures, and all VWD patients require periprocedural VWD-specific therapy to ensure appropriate hemostasis. If older type 1 VWD patients have experienced normalization of VWF levels, and no longer have an increased risk of bleeding, VWD-specific therapy may increase thrombosis risk, especially among patients with underlying cardiovascular disease or related risk factors, subject the patient to other adverse reactions such as hyponatremia, and is unnecessarily costly. For these reasons, investigation into the effect of age on VWF levels and bleeding risk in type 1 VWD patients is sorely needed. Methods This is an NHLBI-funded K23 multicenter, cross-sectional study to determine the effect of age on VWF levels and bleeding risk in patients with type 1 VWD, and to determine if pathogenic VWF mutations alter this effect.Individuals with a new or historical diagnosis of type 1 VWD (defined as clinical symptoms consistent with VWD and VWF antigen level or ristocetin cofactor activity We hypothesize age is associated with increased VWF:Ag levels and lower condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD, and this association is weaker among those with a pathogenic VWF mutation. In addition, we hypothesize multimorbidity partially explains the association between age and VWF:Ag levels, and VWF:Ag levels partially explain the association between age and condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD. A sample size of 250 participants provides 90% power to detect an effect size of Beta=±0.032 points per year of age, which is much smaller than the observed effect size, Beta=-0.080, from preliminary data. The primary analyses will be based on multivariable linear regression models with adjustment for blood type O, exogenous estrogen therapy, multimorbidity (defined as 2 or more of the core set of 20 chronic conditions, i.e., cancer, hypertension, stroke, etc., as selected by the United States Department of Health and Human Services), and medications (aspirin, nonsteroidal antiinflammatory drugs, and anticoagulants). In the regression models, two-sided t-tests will be used with an alpha=0.05. Results This multicenter, cross-sectional study consists of seven HTCs: Hemophilia Center of Western Pennsylvania, Children's Hospital of Pennsylvania, Mary M. Gooley Hemophilia Center, Ohio State University, Bleeding & Clotting Disorders Institute, Mayo Clinic, and University of California, San Diego. During the first year of the study, site initiation visits were conducted, regulatory approval obtained, and contracts executed. Delays in these activities occurred in large part due to the COVID-19 pandemic. As the first year of the study concludes, all sites are now active and enrolling participants. Thus far, 43 participants have been enrolled (Table 1). No barriers to enrollment have been encountered and very few patients have declined study participation. Discussion In conclusion, this ongoing multicenter, cross-section study seeks to determine the effect age has on VWF levels and bleeding risk in patients with type 1 VWD while exploring the role of VWF mutations and multimorbidity in this process. The results will be used to justify a longitudinal study, which is the ideal approach to research the effects of aging in this population. Figure 1 Figure 1. Disclosures Seaman: Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; HEMA Biologics: Consultancy, Honoraria. Ragni: Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Kraut: Uniqure: Consultancy. Pruthi: CSL Behring: Honoraria; Bayer Healthcare AG: Honoraria; Instrumentation Laboratory: Honoraria; Genentech: Honoraria; HEMA Biologics: Honoraria; Merck: Honoraria. Raffini: CSL Behring: Consultancy; HEMA Biologics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; XaTek: Consultancy. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. von Drygalski: Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa.

