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Acquired von Willebrand syndrome (aVWS) has been reported in patients with congenital heart diseases associated with shear stress caused by significant blood flow gradients. Its etiology and impact on intraoperative bleeding during pediatric cardiac surgery have not been systematically studied. This single-center, prospective, observational study investigated appropriate diagnostic tools of aVWS compared with multimer analysis as diagnostic criterion standard and aimed to clarify the role of aVWS in intraoperative hemorrhage. A total of 65 newborns and infants aged 0 to 12 months scheduled for cardiac surgery at our tertiary referral center from March 2018 to July 2019 were included in the analysis. The glycoprotein Ib M assay (GPIbM)/von Willebrand factor antigen (VWF:Ag) ratio provided the best predictability of aVWS (area under the receiver operating characteristic curve [AUC], 0.81 [95% CI, 0.75-0.86]), followed by VWF collagen binding assay/VWF:Ag ratio (AUC, 0.70 [0.63-0.77]) and peak systolic echocardiographic gradients (AUC, 0.69 [0.62-0.76]). A cutoff value of 0.83 was proposed for the GPIbM/VWF:Ag ratio. Intraoperative high-molecular-weight multimer ratios were inversely correlated with cardiopulmonary bypass (CPB) time (r = −0.57) and aortic cross-clamp time (r = −0.54). Patients with intraoperative aVWS received significantly more fresh frozen plasma (P = .016) and fibrinogen concentrate (P = .011) than those without. The amounts of other administered blood components and chest closure times did not differ significantly. CPB appears to trigger aVWS in pediatric cardiac surgery. The GPIbM/VWF:Ag ratio is a reliable test that can be included in routine intraoperative laboratory workup. Our data provide the basis for further studies in larger patient cohorts to achieve definitive clarification of the effects of aVWS and its potential treatment on intraoperative bleeding.

Gastrointestinal (GI) bleeding is an important cause of morbidity and mortality in von Willebrand disease (VWD). It has been noted that GI bleeding caused by angiodysplasia is overrepresented in VWD patients compared to other causes. The bleeding from angiodysplasia is notoriously difficult to treat; recurrences and rebleeds are common. A growing body of basic science evidence demonstrates that von Willebrand factor negatively regulates angiogenesis through multiple pathways. VWD is clinically highly associated with angiodysplasia. The predisposition to angiodysplasia likely accounts for many of the clinical difficulties related to managing GI bleeding in VWD patients. Diagnosis and treatment are challenging with the current tools available, and much further research is needed to further optimize care for these patients with regard to acute treatment, prophylaxis, and adjunctive therapies. In this review we provide an overview of the available literature on GI bleeding in VWD and explore the molecular underpinnings of angiodysplasia-related GI bleeding. Considerations for diagnostic effectiveness are discussed, as well as the natural history and recurrence of these lesions and which therapeutic options are available for acute and prophylactic management.

Von Willebrand disease (VWD), the most common inherited bleeding disorder (IBD), disproportionately affects females, given the hemostatic challenges they may encounter throughout their lifetimes. Despite this, research about VWD remains grossly underrepresented, particularly compared to hemophilia, which is historically diagnosed in males. Structural sexism, stigmatization of menstrual bleeding, delayed diagnosis, and a lack of timely access to care result in an increased frequency of bleeding events, iron deficiency, iron deficiency anemia, and a decreased quality of life. However, we are only beginning to recognize and acknowledge the magnitude of the burden of this disease. With an increasing number of studies documenting the experiences of women with IBDs and recent international guidelines suggesting changes to optimal management, a paradigm shift in recognition and treatment is taking place. Here, we present a fictional patient case to illustrate one woman's history of bleeding. We review the evidence describing the impact of VWD on quality of life, normalization of vaginal bleeding, diagnostic delays, and the importance of access to multidisciplinary care. Furthermore, we discuss considerations around reproductive decision-making and the intergenerational nature of bleeding, which often renders patients as caregivers. Through incorporating the patient perspective, we argue for an equitable and compassionate path to overcome decades of silence, misrecognition, and dismissal. This path moves toward destigmatization, open dialogue, and timely access to specialized care.

BACKGROUND: Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired haemostasis which could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13. METHODS: Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/mL) or control anti-ADAMTS13 mAb 5C11 or PBS. VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella® pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13 and blood parameters were determined. RESULTS: We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella®-induced aVWS calf model. CONCLUSION: Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.

Reproductive tract bleeding is an underappreciated health care problem among adolescent and young adult (AYA) females with inherited bleeding disorders (IBDs) comprising von Willebrand disease, platelet disorders, hemophilia carriership, and rare factor deficiencies. IBDs are prevalent in women of all ages and have been detected in about 50% of women with menorrhagia or heavy menstrual bleeding (HMB) and about 20% of women with postpartum hemorrhage (PPH). The clinical spectrum of gynecologic and obstetric bleeding in AYA with IBDs ranges from HMB, ovulation bleeding, and surgical bleeding to miscarriages and life-threatening PPH. Reproductive tract bleeding adversely affects the quality of life of this patient population, in addition to causing substantial morbidity and mortality. Early diagnosis of IBDs offers the opportunity for timely intervention with hormones, hemostatic agents, and prophylaxis with factor concentrates, thereby improving outcomes. This review summarizes the epidemiology, pathophysiology, clinical manifestations, diagnostic approach, management, and prophylaxis for reproductive tract bleeding in AYA with IBDs. This review provides a multidisciplinary approach to the problem, which is critical to improve the outcomes of this patient population.

