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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)

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.

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.

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.

INTRODUCTION Von Willebrand disease (VWD) is the most common inherited bleeding disorder. The bleeding phenotype is variable, and some individuals have persistent symptoms post-diagnosis. AIM To characterize bleeding patterns in patients with VWD before and after diagnosis. METHODS De-identified claims data for commercially insured patients in the IQVIA PharMetrics® Plus US database (Jan-2006 to Jun-2015) were extracted. Eligible patients had ≥2 claims for VWD (ICD-9 code 286.4), and continuous health-plan enrolment for ≥2 years before and after diagnosis. Bleeding event, treatment and treating-physician type were analysed for 18 months before and 7-24 months after diagnosis, according to pre-diagnosis bleeding phenotype (claims from one vs multiple bleed sites) and post-diagnosis bleeding status (resolved [no post-diagnosis bleed claims] vs continued [≥1 claim]). RESULTS Data for 3756 eligible patients (72.6% female; 71.0% aged ≥18 years at diagnosis) were analysed. Overall, 642 (17.1%) and 805 (21.4%) patients had single- and multiple-site bleed claims pre-diagnosis, respectively, and 1263 (33.6%) patients (38.5% of women, 20.8% of men) continued to bleed post-diagnosis. Multiple-site bleeding was associated with pre-diagnosis heavy menstrual bleeding (HMB), oral contraceptive (OC) use and nasal cauterization. Continued bleeding post-diagnosis was associated with pre-diagnosis gastrointestinal bleeding, HMB and epistaxis; pre-diagnosis use of OCs, aminocaproic acid and nasal cauterization; and younger age at diagnosis. Few patients consulted a haematologist for bleed management. CONCLUSION Many patients with VWD have persistent bleeding from multiple sites and continue to bleed post-diagnosis. Our findings suggest a need to optimize management to reduce the symptomatic burden of VWD following diagnosis.

Introduction While it has been shown that haemophilia patients receiving care at Haemophilia Treatment Centres (HTCs) experience decreased morbidity and mortality, little research has been done on the outcomes of patients with von Willebrand disease (VWD). Aim To compare the quality of periprocedural care received by patients with VWD at HTCs and non-HTCs. Methods We performed a retrospective chart review on all adult VWD patients undergoing an invasive procedure from 2015 to 2017. Quality of periprocedural care was measured using the following surrogate outcomes: periprocedural VWD-specific therapy use per 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines, procedural estimated blood loss (EBL), and post-procedure bleeding. Comparisons were performed according to the setting of care at the time of the invasive procedure, HTC versus non-HTC. Results There were 668 invasive procedures performed on 305 patients, of which 8.2% were HTC cases. Non-type 1 VWD was more likely in HTC cases. VWD-specific therapy was used per NHLBI guidelines in 100% of HTC cases compared with 10.6% of non-HTC cases. Procedural EBL > = 100 ml was more likely to occur in HTC differences cases (OR = 2.34; 95% CI, 1.05 to 5.25). There was no difference in post-procedure bleeding between the two groups (OR = 1.26, 95% CI, .20- 7.86). Conclusion Despite widespread periprocedural use of VWD-specific therapy outside established guidelines at non-HTCs, there was no difference in periprocedural bleeding. Possible explanations include diagnostic error, in disease severity and procedure types, and dataset limitations. Additional studies are needed to investigate this further and compare other patient care outcomes between HTCs and non-HTCs.

INTRODUCTION Published guidelines are available to assist in the management of patients with inherited bleeding disorders in the elective surgical setting however good quality outcome data is lacking. AIM - Evaluate the outcomes of adult patients with inherited bleeding disorders, who received factor replacement for elective surgery in NSW/ACT, Australia. - Assess adherence to relevant guidelines including Haemophilia Treatment Centre (HTC) utilisation and appropriate factor replacement. METHOD A retrospective analysis was performed between 2000 and 2018 to describe patient characteristics, surgical details, factor provision and outcomes. Univariate analysis was used to determine variables associated with guideline adherence. Covariates with p