Importance Recent studies have documented increased bleeding symptoms and related complications in patients with low von Willebrand factor (VWF), highlighting the clinical significance of this entity. Because children and adolescents with VWF deficiencies often present to primary care physicians with bleeding symptoms, physicians need to be aware of this condition for early detection. Observations Studies have found that children and adolescents with low VWF (VWF levels of 30-50 IU/dL) can present with clinically significant bleeding, including mucosal, menstrual, postsurgical, and posttraumatic bleeding, leading to complications such as anemia, iron deficiency, transfusion, hospitalization, and poor quality of life. Detecting and promptly managing low VWF in children and adolescents with bleeding are essential because failure to do so can lead to significant morbidity in adulthood, especially among female patients, including continued heavy menstrual bleeding; postpartum hemorrhage; related gynecologic complications, such as hemorrhagic ovarian cysts; and surgical interventions for heavy menstrual bleeding, including hysterectomy. This narrative review summarizes the observations of several studies that have shed light on the pathophysiologic mechanisms of low VWF and bleeding in these patients and the available diagnostic modalities and treatment options. Conclusions and relevance Studies in children and adolescents have provided important insights into the clinical phenotype, complications, pathophysiologic mechanisms, evaluation, and management of low VWF, now recognized as an important clinicopathologic entity, as presented in this review. As gatekeepers, primary care physicians play an important role in guiding patients with this recently recognized clinicopathologic entity toward appropriate specialty care and providing continued comanagement to prevent future complications as the patients enter adulthood.

Von Willebrand Factor (VWF) levels are known to increase with age in the general population, but that effect is unclear in von Willebrand disease (VWD) patients. Thus, it is important to assess the trends of VWF levels with age, and the extent and rate of their normalization in patients with VWD. In a retrospective cohort study, we reviewed the medical records of 126 patients between 1996 and 2016 who met the NHLBI diagnostic criteria for type 1 VWD or "Low VWF" (LVWF). We followed all their historically documented VWF antigen (VWF:Ag), VWF activity (VWF:RCo), and Factor VIII (FVIII) levels longitudinally over time, correlating data with clinical setting at time of testing. The average duration of follow-up was 10.5 ± 3.7 years (SD). Out of the total study population, 27.8% achieved the primary outcome of complete normalization (CN) of both VWF:Ag and VWF:RCo levels, including 19.6% and 32.5% of those with VWD and LVWF, respectively. Linear regression demonstrated statistically significant positive trends of VWF:Ag, VWF:RCo, FVIII with time, calculated at 2.4, 1.4, and 1.4 U dL-1/year, respectively (P

BACKGROUND Haemate-P/Humate-P (Humate-P) is a pasteurized human plasma-derived concentrate containing both Factor VIII and von Willebrand factor for treatment of hemophilia A and von Willebrand disease (VWD). STUDY DESIGN AND METHODS We analyzed the safety of Humate-P based on more than 33 years of postmarketing pharmacovigilance data, representing an estimated exposure of approximately 25,000 patient-years. The analysis comprises reports of potential adverse drug reactions (ADRs) from all sources, reported as part of routine pharmacovigilance at CSL Behring. ADRs considered clinically relevant or potential risks of Humate-P were identified based on defined and standardized Medical Dictionary for Regulatory Activities queries. Recognizing the limitations of spontaneous reporting, we also reviewed the literature, including clinical trials with mandatory reporting. RESULTS From 1982 to 2015, a total of 670 postmarketing cases had been reported via pharmacovigilance, for an overall reporting rate of approximately one ADR per 3900 administered standard doses. Of these cases, 343 involved ADRs considered clinically relevant risks (33 thromboembolic complications, 97 inhibitor formation, 110 hypersensitivity or allergic reactions) or potential risks (103 suspected virus transmissions) for Humate-P. Most thromboembolic complications occurred in patients undergoing surgery or with other known risk factors. Inhibitor formation occurred mostly in patients with hemophilia A (24 cases were high titer). Most patients with hypersensitivity or allergic reactions had VWD. None of the reported suspected virus transmission cases were confirmed to be associated with Humate-P. Reported results of company-sponsored studies showed a low incidence of adverse events possibly or probably related to Humate-P. CONCLUSIONS More than 33 years of pharmacovigilance data continue to support the safety of Humate-P.