Very few studies have shown the real origin and timing of de novo variants (DNV) implicated in von Willebrand disease (VWD). We investigated four families with type 2 VWD. First, we conducted linkage analysis using single nucleotide variant genotyping to recognize the possible provenance of DNV. Second, we performed amplification refractory mutation system-quantitative polymerase chain reaction to confirm the real origin of variant (~0% mutant cells) or presence of a genetic mosaic variant (0%-50% mutant cells) in three embryonic germ layer-derived tissues and sperm cells. Then, three possible timings of DNV were categorized based on the relative likelihood of occurrence according to the number of cell divisions during embryogenesis. Two each with type 2B VWD (proband 1 p.Arg1308Cys, proband 4 p.Arg1306Trp) and type 2A VWD (proband 2 p.Leu1276Arg, proband 3 p.Ser1506Leu) were identified. Variant origins were identified for families 1, 2 and 3 and confirmed to originate from the mother, father and father, respectively. However, the father of family 4 was confirmed to have isolated germline mosaicism with 2.2% mutant sperm cells. Further investigation confirmed the paternal grandfather to be the origin of variant. Thus, we proposed that DNV originating from the two fathers most likely occurred at the single sperm cell, the one originating from the mother occurred at the zygote during the first few cellular divisions; alternatively, in family 4, the DNV most likely occurred at the early postzygotic development in the father. Our findings are essential for understanding genetic pathogenesis and providing accurate genetic counselling.

The World Federation of Haemophilia (WFH) is a global network of national member organizations (NMOs) that advocate, collectively and individually, to improve lives of people with inherited bleeding disorders. The WFH vision of "Treatment for All" speaks to a future in which all people with an inherited bleeding disorder will have access to care, regardless of their gender or where they live. Over the last several years, initiatives including the WFH Humanitarian Aid program, the World Bleeding Disorders Registry, and Guidelines for the Management of Haemophilia and von Willebrand disease have significantly changed how the WFH and its partners work to improve and sustain care for people with bleeding disorders. Following an extensive consultation that included over 200 stakeholders from 70 countries, a Theory of Change was developed, and strategic priorities identified, to clearly define the WFH's intended impact and point of accountability to its stakeholders, and to determine how and through who those goals will be achieved. Both should help the WFH better support its NMOs and healthcare providers around the world in their efforts to improve access to diagnosis and care, as new therapies revolutionize the treatment landscape and the fallout of the global pandemic continues to challenge the ways in which we work and connect. Global collaboration of all stakeholders, based on their resources, objectives and skills, will be required to achieve these goals and to ensure more people have reliable access to safe treatment and care, regardless of their bleeding disorder, gender, or where they live. Free to Read (see URL)

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, which results from a deficiency or dysfunction of von Willebrand factor (VWF). The major symptoms of patients affected by VWD include mucocutaneous and gastrointestinal bleeding, easy bruising, and prolonged provoked bleeding due to injury or surgery. Although women and men are equally likely to be affected by VWD, women continue to be disproportionately affected by the bleeding challenges. Women with VWD suffer from sex-specific symptoms, such as menorrhagia, and are at higher risk of reproductive problems and recurrent miscarriage. Furthermore, pregnant women with VWD are more likely at higher risk of suffering from primary and secondary peripartal hemorrhage and anemia and the need for transfusions. Despite being affected by gynecologic and obstetrical bleeding, women face multiple barriers in obtaining an accurate diagnosis. This constitutes a problem that needs to be addressed, and early appropriate medical care should be ensured. There are several effective treatment options for women with VWD that can significantly improve their quality of life, including desmopressin, VWF concentrates, hormonal therapy, and antifibrinolytic therapy. During pregnancy, the monitoring of VWF activity levels is essential. The peripartal management depends on the type of VWD and on the measured levels of VWF levels and activity prior to delivery.

Type 2B von Willebrand disease (VWD) is characterized by an increased binding affinity of von Willebrand factor (VWF) to platelet glycoprotein Ib. This can lead to clearance of high-molecular-weight (HMW) multimers and thrombocytopenia with a resulting moderate-severe bleeding phenotype. Rondoraptivon pegol (BT200) is a pegylated aptamer binding to the A1 domain of VWF with a novel mechanism of action: it enhances VWF/factor VIII (FVIII) levels by decreasing their clearance. To study the potential benefit of rondoraptivon pegol in patients with type 2B VWD, we conducted a prospective phase 2 trial. Patients with type 2B VWD received 3 mg rondoraptivon pegol subcutaneously on study days 1, 4, and 7, followed by 6 to 9 mg every week until day 28. Five patients (male:female ratio = 3:2) were included. Rondoraptivon pegol rapidly tripled platelet counts from a median of 60 to 179 × 10E9/L (P < .001). Circulating VWF antigen increased from a median of 64% to 143%, which doubled FVIII activity levels from 67% to 134%. In all thrombocytopenic patients, plasma levels of VWF:GPIbM normalized, VWF ristocetin cofactor and VWF collagen-binding activity increased, and HMW multimers appeared. These pronounced improvements reversed during washout of the drug, thus demonstrating causality. The A1 domain binding aptamer directly corrects the underlying defect of type 2B VWD, thus providing a novel potential option for prophylaxis and treatment of patients with this VWD type. These data provide the basis for a phase 2b/3 trial in such patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

Higher rates of postpartum hemorrhage (PPH) have been reported for women with von Willebrand disease (VWD). Comprehensive multidisciplinary care reduces these rates; thus PPH may not be secondary to VWD.We conducted a retrospective review for the period of 2009-2018, including all VWD pregnancies at 2 tertiary care academic hospitals to determine rates, etiology, and timing of PPH.A total of 63 women with 80 pregnancies were included. Three women had twin pregnancies. Sixty-six pregnancies (82.5%) involved type 1 VWD; 4 (5.0%), type 2 (unclear subtype); 3 (3.8%) type 2A; 3 (3.8%) type 2B; and 2 (2.5%), type 2M. Median age of patients was 32.9 years (range 19-43 y). Most patients were blood type O (65%), and 33 of 80 pregnancies (41.3%) were nulliparous. The mean bleeding assessment score was 8 (range 0-16). Thirty-seven pregnancies (46.3%) received prophylactic hemostatic treatment prior to delivery. Seventy-four percent of pregnancies were delivered vaginally, and 88% received epidural anaesthesia. The majority of pregnancies (78.8%) had von Willebrand factor (VWF) levels assessed during the third trimester, with most (71.3%) achieving VWF levels above 1.00 IU/mL. Four pregnancies (5.2%) were complicated by primary PPH; uterine atony in 2 and placenta previa in 1. Delayed postpartum bleeding occurred in 5 pregnancies (6.3%).Multidisciplinary care of pregnancies with VWD improves outcomes. Rates of primary and delayed PPH in this study are lower than previously described and are similar to those of women without VWD. In women with VWD, uterine etiologies for primary PPH need to be considered, in a manner similar to the assessment of women without VWD, to ensure hemostasis is achieved.