INTRODUCTION Menorrhagia impacts ~40% of adolescent females, with about half having an underlying bleeding disorder, most commonly von Willebrand Disease (VWD). VWD affects ~1 in 1000 individuals, though many are unaware of their condition. Let's Talk Period (LTP) is an online knowledge translation platform aimed at increasing awareness of bleeding disorders symptoms, with a validated self-administered bleeding assessment tool (Self-BAT). AIM To evaluate the effectiveness of the LTP high school outreach program in Grade 9 girls' health classes quantitatively, using baseline, post-presentation, and follow-up quiz scores, and qualitatively, with student and teacher feedback forms. METHODS The 75-minute in-class presentations, developed in alignment with the 2015 Ontario Curriculum for Grade 9 Health and Physical Activity, were led by a haemophilia nurse, clinical research assistant, and undergraduate student from the LTP team. Students completed baseline, post-presentation, and 4-6-week follow-up Kahoot quizzes featuring the same nine questions to evaluate change in knowledge levels and retention. Both student and teacher feedback were collected. RESULTS There was a significant increase (p

Introduction Von Willebrand Disease is a common inherited haemorrhagic disorder due to a deficiency of Von Willebrand Factor (VWF). In case of surgical procedures in patients who are not responsive or have contraindications to desmopressin, replacement therapy with VWF concentrates is indicated. Until recently, only plasma-derived VWF concentrates were available. A new recombinant VWF (rVWF) concentrate that contains no Factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France since 2018. Aim Describe real-world experience of using rVWF in surgical procedures. Methods Sixty-three surgeries for 55 patients were retrospectively analysed in 7 French haemostasis centres. Results During minor surgeries, the median (range) number of infusions was 1 (1-8) with a preoperative loading dose of 35 (19-56) rVWF IU/kg and a total median dose of 37.5 IU (12-288). During major surgeries, the median (range) number of infusions was only 3 (1-14) with a median preoperative loading dose of 36 IU (12-51) rVWF IU/kg, and a total median dose of 108 IU (22-340) rVWF IU/kg. The overall clinical efficacy was qualified as excellent/good in 61 of the procedures (97%), moderate in 1 (1.5%) and poor in 1 (1.5%). There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events, anti-VWF antibodies or adverse events were reported. Conclusion This French 'real-world' experience shows that a few infusions and low doses of rVWF provided effective prevention of bleeding in major and minor surgeries in inherited VWD, with no clinically significant safety concerns.

Introduction HaemoassistTM 2 is an electronic system designed for people with bleeding disorders and their physicians to record prophylactic infusions and treatment of bleeds. It aims to improve adherence by permitting reminders and accuracy of documentation by facilitating real-time reporting. Aim To assess documentation quality and adherence to prophylactic regimens in patients with haemophilia A, haemophilia B or von Willebrand disease who are using HaemoassistTM 2. Methods Ten centres enrolled consecutive patients, who had been using HaemoassistTM 2 for ≥ 3 months (Cohort 1, 'quality of documentation'). Of these, patients who had a specified prophylactic regimen in HaemoassistTM 2 for ≥ 3 months were eligible for inclusion in Cohort 2 ('adherence to prophylaxis'). Results Cohort 1 comprised 796 patients (71% with severe haemophilia A; median 20.5 months of HaemoassistTM 2 use). The most common method of documentation for patients was using the mobile app; the median time between infusion and documentation was 4 hours using the app, compared with 85 hours using a web portal on a stationery device. The median total annualised number of infusions was consistent in the first and last 3 months of documentation (128; IQR: 70-184 and 120; IQR 64-176, respectively). Cohort 2 comprised 202 patients (79% severe haemophilia A; median of 13 months on prophylactic regimen in HaemoassistTM 2). The rate of adherence to prophylaxis was 83%; median deviation between planned and actual infusion time was ± 2 hours. Conclusion HaemoassistTM 2 was used consistently over prolonged periods of time and allowed for precise analysis of adherence to prophylaxis.

Introduction The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations. Aim To describe the development, methodology and achievements of the WFH AGS over the past 20 years. Methods The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues. Results Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry. Conclusion The AGS has provided evidence to support research, programme planning and development activities of the WFH.

Acquired bleeding disorders can accompany hematological, neoplastic, autoimmune, cardiovascular or liver diseases, but can sometimes also arise spontaneously. They can manifest as single factor deficiencies or as complex hemostatic abnormalities. This review addresses (a) acquired hemophilia A, an autoimmune disorder characterized by inhibitory autoantibodies against coagulation factor VIII; (b) acquired von Willebrand syndrome in patients with cardiovascular disorders, where shear stress abnormalities result in destruction of von Willebrand factor; and (c) liver function disorders that comprise complex changes in pro- and anti-hemostatic factors, whose clinical implications are often difficult to predict. The article provides an overview on the pathophysiology, diagnostic tests and state-of-the-art treatment strategies.