Background: Recurrent overt or occult gastrointestinal (GI) bleeding is a serious complication of von Willebrand Disease (VWD) and is the most common cause of hospitalization for patients with VWD. Data from the VWD Prophylaxis Network (VPN) emphasized the importance of prophylaxis in minimizing bleeding episodes in VWD; however, the management of GI bleeding in these patients remains challenging. Despite the availability of von Willebrand factor (VWF) replacement therapy, GI bleeding may be refractory and require the use of multiple treatment approaches. Currently, there are limited published data and no consensus regarding the most effective treatment for GI bleeding in patients with VWD. Aims: To describe the natural history of treatment and management of GI bleeds in patients with VWD, stratified by those patients who have a history of GI bleeding that precedes this chart review versus patients who experienced their first GI bleed within the 5 years of this chart review. Outcomes following the use of VWF replacement products and adjuvant therapy, including recombinant VWF were collected. Methods: This ongoing retrospective, multicenter, observational chart review (abstraction initiated 2019) will include up to 20 patients from 6 US centers with confirmed congenital VWD with ≥1 GI bleed within the last 5 years. Demographics and clinical information, including potential etiology, treatment regimens, will be gathered from patient records on all recorded GI bleeds within the last 5 years. Clinical effectiveness will be defined by treatment response, change in duration of treatment, or time to bleed resolution across treatment cohorts (e.g., prophylaxis vs on-demand; recombinant VWF [rVWF] vs plasma-derived VWF [pdVWF]), at the time of a GI bleed and for any subsequent period of prophylactic treatment to prevent GI bleed recurrence. Data will be analyzed descriptively. Results: To date, data on 37 bleeds in 13 patients with Type 1 (23%), Type 2 (46%) or Type 3 (31%) VWD have been abstracted; 54% were female, mean (±SD) age was 53.9 (22.0) years, 85% had ≥1 recorded GI-specific morbidity, 6 patients (46%) had no history of prior GI bleeding. Three patients (23%) were on regular prophylaxis using pdVWF-factor VIII (FVIII) concentrates at initial GI bleed presentation. All were receiving Humate-P; dose was not recorded for 2 patients and 1 patient received 50 IU/kg. Out of 37 bleeding episodes, 9 (24%) occurred in patients during VWF prophylaxis, of which 7 occurred in 1 patient. Among the 7 patients with a previous history of GI bleeding, 1 was on a prophylactic regimen prior to the initial GI bleeding episode. None of the patients without a history of GI bleeding were on a prophylactic regimen at the initiation of the chart review; 1 patient was receiving prophylaxis at the time the fourth bleed was documented. On-demand treatment for GI bleeding included aminocaproic acid, tranexamic acid, pdVWF-FVIII concentrates, rFVIII, rVWF, corticosteroids, polypectomy, and thalidomide. After resolution of the GI bleeding episode, in 17/37 bleeding events, prophylactic treatment continued (either as part of the final treatment regimen to resolve the bleed and sustained prophylaxis, or after the final treatment regimen purely as prophylaxis). At the conclusion of data collection for the current patients, 4 out of 6 without a GI bleeding history, and 1 out of 7 with a GI bleeding history, were receiving prophylaxis. Conclusions: Data from this retrospective chart review are the first to describe prophylactic regimens prior to and after GI bleeding, in VWD patients with and without a GI bleeding history. More patients with congenital VWD and a history of GI bleeding were treated with prophylaxis following GI bleeds, compared to patients without a history of GI bleeds. These data describe the role of prophylaxis in management of GI bleeding and add to existing data from the VPN describing a modest reduction of GI bleeding in some patients on prophylaxis. These data underscore the continuing unmet need of the successful management of GI bleeding in VWD. Further data will be collected, and additional analyses performed to determine if this trend persists in a larger sample of patients with VWD. Disclosures Roberts: uniQure:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy;Novo Nordisk:Consultancy, Speakers Bureau;Sanofi:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau.Escobar:National Hemophilia Foundation:Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.:Consultancy, Membership on an entity's Board of Directors or advisory committees;Novo Nordisk:Consultancy, Membership on an entity's Board of Directors or advisory committees.Acharya:Novonordisk, BPL:Membership on an entity's Board of Directors or advisory committees.Hwang:Takeda:Honoraria;Shire:Honoraria.Wang:Bioverativ Inc:Honoraria;CSL Behring:Honoraria;Biomarin:Honoraria;Genentech:Honoraria;Takeda:Honoraria;Bayer:Honoraria.Hale:Takeda Pharmaceutical Company Limited:Current Employment.Oladapo:Takeda:Current Employment, Current equity holder in publicly-traded company.Asghar:HCD Economics:Current Employment.