Bleeding disorders are a major group of hematological disorders, which are highly prevalent in the world. Excessive bleeding can result in serious consequences including hypoperfusion and cardiac arrest. The body has its selfmechanism to control excessive bleeding which is termed hemostasis. Hemostasis is achieved in two major steps, the formation of the primary and secondary hemostatic plugs. Endothelium, platelets, and coagulation factors are three components involved in hemostasis. Endothelium and platelets have a major role in forming the primary hemostatic plug. Consequently, the first step in investigating a bleeding disorder is platelet count. Despite normal platelet count, abnormality in the primary hemostatic plug may arise due to functional defects of the platelets including adhesion, activation, and aggregation. Von Willebrand disease (VWD) is an endothelial defect and the most prevalent inherited defect in coagulation. Abnormalities in the secondary hemostatic plug are largely due to coagulation factor deficiencies, and, to a lesser extent, the presence of inhibitors. Techniques involving viscoelastics have been aiding in rapid diagnosis and are useful in point-of-care testing. This article discusses the investigation of bleeding disorders from the perspective of the endothelium, platelet, and coagulation factor physiology. These three components should be properly investigated to achieve the definitive diagnosis of bleeding disorders.

Acquired von Willebrand syndrome (AWS) is a rare and potentially life-threatening bleeding disorder. AWS is primarily associated with lymphocyte-related disorders (AWS-LRD), such as lymphoma and IgM monoclonal gammopathy of undetermined significance (MGUS), and plasmocyte-related disorders (AWS-PRD), such as non-IgM MGUS and myeloma. Symptomatic treatments are important to control and prevent bleeding, but AWS-LRD and AWS-PRD can only be cured by targeting the responsible clonal cell. No reviews exist on this specific subgroup of AWS.We performed a literature review to help manage these rare cases.Thirty-two AWS-PRD and 43 AWS-LRD cases with data on malignancy treatment were reported in 56 articles from the Medline database.LRDs were exclusively indolent and primarily associated with IgM monoclonal compounds. LRDs and PRDs may be treated because of severe bleeding symptoms, but severe VWF deficiency did not necessarily correlate with severe bleeding. Immunosuppressive drugs in AWS-PRD, including rituximab, provided an overall response rate of AWS (AWS-ORR) of 30% (3/10), including short responses. Anti-myeloma drugs provided an AWS-ORR of 71.4% (20/28), with long-lasting remissions. Bortezomib was the most commonly used drug and provided an AWS-ORR of 66.7% (6/9), including therapeutic associations with other anti-myeloma drugs. Autologous and allogeneic stem cell transplantation was performed in eight and two patients, respectively, and some details on the management of AWS during these procedures were provided. Rituximab in AWS-LRD provided an AWS-ORR of 60% (3/5), and a chemotherapy + rituximab regimen increased the AWS-ORR to above 50%. Bleeding syndrome in AWS-PRD and AWS-LRD generally improved prior to AWS biological improvement.Long term remission of AWS due to lymphoid neoplasms is attainable by treating the underlying clonal cell. Some data and recommendations are provided to help answer difficult questions, including treatment timing, choice of drug, and the timing of evaluations and treatment changes.

This review focuses on significant advances in the field of pediatric hemostasis and thrombosis, with a focus on published studies within the past decade. The evaluation and management of patients with excessive bleeding remain cornerstones of consultative hematology. We will describe the development of validated bleeding assessment tools relevant to pediatric practice, laboratory advances in the evaluation of von Willebrand disease, and a shift in clinical practice regarding the interpretation of normal coagulation studies in patients with significant bleeding phenotypes. There have also been critical advances in the management of hemostatic disorders. This review highlights new treatment paradigms in hemophilia and the rise of multidisciplinary medical homes for women living with bleeding disorders. Given the continued increase in the incidence of thrombosis, particularly in the hospital setting, a full call to arms against pediatric venous thromboembolism is now essential. We will describe recently completed clinical trials of direct oral anticoagulants in children and adolescents and ongoing work to elucidate the appropriate duration of therapy for children with provoked thrombosis. Recent work regarding the prevention of pediatric venous thromboembolism is highlighted, including studies of thromboprophylaxis and the development of risk prediction models for hospital-acquired thrombosis. Finally, we review advances in our understanding of thrombotic sequelae and the need for continued refinement of our evaluation tools. Despite the significant advances in pediatric hemostasis and thrombosis over the past decade, many unanswered questions remain for the next generation of investigators.

The von Willebrand disease (vWD) is the most common hereditary bleeding disorder caused by defects of the von Willebrand Factor (vWF), a large extracellular protein in charge of adhering platelets to sites of vascular lesions. vWF performs this essential homeostatic task via specific protein-protein interactions between the vWF A1 domain and the platelet receptor, the glycoprotein Ib alpha (GPIBα). The two naturally occurring vWF A1 domain mutations G1324A and G1324S, near the GPIBα binding site, induce a dramatic decrease in platelet adhesion, resulting in a bleeding disorder classified as type 2M vWD. However, the reason for the drastic phenotypic response induced by these two supposedly minor modifications remains unclear. We addressed this question using a combination of equilibrium-molecular dynamics (MD) and nonequilibrium MD-based free energy simulations. Our data confirms that both mutations maintain the highly stable Rossmann fold of the vWF A1 domain. G1324A and G1324S mutations hardly changed the per-residue flexibility of the A1 domain but induced a global conformational change affecting the region near the binding site to GPIBα. Furthermore, we observed two significant changes in the vWF A1 domain upon mutation, the global redistribution of the internal mechanical stress and the increased thermodynamic stability of the A1 domain. These observations are consistent with previously reported mutations increasing the melting temperature. Overall, our results support the idea of thermodynamic conformational restriction of A1-before the binding to GPIBα-as a crucial factor determining the loss-of-function of the G1324A(S) vWD mutants.

