Perioperative management of patients with von Willebrand disease

Surgical procedures represent a serious hemostatic challenge for patients with von Willebrand disease (VWD), and careful perioperative management is required to minimize bleeding risk. Risk stratification includes not only the nature of the surgery to be performed but the baseline plasma vonWillebrand factor (VWF) levels, bleeding history, and responses to previous challenges. Baseline bleeding scores (BSs) may assist in identification of patients with a higher risk of postsurgical bleeding. There remains a lack of consensus between best practice guidelines as to the therapeutic target and assays to be monitored in the postoperative period. Hemostatic levels are maintained until bleeding risk abates: usually 3 to 5 days forminor procedures and 7 to 14 days formajor surgery. Hemostatic supplementation ismore complex in VWD than in other bleeding disorders owing to the combined but variable deficiency of both plasma VWF and factor VIII (FVIII) levels. For emergency surgery, coadministration of VWF and FVIII is required to ensure hemostasis; however, for elective procedures, early infusion of VWF replacement therapy will stabilize endogenous FVIII. Because endogenous FVIII production is unaffected in patients with VWD, repeated VWF supplementation (particularly with plasma-derived FVIII-containing products) may lead to accumulation of FVIII. Frequent monitoring of plasma levels and access to hemostatic testing are, therefore, essential for patients undergoing major surgery, particularly with more severe forms of VWD

Bleeding disorders in girls and women - setting the scene

The prevalence and impact of bleeding disorders in women is not sufficiently acknowledged, with the organisation of care traditionally biased towards boys and men with haemophilia. In 2017, the European Haemophilia Consortium surveyed women with bleeding disorders, national member organisations (NMOs) and treatment centres to assess the impact of bleeding disorders in women in four domains: physical activity, active life, romantic and social life, and reproductive life. Most women had von Willebrand disease (VWD) or described themselves as a carrier. All reported a negative impact on physical activity, active life and romantic and social life. Up to 70% of women in all groups reported that their bleeding disorder had a significant impact on their ability or willingness to have children, or prevented it. Heavy menstrual bleeding was reported as the having the most significant impact on daily life. Women face barriers to diagnosis and care, including difficulty obtaining a referral and lack of knowledge among general practitioners and gynaecologists. While bleeding disorders share many symptoms, including bleeding after minor injury and trauma, the link between heavy menstrual bleeding and a bleeding disorder often goes unrecognised and its severity is underestimated. Screening is not offered to all eligible women despite the availability of long-established management guidelines; clinical tools to estimate severity may be unreliable. Failure to recognise a bleeding disorder in a woman is a multifactorial problem that is partly due to cultural reluctance to discuss menstruation. Public awareness campaigns are seeking to correct this, and many NMOs involve women in their initiatives and provide women-centred activities. However, a transformation in diagnosis is needed to shift the focus of treatment centres beyond boys and men with haemophilia, and to acknowledge the prevalence and severity of bleeding disorders in women

Preparing for menarche - treatment and management of heavy periods in women with bleeding disorders

Prolonged menstrual bleeding interferes with daily life and causes marked blood loss, resulting in anaemia and fatigue. Treatment centres should address the issue of heavy menstrual bleeding (HMB) with pre-pubertal girls in advance of their first period, in order to best prepare them. It is common for a bleeding disorder to be overlooked in primary care and in gynaecology clinics, and women sometimes struggle to get a correct diagnosis. There are cultural taboos that inhibit open discussion of menstruation, and women tend to minimise the severity of their symptoms. Health professionals should work to destigmatise the issue and seek an accurate account of bleeding severity, with diagnosis and treatment provided in a joint clinic combining gynaecology and haematology expertise. Treatment should be individualised, taking into account personal, social and medical factors, with the aim of improving quality of life. Great care is needed with regard to choice of language when talking about treatment, and treatment centres should consider offering open access to women who need support in dealing with adverse effects. National member organisations have an important role to play in educating people with bleeding disorders, health professionals and the wider public about the burden of HMB associated with bleeding disorders

A role for intravenous immunoglobulin in the treatment of Acquired Von Willebrand Syndrome associated with IgM gammopathy.