Introduction: Low von Willebrand factor (VWF) activity is prevalent in adolescents with heavy menstrual bleeding (HMB). There is a need to better genetically characterize these patients and improve our understanding of the pathophysiology of their bleeding risk. Methods: One of the main objectives of this multi-center, single arm, observational cohort study was to genotype adolescent females with HMB and low VWF (≥ 30 and ≤ 50 IU/dL) by means of whole exome sequencing (WES), to identify variants throughout the exome that may modulate risk for bleeding. Post-menarchal females < 21 years with HMB (defined as PBAC score >100) and low VWF were eligible for the study. All patients were enrolled by participating centers where blood samples were collected. Exome data for 86 cases and 900 unrelated pediatric (0.8, GQ>20, AB between 0.3-0.7 and min DP>8. Case/control analyses included common and rare SNP associations, gene burden analysis of both rare nonsynonymous variants and ClinVar 'pathogenic' variants, and gene-set burden analyses. Variants were considered rare if they had a minor allele frequency of Results: Of the 113 subjects enrolled, 86 had sufficient blood samples collected for WES. The median age was 16.2 years (range: 11.5-19.6). 36% of cases showed variants in VWF vs. 26% of controls (p=0.14). After multiple test correction, WES revealed a significant common variant association in FERMT2 with an LD block with a frequency of 24% in cases and 6% in controls (p=7.5x10-7). Rare variant analysis showed a significant association with an intronic variant in ABCA13 (p=1.6x10-7). Among the gene burden analysis using rare nonsynonymous variants, 2 genes of interest passed multiple test correction: IL12B and DTNBP1. When using ClinVar 'pathogenic' variants as the input for the gene burden analysis, 4 genes of interest passed multiple test correction: HBM, MYLK, RUNX1 and CD36. Gene-set burden analysis revealed 5 significant pathways of interest, including platelet degranulation, platelet alpha granule lumen and erythrocyte differentiation. We then focused a subset of known risk genes and compared the number of missense, nonsense and ClinVar 'pathogenic' variants between cases and controls. GP6, and MTHFR had significantly more missense variants in controls vs. cases (p=0.003 and 0.01, respectively), and F13B approached significance, with more missense variants in controls than cases (p=0.07). Conclusion: We found VWF variants in 36% of subjects, in accordance with previous reports. We found novel SNP associations with variants in FERMT2 and ABCA13.FERMT2 encodes for the integrin, Kindlin 2, which has been shown to be critical for supporting vascular integrity. Several other relevant genes passed multiple test correction in gene burden analyses, including genes known to cause Hermansky-Pudlak syndrome (DTNBP1), familial platelet disorder (RUNX1), platelet glycoprotein IV deficiency (CD36) and aortic aneurysm (MYLK). This association with platelet disorders was strengthened by our gene-set burden results, which implicate several platelet-related pathways. These data suggest that while a subset of HMB patients may have their bleeding explained by variants in VWF, there is a role for other hemostasis, platelet biology and vascular integrity related gene variants which can contribute to the variation in bleeding severity in adolescents with low-VWF related HMB. Study supported by an investigator-initiated research grant from Shire US Inc., now part of Takeda Disclosures O'Brien: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mullins:Takeda, Bayer: Other: Advisory Board. Sidonio:Takeda: Research Funding. Ragni:Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Srivaths:Shire US Inc., now part of Takeda: Research Funding.

