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Abstract Background Hemophilia carriers experience abnormal bleeding symptoms; however, a lack of awareness about this topic coupled with additional knowledge gaps and barriers leads to suboptimal care for this population. Objective The primary objective was to describe the current knowledge gaps and challenges from the perspective of both hemophilia carriers and their health care providers. Methods We carried out a mixed methods descriptive study with two population groups between September and December 2020. The hemophilia carrier perspective was obtained through both focus groups and questionnaires, whereas the health care providers perspective obtained via questionnaire sent to the Association of Hemophilia Care Directors of Canada and the Canadian Association of Nurses in Hemophilia Care. Focus groups were analyzed using descriptive thematic analysis and quantitative survey data was also analyzed. Results Eleven hemophilia carriers participated along with 19 health care providers (11 physicians, eight nurses). Hemophilia carrier focus group discussions identified four areas representing major challenges or knowledge gaps: (1) negative psychosocial impacts; (2) difficulty determining symptom significance; (3) need for self‐advocacy; (4) testing concerns. Survey results from both groups were aligned with the most important topics for ongoing education identified as information on abnormal bleeding symptoms, where to seek treatment, and considerations for heavy menstrual bleeding/menstruation. The majority of both study groups believe obligate or potential carriers should have factor levels checked regardless of age if symptoms of abnormal bleeding occur or before an invasive procedure. However, hemophilia carriers were significantly more in favor of genetic testing under the age of consent than health care providers in all scenarios evaluated.

Abstract Objectives To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. Trial design Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial Participants The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin 1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. Intervention and comparator Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. Main outcomes The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. Randomisation Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. Blinding (masking) No blinding involved. This is an open-label trial. Numbers to be randomised (sample size) 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. Trial Status Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. Trial registration ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Abstract Background Patients with type 1 von Willebrand disease (VWD) undergo a desmopressin (DDAVP) responsiveness challenge at diagnosis to assess whether DDAVP reverses their coagulation deficits. Current practice assumes DDAVP responsiveness remains constant over the lifetime. In patients with type 1 VWD, VWF‐related parameters increase with age. This study explores whether DDAVP responsiveness also differs with age in this population. Methods We conducted a retrospective chart review of 106 patients enrolled at our center since 1990. Our primary outcome was DDAVP responsiveness at 1 hour after DDAVP challenge. Locally weighted scatterplot smoothing fit and Spearman correlation coefficients were used to study the relationship between age and DDAVP responsiveness. For female participants, we used the Kruskal‐Wallis test to compare absolute and relative changes in DDAVP responsiveness at various ages. Results We had 79 patients (56 female) with type 1 VWD with at least 1 DDAVP challenge. In women with type 1 VWD, the absolute change in DDAVP responsiveness did not vary significantly with age (VWF:antigen [Ag], −0.08, P = .56; VWF:ristocetin cofactor [RCo], −0.16, P = .26; low‐molecular‐weight component of factor VIII [FVIII:C], −0.01, P = .93), nor did the relative change in DDAVP responsiveness (VWF:Ag, −0.03, P = .86; VWF:RCo, −0.25, P = .09; FVIII:C, −0.14, P = .34). The data plot suggested a relationship. Conclusion In women with type 1 VWD, DDAVP responsiveness may vary over the life cycle. Our exploratory findings are limited by our retrospective data, cross‐sectional design, and small sample. Future studies should investigate the relationship between age and DDAVP responsiveness prospectively to evaluate whether there is clinical utility in rechallenging postpubertal female patients with type 1 VWD.