Acquired Von Willebrand Syndrome (AVWS) is a rare bleeding disorder resulting from reduction in plasma von Willebrand Factor (VWF) in patients with no previous personal or family history of Von Willebrand Disease (VWD). AVWS may present with significant bleeding, complicated by short-lived responses to DDAVP or VWF-containing concentrate. AVWS is commonly associated with cardiovascular and lymphoproliferative disorders (LPDs) [1]. Amongst the LPDs, monoclonal gammopathy of undetermined significance (MGUS) is the most frequent association. Haemorrhage in MGUS-AVWS may be both spontaneous and severe. Treatment options include DDAVP, tranexamic acid and VWF-containing concentrates however patient co-morbidities, age or poor clinical and laboratory responses often restrict use [2]. Furthermore, individual responses following DDAVP and VWF-containing concentrates are highly variable and response duration may be short [1]. Consequently, the management of bleeding in patients with MGUS-AVWS presents a significant clinical challenge. Multiple second-line therapeutic approaches have been explored including intravenous immunoglobulin (IVIg) [3], plasmapheresis [4] and immunomodulatory drugs such as lenalidomide [5]. While definitive treatment of the underlying LPD may induce AVWS remission, treatment for MGUS is not usually warranted.</p

Validation of risk-adapted venous thromboembolism prediction in multiple myeloma patients

Multiple myeloma (MM) is associated with an increased risk of venous thrombosis (VTE). In the United Kingdom Medical Research Council (MRC) XI study of patients treated with im-munomodulatory therapy, the VTE rate was 11.8% despite 87.7% of the patients being on thrombo-prophylaxis at the time of thrombosis. In order to effectively prevent VTE events in MM patients, a better understanding of patient and disease risk factors that might predict thrombosis is required. We performed a retrospective cohort analysis of over 300 newly diagnosed MM patients at a tertiary referral centre to determine the VTE rate, predictive factors for VTE, value of the Khorana score for MM VTE events and long-term mortality outcomes. Fifty-four percent of the patients were receiving thromboprophylaxis at the time of the VTE event. The mortality odds ratio was 3.3 (95% CI, 2.4–4.5) in patients who developed VTE in comparison to age-matched controls with MM. A younger age at diagnosis and higher white cell count (WCC) were found to be predictive of VTE events. Our data suggest that standard thromboprophylaxis may not be effective in preventing VTE events in myeloma patients, and alternative strategies, which could include higher-intensity thromboprophylaxis in young patients with a high WCC, are necessary

Challenges in the management of women with type 2B von Willebrand disease during pregnancy and the postpartum period: evidence from literature and data from an international registry and physicians’ survey — communication from the Scientific and Standardization Committees of the International Society on Thrombosis and Haemostasis

Background: Management of women with type 2B von Willebrand disease (VWD) during pregnancy is challenging because of dysfunctional von Willebrand factor (VWF) and the complexity resulting from discrepant VWF/factor VIII (VWF/FVIII) levels, impaired platelet-dependent VWF activity, progressive thrombocytopenia, and risks associated with the use of desmopressin. There is a lack of high-quality evidence to support clinical decision making. Objectives: In this study, we examined the current diagnostic and management approaches and outcomes in women with VWD during pregnancy. Methods: Data were collected via 3 avenues: literature review, an international registry, and an international survey on physicians' practices for the management of pregnancy in women with VWD. The registry and survey were supported by the International Society on Thrombosis and Haemostasis. Results: Data on clinical and laboratory features, management and bleeding complications, and pregnancy outcomes of a total of 55 pregnancies from 49 women across the globe (literature: 35, registry: 20) and data reported by 112 physicians were analyzed. We describe the largest dataset on pregnancies in women with type 2B VWD available to date. The data highlight the following key issues: a) bleeding complications remain a concern in these patients, b) the target safe VWF level and the ideal monitoring approach are unknown, c) there is a wide range of hemostatic management practices in the type and timing of treatment, and d) physicians have diverse views on the mode of delivery and use of neuraxial anesthesia. Conclusion: We conclude that an international consensus and guidance are critically required for better care and improved outcomes in this patient cohort.</p

Acquired factor xiii deficiency: An uncommon but easily missed cause of severe bleeding.