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Questions remain regarding the impact of VWD related bleeding phenotype on healthcare utilization, joint health, and health-related quality of life (HRQoL) in the US. Objective: Our study investigated the impact of VWD bleeding phenotype on healthcare utilization, joint health, and HRQoL in a geographically diverse cohort of individuals with VWD who obtain care at seven US Hemophilia Treatment Centers (HTCs). Methods: Hematology Utilization Group Studies (HUGS) prospectively examined the cost and burden of illness in persons with VWD. The current study enrolled individuals age ≥12 with VWD Type 1 (VWF:Ag/RCo: ≤30%), low VWF (VWF:Ag/RCo: 30-50%), Type 2, and 3. Participants completed a standardized interview to collect sociodemographic and clinical data, self-reported healthcare utilization and bleeding in last 6 months, self-reported pain, joint health and HRQoL measured by EQ-5D-3L. Clinical chart reviews abstracted information about VWD type and treatment. Association of bleeding and VWD type with healthcare utilization, joint health, and HRQoL were assessed using Chi-square or Fisher exact tests for categorical variables and Student T-tests or one-way ANOVA for continuous variables. P value ≥0.05 indicates not statistically significant (NS). Results: We analyzed 100 participants with complete baseline information. Mean age was 31.7 (SD=18.6) years, 67.0% were adults ≥18 years, 80.0% were female, 67.7% had Type 1/low VWF, and 3.0% had Type 3 VWD. Mean age at VWD diagnosis was 13.6 (SD=13.0) years. Persons with low VWF were diagnosed and received VWD treatment at an older age (mean 19.2, SD=11.8; 19.4, SD=11.9 years for diagnosis and treatment respectively) than those with Type 1 (13.7, SD=12.7; 15.6, SD=13.7), or Types 2&3 (9.4, SD=12.9; 13.3, SD=16.6), p=0.03 and p=NS. As compared to individuals without bleeding in the previous 6 months, those reported bleeding had significantly higher rate of medical procedures related to treating bleeding events (42.5% vs. 13.3%, p=0.001), and overnight hospitalization (20.0% vs. 3.3%, p Conclusions: Our study demonstrates that persons with VWD who obtain care at US HTCs experience significant illness burden regardless of severity. Self-reported recent bleeding as expected was associated with increased healthcare utilization and negative impact on joint health and HRQoL. Bleeding phenotype was significantly associated with healthcare utilization differences. Delayed diagnosis and treatment for persons with low VWF may impact their HRQoL, and if confirmed in a larger sample size would underscore the fact that low VWF is not necessarily a mild disorder compared to other VWD subtypes. Disclosures Roberts: Octapharma: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy, Research Funding, Speakers Bureau; uniQure: Consultancy. Kulkarni:Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants . Sidonio:Octapharma, Grifols, Takeda and Genentech: Research Funding; Bayer, Bioverativ/Sanofi, Novo Nordisk, Takeda, Uniqure, Biomarin, Octapharma, Catalyst, Grifols, Sigilon, Tremeau, Genentech/Roche: Consultancy. Carpenter:Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board. Konkle:Sigilon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BioMarin: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; Roche: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Curtis:USC Hemophilia Utilization Group Study (HUGS): Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy. Carrasco:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Tran:Novo Nordisk: Consultancy; Bioverativ: Consultancy; Takeda: Consultancy; Bayer: Consultancy. Nichol:Global Blood Therapeutics: Research Funding; Octapharma: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Genentech Inc.: Research Funding.