Abstract Background The Canadian Bleeding Disorders Registry (CBDR) captures data from 24 hemophilia treatment centers and patients directly. Nonacog beta pegol (N9‐GP) was approved in Canada in 2018. Objectives To assess treatment outcomes following switching to N9‐GP in a real‐world setting. Methods CBDR data for Canadian male patients (aged 7–72 years) with hemophilia B receiving prophylactic N9‐GP for ≥6 months as of March 31, 2021, were included. To allow comparison with the previously used products, only patients for whom data were available in the CBDR for at least 6 months before the switch to N9‐GP were included in this retrospective analysis. Results Forty‐two patients were included in the analysis (total observation period: 148.0 patient‐years). The distribution of disease severity was 62% severe, 36% moderate, 2% mild, with 62% of patients previously receiving recombinant factor IX‐Fc‐fusion protein (rFIXFc) and 38% previously receiving standard half‐life (SHL) recombinant factor IX (rFIX). During a median follow‐up period of 2.3 years on N9‐GP prophylaxis, 232 bleeds were reported in 30 patients, 29% of patients reported zero bleeds. The median overall annualized bleeding rate on N9‐GP was 0.73 for patients switching from rFIXFc (previously 1.44) and 2.10 for patients switching from SHL rFIX (previously 6.06). Median total annualized factor consumption (IU/kg) was lower with N9‐GP than with previous SHL rFIX (2152 vs 3018) and previous rFIXFc (1766 vs 2278). Conclusions Results from this first real‐world study of N9‐GP in patients with hemophilia B suggest optimal bleeding control with low factor consumption after switching to N9‐GP, irrespective of the previous product.

Abstract Abnormal or excessive menstrual bleeding affects one‐third of reproductive‐aged women. This number increases to 70% among women on direct oral anticoagulants (DOACs). While there is some variation in frequency of heavy menstrual bleeding (HMB) with different DOAC options, all menstruating individuals should receive counseling about the risk of HMB at the time of DOAC initiation. Management options include progestin‐only therapies such as the levonorgestrel intrauterine system and etonogestrel subdermal implant or the progestin‐only pill. Combined hormonal contraceptives and depot medroxyprogesterone acetate are associated with increased rates of thrombosis in nonanticoagulated women but may be continued, or even initiated, so long as therapeutic anticoagulation is ongoing. Procedural therapies, such as endometrial ablation, uterine artery embolization, or hysterectomy, are considerations for women who have completed childbearing and for whom more conservative measures are objectionable or ineffective. Given the high rates of HMB in women on DOACs, management strategies should be discussed even before heavy bleeding is diagnosed, particularly in women who experienced HMB prior to DOAC initiation. As iron deficiency with or without anemia is a common complication of HMB, complete blood count and ferritin levels should be monitored periodically, and iron deficiency should be treated with oral or intravenous iron supplementation.

Abstract Leaves are colonized by a complex mix of microbes, termed the leaf microbiota. Even though the leaf microbiota is increasingly recognized as an integral part of plant life and health, our understanding of its interactions with the plant host is still limited. Here, mature, axenically grown Arabidopsis thaliana plants were spray inoculated with six diverse leaf‐colonizing bacteria. The transcriptomic changes in leaves were tracked over time and significant changes in ethylene marker (ARL2) expression were observed only 2–4 days after spray inoculation. Whole‐transcriptome sequencing revealed that 4 days after inoculation, leaf transcriptional changes to colonization by nonpathogenic and pathogenic bacteria differed in strength but not in the type of response. Inoculation of plants with different densities of the nonpathogenic bacterium Williamsia sp. Leaf354 showed that high bacterial titers resulted in disease phenotypes and led to severe transcriptional reprogramming with a strong focus on plant defense. An in silico epigenetic analysis of the data was congruent with the transcriptomic analysis. These findings suggest (1) that plant responses are not rapid after spray inoculation, (2) that plant responses only differ in strength, and (3) that plants respond to high titers of nonpathogenic bacteria with pathogen‐like responses.

Mild mucocutaneous bleeding symptoms are common in the general population. Differentiating normal from pathological bleeding complaints begins with a detailed bleeding history that assesses: the pattern (primary versus secondary hemostasis), the severity, and the onset (congenital versus acquired) of bleeding. Bleeding assessment tools have been developed to aid in determining whether bleeding symptoms are outside of the normal range. Although the clinical pattern of bleeding and family history directs laboratory investigations, von Willebrand disease, the most common and best characterized of the primary hemostatic disorders, is often the first diagnosis to be considered. Clinical management focuses on the particular symptoms experienced by the patient. Medical interventions include replacement of the factor that is deficient or defective, or indirect treatments, such as antifibrinolytics (tranexamic acid), desmopression, and hormone-based therapy (e.g., oral contraceptive pill for menorrhagia). [ABSTRACT FROM AUTHOR]