International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von Willebrand factor (rVWF; vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [prior on-demand group] or plasma-derived VWF prophylaxis [pdVWF; switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (VWF:RCo) IU/kg twice weekly (prior on-demand group) or based on prior pdVWF weekly dose/dosing frequency (switch group). The primary endpoint was annualized bleeding rate (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 0.086-3.523, respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).

von Willebrand disease (VWD) type 2 is caused by qualitative abnormalities of von Willebrand factor (VWF). This study aimed to determine the genotypic and phenotypic characterizations of a large VWD type 2 cohort from Milan. We included 321 patients (54% female) within 148 unrelated families from 1995 to 2021. Patients were fully characterized using laboratory phenotypic tests, and the genotypic diagnosis was confirmed by target genetic analysis using Sanger sequencing. Patients were diagnosed with type 2A (n = 98; 48 families), 2B (n = 85; 38 families), 2M (n = 112; 50 families), or 2N (n = 26; 12 families). Eighty-two unique VWF variants, including 8 novel variants, were found. The potential pathogenic effect of novel variants was assessed by in silico analysis. Most patients were heterozygous for a single variant (n = 259; 81%), whereas 37 cases (11%) had 2 variants (4 homozygous, 9 in trans, and 24 in cis). Twenty-five patients (8%) had ≥3 variants, mainly as a result of gene conversions. Among the 82 distinct variants identified, 5 different types, including missense (n = 64), gene conversion (n = 10), synonymous (n = 1), deletion (n = 4), and splice (n = 3), were observed. The results from this large cohort showed that VWD type 2 is invariably due to variants that do not prevent the synthesis of the protein, and a vast majority of patients (88%) had missense variants. Given the complexity of type 2 diagnosis and the necessity of performing several phenotypic tests, genetic analysis for patients suspected of having type 2 is beneficial to establish the correct diagnosis.

von Willebrand factor (VWF) forms high-molecular-weight multimers and plays an essential role in hemostasis, and thus its deficiency leads to bleeding symptoms. Acquired von Willebrand syndrome (AVWS) is rare, but potentially underdiagnosed, and develops in various underlying disorders. AVWS caused by anti-VWF autoantibodies is a rare subcategory of AVWS that can also be referred to as autoimmune VWF deficiency (AiVWFD). We performed a search of patients with autoimmune coagulation factor deficiencies in our nationwide survey in Japan. Among these, suspected cases of AiVWFD were extremely few, with only 11 case consultations in the last 10 years. Of these, three and five were respectively positive for anti-VWF autoantibodies (anti-VWF-Ab) and VWF inhibitor (VWF-inh). We also performed an extensive literature search of other cases from Japan, and in total, 40 cases were finally identified to have AiVWFD, with mean age of 55.0 years. Most underlying disorders were lympho- or myeloproliferative diseases, followed by autoimmune diseases. The major bleeding sites were subcutaneous and mucosal, the bleeding severity was moderate, and there were no hemorrhagic deaths. Bleeding time was prolonged; factor VIII activity, VWF antigen, and VWF activity were decreased, and high-molecular-weight VWF multimers were absent or decreased. These are similar to the common abnormal laboratory findings observed among general AVWS cases. Hemostatic therapy often involved VWF concentrates and vasopressin, and antibody eradication therapy often included corticosteroids and achieved remission. Notably, of all cases, 68% had anti-VWF-Abs, and 83% of anti-VWF-Ab-positive patients were also VWF-inh positive. To accumulate precise clinical information on AiVWFD, it is necessary to verify and improve the measurement methods for both anti-VWF-Ab and anti-VWF-inh. These findings from Japan should be confirmed in other geographic localities.

Introduction The sixth angstrom land Islands Conference on von Willebrand disease (VWD) on the angstrom land Islands, Finland, was held from 20 to 22 September 2018. Aim The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. Results and discussion The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non-haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD.

Patients with essential thrombocythemia (ET) often experience bleeding associated with acquired von Willebrand syndrome (AVWS) when the platelet count is markedly increased.We investigated whether von Willebrand factor (VWF) degradation is enhanced in patients with ET.Seventy patients with ET underwent VWF multimer (VWFM) analysis and measurement of VWF-related parameters. We calculated the VWFM index, defined as the ratio of intensities of a patient's molecular weight-categorized VWFMs, and those of a healthy subject's, using densitometric analysis. VWF degradation product (DP) was measured via ELISA using a monoclonal antibody that specifically recognizes Y1605 at the C-terminal boundary, which is exposed following ADAMTS13-mediated cleavage of the Y1605-M1606 bond of the VWF A2 domain.Patients with higher platelet counts had a significantly reduced high molecular weight (HMW)-VWFM index and an increased VWF-DP:VWF antigen (Ag) ratio compared to those with lower platelet counts. On multivariate analysis, the VWF-DP/VWF:Ag ratio was an independent predictor of the HMW-VWFM index. Patients who underwent cytoreductive therapy had a significantly higher HMW-VWFM index and lower VWF-DP/VWF:Ag ratio than those who did not. Among individual patients, there was also a significant increase in the HMW-VWFM index and a decrease in the VWF-DP/VWF:Ag ratio after cytoreductive therapy compared to pre-therapy values.In patients with ET, an increased platelet count is associated with enhanced cleavage of VWF at the Y1605-M1606 bond, primarily by ADAMTS13, leading to AVWS. Cytoreductive therapy reduces the platelet count, prevents excessive VWF cleavage, and improves VWFM distributions.