Introduction: Most studies on the diagnostic yield of bone marrow biopsy including the one by Hot et al. have focused on the yield of bone marrow biopsies in diagnosing the source of fever of unknown origin. However, there have not been any studies performed to our knowledge looking at overall practice patterns and yield of bone marrow biopsies for diagnoses other than fever of unknown origin. We aim to determine the most common indications for performing bone marrow biopsies in a community-based teaching hospital as well as the yield of the biopsies in patients with specified and unspecified pre-test indications to estimate the rate of uncertain post-test diagnoses. Methods: We performed a retrospective data collection study at Rochester General Hospital, NY. A comprehensive search was conducted in our electronic medical data to identify all patients who underwent bone marrow biopsies over a 5 year period from January 2011 - December 2016 for indications other than fever of unknown origin. Patient data including demographics, pre-bone marrow biopsy diagnosis and post-bone marrow diagnosis was obtained. All patients above the age of 18 who underwent bone marrow biopsy for indications other than fever of unknown origin or follow up treatment of a hematological malignancy were included. Results: A total of 223 biopsies were performed. The median age was 59 years (age range- 23-95). One hundred and sixteen patients were male and 107 were female. The most common indications for performing bone marrow biopsy were evaluation of the following possible conditions: multiple myeloma (n=54), myelodysplastic syndrome [MDS] (n=47), lymphoma (n=28) and leukemia (n=18) as well as non-specific indications such as pancytopenia (n=40), anemia (n=22) and thrombocytopenia (n=11). The proportion of cases confirmed by bone marrow biopsy was 45/54 (83%) with the pre-marrow diagnosis of multiple myeloma, 34/47 cases (72%) with the pre-marrow diagnosis of MDS, 15/18 (83%) with the pre-marrow diagnosis of leukemia and 13/28 (46%) in those with the pre-marrow diagnosis of rule out lymphoma. Thirteen cases (18%) with possible MDS had post-bone marrow diagnoses of leukemia, anemia of chronic disease, myelofibrosis or medication-related changes. Five out of twenty two cases (23%) for anemia and 3/11 cases (27%) for thrombocytopenia without otherwise specified pre-bone marrow etiology had uncertain diagnosis after bone marrow biopsy. Conclusion: In about a fifth of patients necessitating a bone marrow, the diagnosis is discordant and can be surprising. It is also worth reporting that in these discordant results, non-hematological causes such as medications, anemia due to chronic diseases or conditions such as cirrhosis or splenomegaly from other etiologies were among the final diagnoses. Interestingly, 20% of the patients with unspecified pre-bone marrow diagnoses such as anemia or thrombocytopenia in our study had an unclear post-bone marrow diagnosis despite undergoing bone marrow biopsy. Our findings are a reminder that the bone marrow exam does not always lead to a definitive diagnosis and the need by exclusion to include in the differential non-hematological etiologies such as nutritional deficiencies, chronic kidney disease or autoimmune disorders. Disclosures No relevant conflicts of interest to declare.

Leukemic infiltration of the myocardium is an extremely rare complication and requires high clinical suspicion, as

von Willebrand disease (VWD) type 2B is a rare bleeding disorder, presenting with moderate-to-severe lifelong bleeding. We present the case of a 61-year-old woman who was misdiagnosed as immune thrombocytopenic purpura during her three pregnancies resulting in a delayed diagnosis of VWD type 2B. This genetically confirmed diagnosis resulted in testing and the establishment of the diagnosis in her otherwise asymptomatic adult son as well. VWD may not be diagnosed till beyond mid adulthood in women with thrombocytopenia previously attributed to pregnancy and should be considered as a differential in female patients developing thrombocytopenia less than 100 × 10/μl with an increased bleeding assessment tool score.

Background Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. Aim To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. Methods Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months. Results Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). Conclusion Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.