BACKGROUND The aim of the study was to compare the perioperative blood loss, need for transfusion and one-year revision rates in patients undergoing hip and knee arthroplasty who also have a diagnosis of von Willebrand disease (VWD) with a matched control group. METHODS A retrospective single-centre case-control study was conducted. Fifty-eight patients with VWD and 116 controls (1:2 match) who were operated for primary or revision hip and knee arthroplasty at our hospital were included. Blood loss, haemoglobin (Hb)-drop, need for blood transfusion, intraoperative complications and revision rates within one year were noted in all cases. Outcome measures for subgroups of the primary hip, primary knee, revision hip and revision knee procedures, were also analysed. RESULTS The mean perioperative Hb-drop was 3.47 (±1.27) g/dL and blood loss was 293 (±97) ml for the VWD group while Hb-drop was 2.85 (±1.21) g/dL and blood loss was 232 (±105) mL for the control group (P

Introduction von Willebrand disease (VWD) diagnosis starts with first level tests: factor VIII coagulant activity, VWF antigen (VWF:Ag) and platelet-dependent VWF activity (VWF:RCo, VWF:Ab, VWF:GPIbR or VWF:GPIbM). The VWF collagen binding (VWF:CB) assay measures the binding capacity of von Willebrand factor (VWF) to collagen. Aim To assess, in previously diagnosed VWD patients, the performance of a fully automated chemiluminescent test panel including VWF:Ag, VWF:GPIbR and VWF:CB assays. Methods The patients, historically evaluated using in-house VWF:Ag and VWF:CB assays and an automated latex enhanced immunoassay VWF:GPIbR method, were re-evaluated using the VWF test panel HemosIL AcuStar. Results The VWF:GPIbR/VWF:Ag and VWF:CB/VWF:Ag obtained by means of AcuStar showed an overall good concordance with the corresponding data obtained at the time of the historical diagnosis. When discrepancies occurred, these were generally due to the lower VWF:CB/VWF:Ag obtained with AcuStar as compared with that obtained with the historical methods and this affected particularly the diagnosis of VWD type 2M. Together, the AcuStar VWF:GPIbR/VWF:Ag and VWF:CB/VWF:Ag were able to distinguish type 1 from types 2A, 2B and 2M, whereas no distinction was possible between type 2A and 2B. Conclusion The AcuStar panel offers a good performance in the differential diagnosis between VWD type 1 and 2A/2B patients. A high rate of coincidence with historical diagnosis was obtained for VWD types 3, 2A/2B and 1. Even though in some cases more tests (eg, RIPA/multimeric analysis) are needed to complete an accurate VWD classification, the AcuStar panel is considered a sensitive, rapid and reliable tool to diagnose VWD patients.

Introduction Postpartum haemorrhage (PPH) is the main cause of maternal morbidity and mortality globally, but it is far more important in non-developed countries. PPH represents 25% of all maternal deaths worldwide. Women with von Willebrand disease (VWD) and other inherited haemorrhagic disorders are at increased risk of PPH. Our aim was to establish a probable association of severe PPH in women with a history of haemostatic abnormalities. Methods An observational, controlled study of adult women with a one or more episodes of severe PPH requiring treatment in an intensive care unit or >10 units of blood products during the 24-hour period after diagnosis and their controls. The tests performed were blood cell count, blood group, renal, viral, liver function and haemostatic tests, fibrinogen, activity of the plasma factors and specific test to diagnose and classify VWD. Results We included 124 women with 133 PPH events and their controls. The median age at the first event was 25.5 years old. Results were significantly different between the groups in terms of fibrinogen concentration, VWF:Ag, VWF:RCo and FVIII. A specific diagnosis was established in 69 (55.6) and 4 (3.2%) patients in the PPH group and controls, respectively. Of 61 patients with VWD, 57 had type 1, two had type 2A, and another two had type 2B. Conclusion Our results show a relationship between PPH and inherited haemostatic disorders. VWD was the most frequent diagnosis. Appropriate and opportune diagnosis before pregnancy of inherited haemostatic disorders may be important to effectively prevent and treat PPH.