A 65-year-old man experienced sudden onset of abdominal pain while working on his farm without significant trauma. He heard a ‘pop’ sound, followed by abdominal pain, lightheadedness and diaphoresis. He has a history of polycythemia vera (PV) and chronic severe splenomegaly, treated with

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder caused by von Willebrand factor (vWF) dysfunction of various types and severities. Clinical manifestations and differences in the intensity of bleeding are then given by the diversity of vWF disorders. AvWS usually occurs in adult patients with a negative personal or family history of bleeding symptoms and is associated with underlying disease. In recent years, vWF dysfunction has been most commonly attributed to cardiovascular, autoimmune, lymphoproliferative or myeloproliferative comorbidities. The true prevalence of AvWS is unknown, since many cases may be clinically or laboratory silent and remain undiagnosed. Thus, a higher incidence can be expected in the above-mentioned specific patient population. We present a case report of a 90year-old patient with the very first episode of bleeding manifestation and newly diagnosed vWF dysfunction. By describing the case, we will try to present the diagnostic and treatment options of AvWS, including their pitfalls, and draw attention to situations in which to think about AvWS.

Background A plasma-derived factor VIII product (pdFVIII; Factane 100 or 200 IU/mL) and a plasma-derived von Willebrand factor product (pdVWF; Wilfactin 100 IU/mL) are approved for replacement therapy by intravenous bolus injections in hemophilia A (HA) and von Willebrand disease (VWD), respectively. However, in situations requiring intensive treatment, continuous infusion (CI) may be desirable to better control target plasma factor levels. Aim To evaluate the perioperative hemostatic efficacy and safety of these concentrates administered by CI. Methods Three phase III trials were conducted. Adults with HA (FVIII:C Results Studies 1, 2, and 3 included 12, 4, and 6 patients, respectively. Efficacy outcomes were excellent/good in all 22 major surgeries including 18 orthopedic procedures. Most daily measured FVIII and VWF levels (92%) were on target. No safety concerns, thrombotic events, or inhibitors were identified. Conclusion pdFVIII and pdVWF administered by CI represent an effective and safe alternative to bolus injections in patients with severe HA or VWD undergoing surgery.

Left ventricular assist devices (LVADs) have been used as a standard treatment option for patients with advanced heart failure. However, these devices are prone to adverse events. Nonsurgical bleeding (NSB) is the most common complication in patients with continuous flow (CF) LVADs. The development of acquired von Willebrand syndrome (AVWS) in CF-LVAD recipients is thought to be a key factor. However, AVWS is seen across a majority of LVAD patients, not just those with NSB. The purpose of this study was to examine the link between acquired platelet defects and NSB in CF-LVAD patients.Blood samples were collected from 62 CF-LVAD patients at pre- and 4 post-implantation timepoints. Reduced adhesion receptor expression (GPIbα and GPVI) and activation of platelets (GPIIb/IIIa activation) were used as markers for acquired platelet defects.Twenty-three patients experienced at least one NSB episode. Significantly higher levels of platelet activation and receptor reduction were seen in the postimplantation blood samples from bleeders compared with non-bleeders. All patients experienced the loss of high molecular weight monomers (HMWM) of von Willebrand Factor (vWF), but no difference was seen between the two groups. Multivariable logistic regression showed that biomarkers for reduced platelet receptor expression (GPIbα and GPVI) and activation (GPIIb/IIIa) have more predictive power for NSB, with the area under curve (AUC) values of 0.72, 0.68, and 0.62, respectively, than the loss of HMWM of vWF (AUC: 0.57).The data from this study indicated that the severity of acquired platelet defects has a direct link to NSB in CF-LVAD recipients.

Hemophilia, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura (TTP) are rare diseases affecting normal hemostasis. Although they differ in their pathogenesis and clinical manifestation, if left undiagnosed and untreated, all these conditions can result in severe long-term consequences and can be potentially life-threatening. This article summarizes a poster series funded by Takeda and presented virtually at the 29th annual congress of the International Society on Thrombosis and Haemostasis (ISTH) in 2021: Data from real-world evidence highlight the importance of joint health and personalized prophylaxis to prevent bleeding for patients with hemophilia, the need to further raise disease awareness in support of timely diagnosis and access to treatment in general practice settings for patients with VWD, and describe the clinical burden for patients with TTP and the importance to advance treatment options for these patients.

Type 3 von Willebrand disease (VWD), a rare and severe subtype, can produce inhibitors in roughly 5% to 10% of cases. We present a case of type 3 VWD with inhibitors in late pregnancy, which was successfully managed with a combination of neutralization and factor (F)VIII replacement during cesarean delivery. The patient, a 30-year-old woman, had no history of inhibitors despite over 100 exposures to VWF/FVIII. She developed inhibitors after 28 weeks of weekly pd VWF/FVIII prophylaxis for recurrent urolithiasis-associated hematuria during pregnancy. Genetic analysis detected two novel frameshift mutations: VWF Exon7 c.777_784dup and Exon14 c.1625_1646del. Titers of inhibitors to factors VIII and VWF using the Bethesda assay were 1.2 and 1.1 BU/mL, respectively. Pharmacokinetics revealed significantly low in vivo recovery of FVIII:C and VWF:Rcof and shortened half-life. During cesarean delivery, a combination of bolus pd VWF/FVIII once daily for neutralizing inhibitors plus continuous infusion of recombinant FVIII Fc fusion protein resulted in minimal bleeding without allergic reactions. Both VWF:Rcof and FVIII:C levels increased transiently during the 7-h of combination therapy without thrombotic events. In conclusion, combination therapy with neutralization and continuous FVIII replacement was effective for hemostasis with a low VWD inhibitor titer, though further optimization is required.

Desmopressin (DDAVP) is a proven therapy for bleeding disorders; however, the therapeutic efficacy of different parenteral formulations has never been systematically analyzed. This study investigated whether subcutaneous (SC) DDAVP provides equivalent hemostatic efficacy to intravenous (IV) desmopressin, particularly in patients with mild to moderate bleeding tendencies from hemophilia A (HA) or von Willebrand disease (vWD).We searched PubMed, EMBASE, MEDLINE, Cochrane, and CINAHL databases for observational studies and randomized controlled trials which compared the hemostatic efficacy of parenteral formulations of DDAVP in healthy patients and those with bleeding disorders. Two reviewers independently performed screening and data extraction. Extracted data included Factor VIII (FVIII) levels, von Willebrand factor (vWF) antigen levels, and vWF activity.The search strategy yielded a total of 5519 studies. Twelve studies met the inclusion criteria and were included in the review. Seven out of eight studies conducted in patients with bleeding disorders and all four studies conducted in healthy subjects found no difference in hemostatic efficacy between parenteral formulations. A meta-analysis was not performed due to disparities between study design and outcomes of interest.Our study showed that IV and SC administration of DDAVP appeared to result in near equivalent hemostatic efficacy; however, the strength of these findings is limited by the small number and lack of comparability in the primary studies. A sizable contemporary study powered to detect differences in coagulation factor levels would be required to confirm our findings.

