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.

No validated biomarkers exist for acute graft-versus-host disease (GVHD). We screened plasma with antibody microarrays for 120 proteins in a discovery set of 42 patients who underwent transplantation that revealed 8 potential biomarkers for diagnostic of GVHD. We then measured by enzyme-linked immunosorbent assay (ELISA) the levels of these biomarkers in samples from 424 patients who underwent transplantation randomly divided into training (n ‫؍‬ 282) and validation (n ‫؍‬ 142) sets. Logistic regression analysis of these 8 proteins determined a composite biomarker panel of 4 proteins (interleukin-2-receptor-alpha, tumornecrosis-factor-receptor-1, interleukin-8, and hepatocyte growth factor) that optimally discriminated patients with and without GVHD. The area under the receiver operating characteristic curve distinguishing these 2 groups in the training set

Hemophilia A (HA) and hemophilia B (HB) are the most common severe bleeding disorders. Replacement therapy, providing the missing coagulation factor, has been the mainstay of treatment both prophylactically and to treat bleeding. Despite widespread availability of safe and effective replacement therapy, patients with HA and HB continue to experience a tremendous burden of treatment, breakthrough bleeding, and progressive joint disease, as well as high rates of inhibitor development. These remaining challenges are now being addressed by incredible advances in bioengineering. Recombinant bioengineering has led to replacement therapies with easier modes of administration, decreased immunogenicity, increased efficacy, and extended half-lives. Emicizumab, a bispecific antibody that acts as a substitutive therapy for HA, has been approved for patients with and without inhibitors. Novel compounds are in development to exploit the natural balance of hemostasis by targeting the natural anticoagulants protein C, protein S, tissue factor pathway inhibitor, and antithrombin. The substitution and rebalancing therapies provide an opportunity for steady-state hemostatic control without exposure to immunogenic clotting factor proteins. As such, they may have broader applications outside those being investigated in the clinical trial programs.

Approximately one-third of the mammalian proteome is transported from the endoplasmic reticulum-to-Golgi via COPII-coated vesicles. SEC23, a core component of coat protein-complex II (COPII), is encoded by two paralogous genes in vertebrates ( and ). In humans, SEC23B deficiency results in congenital dyserythropoietic anemia type-II (CDAII), while SEC23A deficiency results in a skeletal phenotype (with normal red blood cells). These distinct clinical disorders, together with previous biochemical studies, suggest unique functions for SEC23A and SEC23B. Here we show indistinguishable intracellular protein interactomes for human SEC23A and SEC23B, complementation of yeast Sec23 by both human and murine SEC23A/B, and rescue of the lethality of deficiency in zebrafish by a -expressing transgene. We next demonstrate that a coding sequence inserted into the murine locus completely rescues the lethal SEC23B-deficient pancreatic phenotype. We show that SEC23B is the predominantly expressed paralog in human bone marrow, but not in the mouse, with the reciprocal pattern observed in the pancreas. Taken together, these data demonstrate an equivalent function for SEC23A/B, with evolutionary shifts in the transcription program likely accounting for the distinct phenotypes of SEC23A/B deficiency within and across species, a paradigm potentially applicable to other sets of paralogous genes. These findings also suggest that enhanced erythroid expression of the normal gene could offer an effective therapeutic approach for CDAII patients.

Purpose of review Although the zebrafish has been established as a research tool over the past 2–3 decades, in hematology it has primarily been used to investigate areas distinct from coagulation. Advantages of this vertebrate model include high fecundity, rapid and external development, and conservation of virtually all clotting factors in the zebrafish genomic sequence. Here we summarize the growing application of this technology to the study of hemostasis and thrombosis. Recent findings Loss of function studies have demonstrated conservation of function for a number of zebrafish coagulation factors. These include positive and negative regulators of coagulation, as well as key components of the thrombus itself, such as von Willebrand factor, fibrinogen, and thrombocytes. Such analyses have also been leveraged to aid in the understanding of human variation and disease, as well as perform in vivo structure/function experiments. Summary The zebrafish is an organism that lends itself to a number of unique and powerful approaches not possible in mammals. This review demonstrates that there is a high degree of genetic and functional conservation of coagulation, portending future insights into hemostasis and thrombosis through use of this model.

Sexism has been an issue in bleeding disorders for centuries. Women with bleeding disorders have been underrecognized and underdiagnosed. Those who are diagnosed often experience delays in diagnosis and feel that their symptoms are dismissed or minimized. Several factors contribute to this sexism. Historically, the clinical and research focus within the bleeding disorder community has been on men and hemophilia. Von Willebrand disease, a disease that has long been recognized as affecting women, is much more common than hemophilia, yet has significantly fewer resources devoted to it. The lack of knowledge and comfort that patients and health care providers have regarding menstruation compounds the issue, as heavy menstrual bleeding is one of the most common symptoms seen in women with bleeding disorders. Stemming from the universal stigmatization of periods, this lack of comfort and knowledge results in fewer women seeking care, fewer health care providers addressing the issue, and fewer women getting the care they deserve. Progress has been made, with many organizations dedicating resources to improving the care of these women. The road is long, and much more work is needed to ensure that women with bleeding disorders receive the care they deserve.

Key Points Type 3 von Willebrand disease with alloantibodies is a rare clinical entity with few treatment options. Emicizumab prophylaxis in such patients may result in improved hemarthrosis control, lower cost, and enhanced quality of life.

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic1,2. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches1, while maintaining proven prevention measures using a vaccines-plus approach2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.