Background Laboratory diagnosis of von Willebrand Disease (VWD) is complex. Reliance on laboratory testing can be problematic as different VWD screening panels, assays and methodologies can produce analytic variability in test results. Objectives To compare the degree of imprecision among the VWD assays and within the platelet binding activity (PBA) assays, to determine the consensus among the VWD assays for correct classification of sample results, and to determine consensus among laboratories' von Willebrand factor (VWF) multimer interpretations and final interpretations of the VWD panels. Patients/methods Proficiency testing results from the North American Specialized Coagulation Laboratory Association (NASCOLA) submitted by laboratories from 2010 to 2019 for all normal, type (T) 1 VWD and T2 VWD samples were analysed. Results and conclusions Imprecision was lowest for VWF antigen and highest for collagen binding activity (CBA) with median coefficient of variation (CV) of 12% (interquartile range (IQR) 7%) and 23% (IQR 21%) respectively. Within the VWF PBA assays, the gain-of-function mutant GP1b binding (VWF: GP1bM) methods had the least imprecision (CV 9%, IQR 10%). All assays, including the various PBA methods had excellent consensus. The majority of laboratories agreed that normal (median consensus-82%, IQR 16%) and T1 VWD (median consensus-100%, IQR 9%) samples had normal multimer distribution. Consensus among laboratories for final interpretations was excellent for normal samples (median 81%, IQR 8%), good for T1 VWD samples (median 59%, IQR 9%), and fair for T2 VWD samples (median 44%, IQR 21%). Consensus on final interpretation decreased as sample complexity increased.

Introduction: It has been hypothesized that persons with von Willebrand disease (VWD) may be protected against arterial thrombosis despite having atherosclerosis. Aim: To calculate a nationwide estimate of the absolute and comparative burden of cardiovascular disease (CVD) hospitalization and mortality among persons with VWD using birthdate and sex-matched comparisons from the general population in Sweden. Methods: Persons with VWD regardless of the type and severity, diagnosed by a medical doctor, who lived in Sweden for some time during the observation period 1987 through 2008 were included. For each participant with VWD, up to five randomly selected birthdate- and sex-matched persons from general population were selected as controls. Results: A total of 2790 participants with VWD including 888 male and 1902 female subjects and 13 938 controls were included. Overall, the hazard of CVD-related hospitalization was 1.3-fold (95% CI: 1.1, 1.5) among participants with VWD after adjusting for sex, birthdate, diabetes and cancer. However, they had a 0.4-fold (95% CI: 0.3, 0.6) hazard of CVD-related mortality compared to general population sample. Conclusions: In this nationwide, long-term register study with individually matched controls, we have been able to show that persons with VWD have a higher hospitalization rate due to CVD events. However, the mortality rates appear lower than in the control population. The latter finding is consistent with previous studies and indicates a protective effect of the clotting factor deficiency inherited with VWD. (Less)

Introduction Patients with bleeding disorders may experience limitations in sports participation and physical activity. Several studies on sports participation have been performed in haemophilia patients, but studies in patients with von Willebrand disease (VWD) are lacking. Aim We assessed the sports participation and physical activity of a large cohort of VWD patients. Methods Patients were included from the "WiN study." All patients completed a questionnaire on sports participation, physical activity, quality of life and bleeding symptoms (Tosetto bleeding score). Results From the 798 included patients, 474 had type 1, 301 type 2 and 23 type 3 VWD. The mean age was 39 +/- 20 (standard deviation) years. Five hundred and fifty-two patients (69.3%) participated in various types of sports. Type 3 VWD patients more often did not participate in sports due to fear of bleeding and physical impairment, respectively, OR = 13.24 (95% CI: 2.45-71.53) and OR = 5.90 (95% CI: 1.77-19.72). Patients who did not participate in sports due to physical impairment had a higher bleeding score item for joint bleeds 1.0 (+/- 1.6) vs 0.5 (+/- 1.1) (P = 0.036). Patients with type 3 VWD and patients with a higher bleeding score frequently had severe limitations during daily activities, respectively, OR = 9.84 (95% CI: 2.83-34.24) and OR = 1.08 (95% CI: 1.04-1.12). Conclusion The majority of VWD patients participated in sports. Patients with type 3 VWD, a history of joint bleeds and a more severe bleeding phenotype frequently experienced limitations in sports participation and physical activities during daily life.