Type 1 and type 3 von Willebrand disease (VWD) are caused by partial and complete, quantitative deficiency of von Willebrand factor (VWF), respectively, and factor (F)VIII/VWF complex concentrates are used for haemostatic treatment. Emicizumab, mimics activated FVIII, reduces bleeding in haemophilia A patients. The effects of emicizumab on haemostasis in both types of VWD remain to be fully established, however.To examine the effects of emicizumab on thrombogenesis in type 1 and type 3 VWD.Perfusion chamber experiments under high shear conditions (2500 sThe addition of FVIII (1 U/ml) to type 1 blood did not affect thrombus formation, whilst supplementation with VWF (1.6 U/ml) or FVIII/VWF (1 U/ml/1.6 U/ml) enhanced thrombogenesis to a similar extent. FVIII/VWF promoted thrombus formation significantly more than VWF alone, however, in type 3 blood. Emicizumab (100 μg/ml) augmented thrombus formation in type 3 blood compared to FVIII, and this potency seemed to be somewhat greater than that of VWF. Surface coverage of formed thrombus in type 3 VWD was less than that in type 1 VWD, but thrombus height was comparable in both. The addition of emicizumab to type 3 blood enhanced thrombin generation and fibrin formation compared to control IgG.Emicizumab promoted mechanisms of thrombus formation in vitro in type 3 and type 1 VWD, suggesting the possibility of alternative therapeutic protocols in these patients.

von Willebrand factor (VWF) plays a key role in normal hemostasis, and deficiencies of VWF lead to clinically significant bleeding. We sought to identify novel modifiers of VWF levels in endothelial colony-forming cells (ECFCs) using single-cell RNA sequencing (scRNA-seq). ECFCs were isolated from patients with low VWF levels (plasma VWF antigen levels between 30 and 50 IU/dL) and from healthy controls. Human umbilical vein endothelial cells were used as an additional control cell line. Cells were characterized for their Weibel Palade body (WPB) content and VWF release. scRNA-seq of all cell lines was performed to evaluate for gene expression heterogeneity and for candidate modifiers of VWF regulation. Candidate modifiers identified by scRNA-seq were further characterized with small-interfering RNA (siRNA) experiments to evaluate for effects on VWF. We observed that ECFCs derived from patients with low VWF demonstrated alterations in baseline WPB metrics and exhibit impaired VWF release. scRNA-seq analyses of these endothelial cells revealed overall decreased VWF transcription, mosaicism of VWF expression, and genes that are differentially expressed in low VWF ECFCs and control endothelial cells (control ECs). An siRNA screen of potential VWF modifiers provided further evidence of regulatory candidates, and 1 such candidate, FLI1, alters the transcriptional activity of VWF. In conclusion, ECFCs from individuals with low VWF demonstrate alterations in their baseline VWF packaging and release compared with control ECs. scRNA-seq revealed alterations in VWF transcription, and siRNA screening identified multiple candidate regulators of VWF.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder caused by various underlying diseases or conditions and should be distinguished from the inherited type of von Willebrand disease. AVWS is associated with underlying diseases such as cardiovascular, autoimmune, malignant, proliferative disorders, or with mechanical circulatory support (MCS). AVWS was first reported in 1968 and most case reports describe AVWS in adults. However, AVWS can appear in pediatric patients occasionally as well. Because bleeding complications are rare in everyday life, AVWS may be underdiagnosed in pediatric patients. Therefore, the diagnosis should be suspected in a pediatric patient who is known for one of these underlying diseases or conditions and who presents with an onset of bleeding symptoms, especially before the child will undergo an invasive procedure. Here, we present an overview of the diagnostic analyses regarding AVWS and of the underlying diseases or conditions in which AVWS should be considered. Importantly, the patient's history should be investigated for bleeding symptoms (mucocutaneous or postoperative bleeding). As no single routine coagulation test can reliably confirm or exclude AVWS, the diagnosis may be challenging. Laboratory investigations should include analysis of von Willebrand factor (VWF):antigen, VWF:collagen-binding capacity, VWF:activity, and VWF multimeric analyses. For treatment, tranexamic acid, 1-desamino-8-D-arginine vasopressin, and VWF-containing concentrate can be used. AVWS disappears after the underlying disease has been successfully treated or the MCS has been explanted.

Background: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. Methods: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. Results: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation did not modify multimers profile of VWF in contrast to Heartmate II and Heartmate III. Furthermore, fluid structure interaction coupled with computational fluid dynamics showed a gradually increase of blood damage according to increase of cardiac output ( P Conclusions: We demonstrated that A-TAH does not cause hemolysis or AWVS. However, relationship between HMWM and cardiac output depending flow confirms relevance of VWF as a biological sensor of blood flow, even in normal range.