Factor XIII (FXIII) is a plasma clotting protein involved in clot stabilization. Severe FXIII deficiency may present with severe, even fatal bleeding. Critically however, routine coagulation assays may be normal and only specific FXIII assays will detect the abnormality. Herein we discuss a case report of a patient with acquired FXIII deficiency in order to highlight the clinical challenges associated with establishing the diagnosis and discuss the treatment approach. A 70-year-old man presented with a gluteal haematoma despite no preceding personal history of bleeding. Extensive initial haemostatic investigations were normal until a specific FXIII assay showed a marked reduction in FXIII levels. With directed treatment, bleeding episodes ceased and remission was achieved. Clinical awareness of FXIII deficiency is important, so appropriate testing can be implemented in patients with unexplained bleeding diatheses, particularly those in whom bleeding responds poorly to standard replacement therapy.</p

An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland

Introduction: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. However, recognition of the disease by both the public and healthcare professionals lags behind that of other bleeding disorders, leading to delays in diagnosis and treatment for patients. Updated national guidelines are needed to highlight an appropriate pathway for managing VWD patients in a timelier manner. Aim: To identify ways in which care for VWD can be achieved on a more equitable basis. Methods: Using a modified Delphi approach, a panel of VWD experts developed 29 statements across five key themes. These were used to form an online survey that was distributed to healthcare professionals involved in VWD care across the UK and Republic of Ireland (ROI). Stopping criteria comprised 50 responses received, a 3-month window for response (February-April 2022) and 90% of statements passing consensus threshold. Threshold for consensus for each statement was agreed at 75%. Results: A total of 66 responses were analysed with 29/29 statements achieving consensus of which 27 attained ≥90% agreement. From the high degree of consensus, eight recommendations were derived regarding how detection and management of VWD can be improved to provide equity of care between men and women. Conclusion: Implementation of these eight recommendations across the VWD pathway has the potential to raise the standard of care for patients in the UK and ROI by reducing delays to diagnosis and treatment initiation.</p

Reported prevalence of von Willebrand disease worldwide in relation to income classification

Introduction: The diagnosis of von Willebrand disease (VWD) is complex and challenging, especially when diagnostic resources are limited. This results in a lack of consistency in identifying and reporting the number of people with VWD and variations in the VWD prevalence worldwide. Aim: To analyze the reported prevalence of VWD worldwide in relation to income classification. Methods: Data on the VWD prevalence from the World Federation of Hemophilia Annual Global Survey, national registries of Australia, Canada, and the United Kingdom, and the literature were analysed. The income level of each country was classified according to the World Bank. Results: The mean VWD prevalence worldwide was 25.6 per million people. The VWD prevalence for high-income countries (HIC) of 60.3 per million people was significantly greater (p Conclusion: The reported VWD prevalence varied considerably across and within income classifications. The variability of type 3 VWD prevalence was less than the VWD prevalence (all types). The variability in detection and diagnosis of type 1 VWD presents a challenge in forming a consistent prevalence value across countries and income classifications.</p

Variability in International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) score with normal aging in healthy females: contributory factors and clinical significance

Background: Bleeding assessment tools are key screening tests used in the evaluation of patients with suspected inherited bleeding disorders. The International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) has differing reference ranges for adult males (0-3), adult females (0-5), and children (0-2), reflecting differing bleeding symptoms and exposure to hemostatic challenges in these healthy population subgroups. Age is known to markedly impact bleeding score in individuals with von Willebrand disease. However, the influence of age on bleeding score in healthy adult controls is poorly understood. Objectives: We aimed to assess variability in ISTH-BAT score with age among healthy control females. Methods: We used the legacy "Merging Project" dataset of normal healthy controls upon which current ISTH-BAT normal ranges are based. We included women, totaling 646 individuals. The normal range (middle 95th percentile) of total ISTH-BAT and grouped subdomain scores between age quartiles was assessed. Results: The normal range of ISTH-BAT scores increased with age, ranging from 0 to 4 in the youngest quartile (age range, 18-30) to 0 to 6 in the oldest (age range, 52-88). This increased variability with aging was related both to high menorrhagia domain scores in older women and an increase in postprocedural bleeding with accumulated exposure to hemostatic challenges. Conclusions: Cumulatively, our data highlight that normal aging leads to increased variability in bleeding scores in healthy adult females. Further refinement of the ISTH-BAT with age-adjusted reference ranges may improve the sensitivity and specificity of the tool among females.</p