Introduction We present the first registry of patients with congenital bleeding disorders and COVID‐19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID‐19, the course of the disease if it occurs and the psychosocial and occupational impact on this population. Methods We included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, 2 rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data. Results 42 patients presented symptoms suggestive of infection by COVID‐19 and in 6 cases the disease was confirmed by RT‐PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID‐19 in two patients on prophylaxis with non‐factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognised disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75%of cases. Only 4.4% of consultations were held in person. Conclusions Patients with congenital bleeding disorders infected with SARS‐CoV‐2presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center is essential to make a correct assessment of the risk of haemorrhage/thrombosis.COVID‐19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.

von Willebrand disease (VWD) and haemophilia represent the most common inherited or acquired bleeding disorders. However, many laboratories and clinicians may be challenged by their accurate diagnosis or exclusion. Difficulties in diagnosis/exclusion may include analytical issues, where assays occasionally generate an incorrect result (ie representing an analytical error) or have limitations in their measurement range of and/or low analytical sensitivity. Also increasingly recognized is the influence of preanalytical issues on the diagnosis of VWD or haemophilia. Unfortunately, postanalytical considerations are often not well considered in the diagnostic process. Therefore, this narrative review aims to provide an overview of some important postanalytical considerations that may help improve the diagnosis of VWD and haemophilia. This review primarily discusses aspects around reporting of test results. However, we also discuss other less well-recognized postanalytical considerations, including the use of assay ratios to help identify differential diagnoses and then guide further investigation.

The inherited bleeding disorder von Willebrand disease (VWD) is challenging to diagnose owing to disease heterogeneity, lack of a definitive laboratory test and variations in diagnostic criteria. We evaluated the impact of diagnosis and diagnostic delay on patient outcomes. The PharMetrics Plus Database was interrogated for medical claims for VWD (ICD-9 286.4) and bleeding events between 1 January 2006 and 30 June 2015. Longitudinal analysis was performed of patients newly diagnosed with VWD (≥9 months' continuous enrolment before first VWD claim) through 24 months following diagnosis. In total, 32 028 diagnosed, including 18 182 newly diagnosed, patients were identified. Most patients (72%) were female. Prediagnosis, bleeding symptoms were most commonly managed by a hospitalist/emergency room physician. Misrecognition of VWD was common, with 25% of patients visiting the same specialist type at least twice for an episodic bleed before diagnosis. Thirty-seven percentage of patients had no diagnostic laboratory test within 24 months of their initial diagnostic claim. Bleed claims reduced following diagnosis: 41% and 26% of female and male patients, respectively, had claims in the year prediagnosis, falling to 21% and 9% of patients at 1-2 years postdiagnosis. The proportion of patients with multiple bleed claims also decreased, from 17% to 6% (females) and 7% to 3% (males). Serially misrecognized patients continued to have more bleeding episodes than other patients, although bleed frequency was lower than before diagnosis. There is a need for improved patient management from bleeding presentation onward to reduce the time to VWD diagnosis and to enhance patient outcomes.

Background Red blood cells (RBCs) contribute to hemostasis under blood-flow, and anemia might contribute to a hemorrhagic diathesis. The majority of current laboratory techniques to assess hemostasis do not consider the effects of RBCs. An assay to determine the role of RBCs in hemostasis could be beneficial for clinical management. Objectives To investigate the influence of RBCs in hemostasis. Methods Hemostasis was investigated using a novel microchip flow-chamber system (T-TAS®) in an anemic patient with von Willebrand disease. Subsequently, the effects of RBCs in total thrombus analysis system (T-TAS) were examined using reconstituted whole blood at various hematocrit levels. Results In vivo: When the patient was anemic and demonstrated persisted hemorrhagic symptoms despite the maintained adequate von Willebrand factor ristocetin cofactor activity levels, thrombus formation determined by T-TAS was delayed. However, transfusions of RBCs resolved bleeding symptom and, accordingly, the thrombus formation in T-TAS improved. In vitro: Thrombus formation determined by T-TAS at 1000 s−1 was dose-dependent on hematocrit (the time to reach 10 kPa (T10): 10.0 ± 0, 9.5 ± 1.4, 6.7 ± 2.4, 2.8 ± 1.6 min at hematocrits of 0%, 12.5%, 25% and 50%, respectively). Markedly defective thrombus formation (T10 >10 min) was confirmed at a hematocrit