Background von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. Methods We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms ‘von Willebrand factor,’ ‘menorrhagia’ and ‘von Willebrand disease’ to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Results Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011–2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33–100 IU kg−1 on day 1–6 of menstrual cycle. Conclusions This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

Introduction Epidural and spinal hematoma are rare but potentially devastating complications of neuraxial anesthesia. Individuals with pre-existing bleeding disorders and tendencies are likely at higher risk of these feared complications, however there are currently no comprehensive recommendations to direct the use of neuraxial anesthesia in these patients. Objective Our objectives were to create a set of consensus recommendations to advise clinicians on appropriate treatment thresholds prior to neuraxial anesthesia for patients with a variety of common and uncommon bleeding disorders and tendencies, and to propose safe hemostatic thresholds for administration and removal of neuraxial anesthetics in these individuals. Materials and Methods A steering committee comprised of 14 hematologists, anesthesiologists and methodologists created and refined a set of Delphi statements regarding the use of neuraxial anesthesia in the following pre-existing bleeding disorders and tendencies: von Willebrand disease, immune thrombocytopenia, gestational thrombocytopenia, platelet function disorders, thrombocytopenia associated with hypertensive disorders of pregnancy, coagulation factor deficiencies and fibrinogen disorders. Statements were developed using data obtained from a previously conducted scoping review of existing literature supplemented with the expert opinion of the steering committee in areas where there are minimal published data. Statements include varying hemostatic laboratory parameters in the context of high or low bleeding risk as measured by either a validated bleeding assessment tool (BAT) or pre-defined criteria for excessive bleeding. We plan to recruit approximately 30 international panelists from the fields of hematology and anesthesiology to participate in a modified (i.e. electronic) Delphi technique. Three Delphi rounds will be conducted, during which we will ask panelists to rate their agreement with each Delphi statement on a 5-point Likert scale. Results will be analyzed for statistical consensus, defined as a Cronbach's alpha value of greater than or equal to 0.70. Statements that achieve consensus will be included in the final recommendations. Results Results of the modified Delphi study are pending. Conclusions Administration of neuraxial anesthesia in patients with pre-existing bleeding disorders and tendencies continues to present a significant management challenge for clinicians. We anticipate that the resultant recommendations will become a helpful tool for the future management of neuraxial anesthesia in these patients. Disclosures Martin: Borden Ladner Gervais LLP:Consultancy.Carvalho:Gauss Surgical:Consultancy.Kuter:Dova:Consultancy, Honoraria;Daiichi Sankyo:Consultancy, Honoraria;Actelion (Syntimmune):Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Principia Biopharma:Consultancy, Honoraria, Other, Research Funding;Protalix Biotherapeutics:Consultancy;Shionogi:Consultancy;Protalex:Consultancy, Honoraria, Research Funding;Kezar Life Sciences, Inc:Other, Research Funding;CRICO:Consultancy, Honoraria;Genzyme:Consultancy, Honoraria;Principia:Consultancy, Research Funding;Shire:Consultancy, Honoraria;Shionogi:Consultancy, Honoraria;Sanofi (Genzyme):Consultancy, Honoraria;Incyte:Consultancy, Honoraria;Immunovant:Consultancy, Honoraria;Kyowa-Kirin:Consultancy, Honoraria;Merck Sharp Dohme:Consultancy, Honoraria;Momenta:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;Pfizer:Consultancy, Honoraria;Zafgen:Consultancy, Honoraria;Up-To-Date:Consultancy, Honoraria, Patents & Royalties;UCB:Consultancy, Honoraria;Platelet Disorder Support Association:Consultancy, Honoraria;Argenx:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Bristol-Myers Squibb:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Caremark:Consultancy, Honoraria;Immunovant:Other: Travel Expenses, Research Funding;Alnylam:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Agios:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Amgen:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Takeda (Bioverativ):Consultancy, Honoraria, Other, Research Funding;Rigel:Consultancy, Honoraria, Other, Research Funding;Protalex:Consultancy, Honoraria, Other, Research Funding.Lavin:Tremeau Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Siemens Healthineers:Other: Speaker's fees;Takeda:Research Funding;Shire:Research Funding.Sholzberg:Takeda:Honoraria, Other: Scientific Advisory Board, Research Funding;Novartis:Honoraria, Other: Scientific Advisory Board;NovoNordisk:Honoraria, Other: Scientific Advisory Board;Octapharma:Honoraria, Other: Scientific Advisory Board, Research Funding;Amgen:Honoraria, Other: Scientific Advisory Board, Research Funding.