In Canada, care for individuals with inherited bleeding disorders, including Von Willebrand disease, is provided by 26 tertiary care multidisciplinary Inherited Bleeding Disorders clinics geographically spread across the country. The Association of Hemophilia Clinic Directors of Canada, the Canadian Association of Nurses in Hemophilia Care, the Canadian Physiotherapists in Hemophilia Care, the Canadian Social Workers in Hemophilia Care, and the Canadian Hemophilia Society all collaborate to provide optimal management for patients with inherited bleeding disorders. The standards of care for these patients were explicitly laid out in a 2007 document published by the Canadian Hemophilia Standards Group (with representation from all of the groups just mentioned) entitled CANADIAN COMPREHENSIVE CARE STANDARDS FOR HEMOPHILIA AND OTHER INHERITED BLEEDING DISORDERS. Separate Canadian guidelines for the management of patients with Hemophilia and Von Willebrand disease also exist, focused on diagnosis, comprehensive care, assessment, and treatment. [ABSTRACT FROM AUTHOR]

Purpose. To test whether implementing a staff wellness program affects the nutrition and physical activity environment at child care centers. Design. Quasi-experimental controlled trial. Setting. Child care centers in low income neighborhoods in California. Subjects. Eighty-two staff members at 13 centers completed the study. Intervention. Intervention and control groups received training and education about nutrition and physical activity. The intervention group also participated in a worksite wellness program. Measures. Staff members' personal health habits, self-efficacy in working with families on nutrition and physical activity, and changes in children's food and physical activity environments were assessed. Analysis. Statistical software was used to analyze change scores for pre-post measures and to test differences for end point-only measures. Results. Although significant differences in staff members' personal health behaviors were not observed, staff from intervention sites exhibited more positive changes in their comfort level in talking to parents about nutrition and physical activity. Intervention sites reported providing more fresh fruits (p = .004) and vegetables (p = .03) to children as part of regular meals and snacks and serving more fresh fruits (p = .05) at children's celebrations. Control sites reported greater increases in sweetened foods (p = .02) and sweetened beverages (p = .05) at children's celebrations. Conclusion. The wellness intervention shows promise in improving the children's food environment in a child care setting. [ABSTRACT FROM AUTHOR]

von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans, but its diagnosis, using conventional clinical criteria and phenotypic hemostasis test results, can be problematic. The von Willebrand factor gene was cloned in the mid-1980s, and since that time, a significant amount of information has been gathered with respect to the molecular pathology responsible for this trait. This accumulated information, along with advances in genetic technology, has now made the integration of molecular genetic testing for VWD a feasible option in some instances. In this review, we have summarized the current state of knowledge concerning the genetic causation of the various forms of VWD. We have also provided guidelines as to how genetic testing can be used to clarify diagnostic uncertainty that might remain after a clinical evaluation and routine coagulation testing has been completed. [ABSTRACT FROM AUTHOR]

A reference genotyping laboratory was established in 2000 at Queen's University, Kingston, to provide genetic testing for Hemophilia A (HA) and B (HB) and create a Canadian mutation database. Canadian hemophilia treatment centers and genetics clinics provided DNA and clinical information from November 2000 to March 2011. The factor VIII (F8) gene was analyzed in 1,177 patients (47% of HA population) and 787 female family members and the factor IX (F9) gene in 267 patients (47% of HB population) and 123 female family members, using Southern Blot, PCR, conformation sensitive gel electrophoresis, and/or direct sequencing. The mutation detection rates for HA and HB were 91% and 94%, respectively. 380 different F8 mutations were identified: inversions of intron 22 and intron 1, 229 missense, 45 nonsense, eight deletions, 70 frameshifts, 25 splice site, and one compound mutation with a splice site and intron 1 inversion. Of these mutations, 228 were novel to the Hemophilia A Database (HADB, http://hadb.org.uk/). A total 125 different F9 mutations were identified: 80 missense, 12 frameshift, 12 splice site, nine nonsense and seven promoter mutations, three large deletions, and two compound mutations with both missense and nonsense changes. Of these mutations, 36 were novel to the International Haemophilia B Mutation database (http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html). The Canadian F8 and F9 mutation database reflects the allelic heterogeneity of HA and HB, and is similar to previously described populations. This report represents the largest and longest duration experience of a national hemophilia genotyping program documented, to date., (Copyright © 2013 Wiley Periodicals, Inc.)