INTRODUCTION Family members of Von Willebrand disease (VWD) patients may have low levels of VWF without major bleeding episodes and often remain undiagnosed. AIM The purpose of this study was to assess the utility of a modified Screening Tool in identifying previously untested reproductive age female family members of VWD patients for haemostatic evaluation. METHODS Ninety-four reproductive age women including 41 previously untested family members of VWD patients, 26 previously diagnosed VWD patients and 27 healthy controls were administered a modified Screening Tool and had blood drawn for CBC, ferritin, and VWF testing. Participants completed a pictorial blood assessment chart (PBAC) with menses. RESULTS The modified Screening Tool was positive in 32% family members, 77% VWD patients, and 19% controls (P < 0.001). Combined with low ferritin, the modified Screening Tool was positive in 66% family members, 92% VWD patients, and 44% controls (P = 0.001). In family members, incorporating low ferritin with the modified Screening Tool resulted in a sensitivity of 86% (95% CI, 42-100) and negative predictive value of 93% (95% CI, 66-100). In the control group, NPV was between 92% and 95% for the modified Screening Tool and also for the modified Screening Tool combined with low ferritin or a positive PBAC. CONCLUSION These data in a racially diverse population suggest the usefulness of a simple, easy to administer modified Screening Tool. In conjunction with ferritin it could be used in a primary care setting to stratify reproductive age women with a family history of VWD for haemostatic evaluation.

Item does not contain fulltext INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients. AIM: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients. METHODS: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score. RESULTS: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL-1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL-1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age

INTRODUCTION von Willebrand disease (VWD) is one of the most common inherited bleeding disorders. AIM Investigate the impact of the VWD bleeding tendency on in-hospital management of acute coronary syndromes (ACS). METHODS Using discharge data from the National Inpatient Sample (NIS), the features of presentation and in-hospital treatment among ACS hospital discharges with and without a VWD diagnosis were investigated. A total of 264 case discharges and 705 860 control discharges were identified. RESULTS AND CONCLUSIONS There was a significantly higher percentage of women among the case discharges compared to the control discharges (59.5% and 39.4%, respectively; P < 0.001). The rate of medical therapy alone [i.e. avoidance of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)] was significantly higher among unstable angina cases than controls (55.0% vs. 46.4%; P = 0.01), and among cases undergoing PCI, bare-metal stents (BMS) were utilized in preference to drug-eluting stents (DES) (adjusted OR = 3.5); P < 0.001). No difference in in-hospital death was identified, but reported bleeding among discharges that underwent CABG was higher in cases compared to controls (12.9% vs. 5.2%; P = 0.047). Although medical and interventional management of ACS appears to be well tolerated in the majority of hospitalized patients with VWD, the gender ratio is reversed, interventions and DES are utilized less frequently and procedure-related bleeding may be increased, calling for further study.

Introduction von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Currently, studies investigating the health-related quality of life (HR-QoL) in VWD using standardized tools are limited, particularly among patients with mild decreases in von Willebrand factor or activity. Aim To determine HR-QoL and its predictors among patients with mild, moderate and severe forms of VWD. Methods Patients with clinical diagnosis of VWD were recruited from a tertiary Inherited Bleeding Disorder Clinic. Upon informed consent, bleeding scores were obtained via a standardized, self-administered tool. Each participant also completed a HR-QoL questionnaire (SF-36). Analyses included paired t-test, independent t-test, one-way anova and multivariate regression. Results A total of 102 patients were recruited (consent rate = 95%). Participants were 38 years on average (SD 14.8), 78% were female and 80% were diagnosed with VWD Type 1. Compared to age- and sex-matched normative data, VWD patients had clinically and statistically significant reductions in seven of eight HR-QoL domains and the physical and mental component summaries. Adjusted for age, sex, socioeconomic status and rurality, there was a trend towards lower physical component summary with increasing bleeding score, and lower mental domains with iron deficiency status (P = 0.07 and P = 0.08 respectively). Conclusion This study is the first to examine the impact of VWD on HR-QoL across disease severity while incorporating socioeconomic status and rurality. Significant reductions in HR-QoL among VWD patients, especially the relationship between iron status and mental HR-QoL, strengthen the rationale for prospective studies to evaluate the efficacy of iron replacement in this setting.