Background Acquired von Willebrand syndrome (AVWS) is frequent in patients with myeloproliferative neoplasms (MPNs). For von Willebrand factor (VWF) functional evaluation, ristocetin cofactor activity by aggregometry (VWF:RCo) is considered the gold standard but has limitations, and automated activity measurement has been developed such as the HemosIL VWF:RCo Werfen with particle agglutination (VWF:GPIbR). Objectives To evaluate the performance of VWF:GPIbR with HemosIL VWF:RCo Werfen (VWF:GPIbR) versus VWF:RCo in patients with thrombocytosis in the context of MPNs (T-MPNs) and in patients with secondary thrombocytosis (ST). Methods MPN patients with thrombocytosis >450 G/L (T-MPNs) were compared with patients with ST due to inflammation or iron deficiency. VWF activity (VWF:Act) was analyzed using VWF:RCo or VWF:GPIbR. VWF analysis was completed by analysis of VWF multimers and VWF collagen binding (CB) assay (VWF:CB). Results A total of 33 T-MPNs and 18 ST patients were included. Compared with aggregometry, evaluation of VWF:Act by VWF:GPIbR led to lower values in T-MPN patients, but also in ST patients. Interestingly, although the VWF:RCo/VWF:Ag ratio did not reveal differences between T-MPNs and ST patients, the VWF:GPIbR/VWF:Ag ratio analysis allowed us to suspect AVWS only in T-MPN patients. Using the distribution of VWF multimer analysis and VWF:CB, we here demonstrated that VWF:GPIbR allows AVWS diagnosis in nine T-MPNs as opposed to aggregometry. Conclusion Evaluation of VWF:Act using VWF:GPIbR has a greater sensitivity compared with aggregometry to detect AVWS in T-MPN patients.

Von Willebrand factor (VWF) is a glycoprotein that is secreted into the circulation and controls bleeding by promoting adhesion and aggregation of blood platelets at sites of vascular injury. Substantial inter-individual variation in VWF plasma levels exists among the healthy population. Prior to secretion, VWF polymers are assembled and condensed into helical tubules, which are packaged into Weibel-Palade bodies (WPBs), a highly specialized post-Golgi storage compartment in vascular endothelial cells. In the inherited bleeding disorder Von Willebrand disease (VWD), mutations in the VWF gene can cause qualitative or quantitative defects, limiting protein function, secretion, or plasma survival. However, pathogenic VWF mutations cannot be found in all VWD cases. Although an increasing number of genetic modifiers have been identified, even more rare genetic variants that impact VWF plasma levels likely remain to be discovered. Here, we summarize recent evidence that modulation of the early secretory pathway has great impact on the biogenesis and release of WPBs. Based on these findings, we propose that rare, as yet unidentified quantitative trait loci influencing intracellular VWF transport contribute to highly variable VWF levels in the population. These may underlie the thrombotic complications linked to high VWF levels, as well as the bleeding tendency in individuals with low VWF levels.

Background Platelet-binding Von Willebrand Factor (VWF) strings assemble upon stimulated secretion from endothelial cells. Objectives To investigate the efficiency of platelet binding to multi-molecular VWF bundles secreted from endothelial cells and to investigate the role of osteoprotegerin, a protein located in Weibel-Palade bodies that interacts with the VWF platelet binding domain. Methods The nanobody VWF/AU-a11 that specifically binds to VWF in its active platelet-binding conformation was used to investigate the conformation of VWF. Results Upon stimulated secretion from endothelial cells, VWF strings were only partially covered with platelets, while a VWD-type 2B mutation or ristocetin enhanced platelet binding by 2-3-fold. Osteoprotegrin, reduces platelet adhesion to VWF by 40±18% in perfusion assays. siRNA-mediated down-regulation of endothelial osteoprotegerin expression resulted in a 1.8-fold increase in platelet adhesion to VWF strings. Upon viral infection, there is a concordant rise in VWF and osteoprotegerin plasma levels. Unexpectedly, no such increase was observed in plasma of desmopressin-treated hemophilia A-patients. In a mouse model, osteoprotegerin expression was low in liver endothelial cells of vehicle-treated mice, and concanavalin A-treatment increased VWF and osteoprotegerin expression 4- and 40-fold, respectively. This increase was translated in a 30-fold increased osteoprotegerin/VWF ratio in plasma. Conclusions Release of VWF from endothelial cells opens the platelet-binding site, irrespective of the presence of flow. However, not all available platelet-binding sites are being occupied, suggesting some extent of regulation. Part of this regulation involves endothelial proteins that are co-secreted with VWF, like osteoprotegerin. This regulatory mechanism may be of more relevance under inflammatory conditions.

Patients referred for evaluation of bleeding symptoms occasionally have a prolonged platelet function analyser (PFA) closure time, without evidence for von Willebrand disease or impaired platelet aggregation. The aim of this study was to establish a shear-dependent platelet function defect in these patients. Patients were included based on high bleeding score and prior PFA prolongation. Common tests of von Willebrand factor (VWF) and platelet function and exome sequencing were performed. Microfluidic analysis of shear-dependent collagen-induced whole-blood thrombus formation was performed. In 14 PFA-only patients, compared to healthy volunteers, microfluidic tests showed significantly lower platelet adhesion and thrombus formation parameters. This was accompanied by lower integrin activation, phosphatidylserine exposure and P-selectin expression. Principal components analysis indicated VWF as primary explaining variable of PFA prolongation, whereas conventional platelet aggregation primarily explained the reduced thrombus parameters under shear. In five patients with severe microfluidic abnormalities, conventional platelet aggregation was in the lowest range of normal. No causal variants in Mendelian genes known to cause bleeding or platelet disorders were identified. Multiparameter assessment of whole-blood thrombus formation under shear indicates single or combined effects of low-normal VWF and low-normal platelet aggregation in these patients, suggesting a shear-dependent platelet function defect, not detected by static conventional haemostatic tests.

Type 2B von Willebrand disease (VWD) is caused by gain-of-function mutations in von Willebrand factor (VWF). Increased VWF affinity for GPIba results in loss of high molecular weight multimers and enhanced platelet clearance, both contributing to the bleeding phenotype. Severity of the symptoms vary among type 2B VWD patients, with some developing thrombocytopenia only under stress conditions. Efforts have been made to study underlying pathophysiology for platelet abnormalities, but animal studies have been limited because of species specificity in the VWF-GPIba interaction. Here, we generated a severe form of type 2B VWD (p.V1316M) knockin mice in the context of human VWF exon 28 (encoding A1 and A2 domains) and crossed them with human GPIba transgenic strain. Heterozygous mutant mice recapitulated the phenotype of type 2B VWD in autosomal dominant manner and presented severe macrothrombocytopenia. Of note, platelets remaining in the circulation had extracytoplasmic GPIba shed-off from the cell surface. Reciprocal bone marrow transplantation determined mutant VWF produced from endothelial cells as the major cause of the platelet phenotype in type 2B VWD mice. Moreover, altered megakaryocyte maturation in the bone marrow and enhanced extramedullary megakaryopoiesis in the spleen were observed. Interestingly, injection of anti-VWF A1 blocking antibody (NMC-4) not only ameliorated platelet count and GPIba expression, but also reversed MK ploidy shift. In conclusion, we present a type 2B VWD mouse model with humanized VWF-GPIba interaction which demonstrated direct influence of aberrant VWF-GPIba binding on megakaryocytes.

Coagulopathic bleeding is common during adult extracorporeal membrane oxygenation (ECMO), and acquired von Willebrand syndrome is a contributing factor. We compared ECMO patient blood samples that were treated in vitro with recombinant von Willebrand Factor concentrate and plasma-derived von Willebrand Factor concentrate. Our hypothesis was that recombinant von Willebrand Factor (vWF) would have greater efficacy in increasing vWF function. Secondarily, we hypothesized that recombinant vWF would have less impact on thrombin generation.Thirty ECMO patients and 10 cardiac surgical controls were enrolled in the study. ECMO patient blood samples were treated in vitro with low- and high-dose recombinant vWFs and low- and high-dose plasma-derived vWFs. Whole blood ristocetin-induced platelet aggregation (RIPA), plasma ristocetin cofactor activity (RCo), and thrombin generation were compared between ECMO patient blood samples and control blood samples and between vWF-treated ECMO patient blood samples and nontreated samples.ECMO patient blood samples had severely reduced median RIPA compared to control samples 2 ohms (1-12 [25th-75th percentile]) vs 20 ohms (11-42) (P.001). Treatment of ECMO patient blood samples with high-dose recombinant vWF significantly increased median RIPA to 10 ohms (2-15) (P.001), while low-dose recombinant vWF and low- and high-dose plasma-derived vWFs did not significantly increase RIPA; 6 ohms (3-14), 4 ohms (1-13), and 6 ohms (2-10), respectively (P = .25,.99, and.99). Treatment with high-dose recombinant vWF and low- and high-dose plasma-derived vWFs significantly increased median plasma RCo to 4.7 international units (IU)/mL (3.7-5.9), 3.3 IU/mL (2.7-4.8), and 3.9 IU/mL (3.4-5.3), respectively, compared to controls 1.8 IU/mL (1.5-2.3) (all P.001). Treatment with low- and high-dose plasma-derived vWFs significantly increased mean endogenous thrombin potential (6270.2 ± 2038.7 and 6313.1 ± 1913.3) compared to nontreated samples (5856.7 ± 1924.6) (P = .04 and .006), whereas treatment with low- and high-dose recombinant vWFs had no significant effect on mean endogenous thrombin potential (5776.1 ± 2087.3 and 5856.2 ± 1946.4) (P.99 for both comparisons).In vitro treatment of ECMO patient blood samples with high-dose recombinant vWF was superior to low-dose recombinant vWF and plasma-derived vWF in terms of improving RIPA. In addition, recombinant vWF treatment did not increase endogenous thrombin potential, which may reduce overall thrombotic risk if it used to treat acquired von Willebrand syndrome in ECMO patients.

In older patients, multiple chronic conditions lead to the intake of multiple medications and a higher risk of adverse drug events. The exposure to inappropriate medications in older patients with bleeding disorders is poorly explored. The aim of this study was to describe the exposure to potentially inappropriate medications (PIMs) and medications with anticholinergic and sedative properties in older community-dwelling patients with haemophilia or von Willebrand Disease (VWD).The M'HEMORRH-AGE study (Medication in AGEd patients with HAEMORRHagic disease) is a multicentre prospective observational study. Community-dwelling patients over 65 years with haemophilia or VWD were included in the study. PIMs were identified using the EU(7)-PIM list, and the anticholinergic and sedative drug exposure was measured using the Drug Burden Index.142 older community-dwelling patients with haemophilia (n = 89) or VWD (n = 53) were included (mean age: 72.8 ± 5.8 years). PIMs were used by 45.8% of older patients and were mainly represented by cardiovascular (34.9%), nervous systems (26.7%) and alimentary tract and metabolism PIMs (25.6%). Regarding anticholinergic and/or sedative medications, 37.3% of older patients were exposed mainly due to nervous system medications (68.3%), for example analgesics.The M'HEMORRH-AGE study showed the exposure to PIMs and anticholinergic/sedative medications was high in older community-dwelling patients with haemophilia or VWD. Interventions focusing on deprescription of these inappropriate medications should be conducted in this specific population.

To describe the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database, its key components, and exploratory analyses of surgeries conducted between 1998 and 2019.Surgical data across bleeding disorders collected retrospectively (1998-2006) and prospectively (2006-2019) were analyzed. Perioperative hemostasis, complications, and surgical plan deviations were compared by bleeding disorder diagnosis and data collection period.Within the 21-year period, 3246 procedures were conducted in 1413 patients with a diagnosis of von Willebrand disease (vWD), hemophilia A (HA), hemophilia B (HB), and other bleeding disorders. Majority of the procedures were minor (63.3%), and median number of surgeries per patient was 1 (range: 1-22). Adequate perioperative hemostasis was achieved in 90.9%, complications occurred in 13.6%, and surgical plan deviations occurred in 31.3% of procedures. Inadequate perioperative hemostasis and surgical plan deviations occurred more frequently in procedures involving HB compared with other bleeding disorders. Complications were not significantly different across bleeding disorders (p = .164). The prospective data collection period was associated with higher rates of hemostatic efficacy (92.4% vs. 88.3%; p .001), complications (14.3% vs. 12.3%; p .001), and plan deviations (34.2% vs. 25.1%; p .001).The surgical database is an important resource in surgical management in patients with bleeding disorders. Further evaluation will facilitate use for the development of predictive models and principles of care.

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.

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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.

von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.These evidence-based guidelines of 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 other health care professionals in their decisions about VWD diagnosis.ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment.The panel agreed on 11 recommendations.Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.

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.