INTRODUCTION:Reducing bleeding episodes is very important in haematology disorders like von Willebrand disease (VWD) and Glanzmann thrombasthenia (GT). Replacement factors are very expensive although prophylactic drugs are affordable. OBJECTIVE:To study the prophylactic effects of tranexamic acid (TXA) for reduction of bleeding episodes in patients with VWD and GT in non-invasive conditions. METHODS:A controlled, double-blind before and after single-centre trial was performed in Amir-Kabir Hospital (Arak, Iran). The study was done on 17 patients with VWD and three patients with GT with minimum age of 2 years. Patients were received placebo for 6 months to evaluate the frequency and severity of bleeding and also to record the frequency of use of factor concentrates and platelet transfusion. After that, patients were given oral single dose of TXA 25 mg kg(-1) day(-1) for 6 months. The mentioned outcomes were studied and compared between two phases of study. Safety assessment was done in all patients. RESULTS:Tranexamic acid caused a significant reduction in number of Grade 1 and Grade 2 bleeding episodes in VWD patients (P < 0.001 and P < 0.01 respectively). In addition, TXA therapy was associated with significant decrease in the use of factor concentrates (P < 0.05). Number of bleeding episodes decreased in GT patients who used TXA; however, difference between two phases of studies was not significant (P = 0.1). TXA had no effect in the frequency of platelet transfusions in GT patients. TXA therapy was associated with headache, back pain and musculoskeletal pain. No case of allergy or thromboembolic events was seen following treatment. CONCLUSIONS:The results suggest that TXA is safe and effective to reduce bleeding and use of factor concentrates in VWD patients. In addition, TXA therapy can decrease bleeding in GT patients. KEYWORDS:Glanzmann thrombasthenia; VWD; bleeding; tranexamic acid

Introduction Haemostatic assessments of patients with von Willebrand disease (VWD) who undergo total knee arthroplasty (TKA) and total hip arthroplasty (THA) have mainly relied on subjective parameters. Aims To compare objective haemostatic outcomes of TKA/THA in VWD patients and controls without bleeding disorders. Methods We retrospectively analysed haemostatic outcomes in VWD patients undergoing TKA/THA from 1993 to 2011 and compared them with two matched controls per operation. Using one-way analysis of variance, we tested the effect of VWD on bleeding risk after TKA and THA. Results Twelve VWD patients (6 type 1, 3 type 2M, 1 each of types 2A/2B/3) undergoing 19 operations (12 TKA, 7 THA) were matched to 38 controls. One (5%) of 19 operations in VWD patients and none of the control operations met clinical criteria for major bleeding. Baseline and postoperative day 1 haemoglobin levels, postoperative blood loss, transfused red blood cells (RBCs) and mean hospitalization days were not significantly different. More VWD patients than controls received RBC transfusions [12 (63%) vs. 12 (32%)]. Only 9 (47%) VWD patients vs. 38 (100%) controls received pharmacologic VTE prophylaxis. No postoperative symptomatic VTE occurred in either group. Conclusion In this largest, single-institutional study, von Willebrand factor replacement based on daily levels resulted in low frequency of major bleeding in VWD patients after TKA/THA. RBC transfusion was more frequent compared with matched controls, but other objective measures of haemostasis were similar. Lack of sufficient details in published reports precluded comparison of haemostatic outcomes.

Introduction Despite the availability of subcutaneous desmopressin (1-deamino-8-d-arginine vasopressin, SC-DDAVP) as a haemostatic agent for children with mild bleeding disorders, few publications specifically address the safety or efficacy of this mode of administration. Aim Our aim was to assess whether a defined fluid restriction protocol was effective in preventing hyponatremia in children receiving perioperative SC-DDAVP, and to document adequate biological and clinical response in this setting. Methods We retrospectively analysed a cohort of children with mild bleeding disorders prescribed SC-DDAVP over a 5-year period following institution of a ‘two-thirds maintenance’ fluid restriction protocol. Results Sixty-nine patients received SC-DDAVP following this protocol, including 15 with mild haemophilia A, 49 with von Willebrand disease (VWD) and five with platelet storage pool disorder. In patients who underwent formal preoperative assessment a complete or partial response was observed in 28/29 with type 1 VWD and 14/15 with mild haemophilia A. Perioperative SC-DDAVP provided excellent haemostasis in all patients, with no requirement for factor concentrate or blood products. Mild asymptomatic hyponatremia was detected in seven children who received multiple doses of DDAVP (lowest sodium 129 mmol L−1); however, adherence to the prescribed fluid restriction protocol was questionable in six of these cases. Symptomatic hyponatremia was not observed. Conclusion Subcutaneous desmopressin was well-tolerated, with no serious side-effects observed, and good biological responses in preoperative trials. A two-thirds maintenance fluid regimen was effective at preventing symptomatic hyponatremia in our cohort, and is now the standard protocol for fluid restriction post-DDAVP administration in our centre.