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Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges. Objective: 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. Methods: 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. Results: The panel agreed on 11 recommendations. Conclusions: 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: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients. Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD. Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 12 recommendations and outlined future research priorities. Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.

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Gynecological bleeding is frequently reported in women with von Willebrand disease (VWD). Low von Willebrand factor (VWF) may be associated with significant bleeding phenotype despite only mild plasma VWF reductions. The contribution of gynecological bleeding to this phenotype has yet to be described. The optimal clinical bleeding assessment tool (BAT) to evaluate bleeding remains unclear. Using a standardized approach to phenotypic assessment, we evaluated gynecological bleeding and directly compared the Condensed Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD (Condensed MCMDM-1 VWD) and International Society on Thrombosis and Haemostasis (ISTH) BAT scores in 120 women enrolled in the Low von Willebrand in Ireland Cohort study. Heavy menstrual bleeding (HMB) was reported in 89% of female participants; 45.8% developed iron deficiency. Using identical data, Condensed MCMDM-1 VWD menorrhagia domain scores were significantly lower than ISTH BAT scores (2 vs 3; < .0001), the discrepant results related to 40% of women not seeking medical consultation for HMB, reducing the sensitivity of the Condensed score. For those who reported HMB to physicians, the low VWF diagnosis was not expedited (age at diagnosis 34.2 vs 33.4 years in women failing to present; = .7). Postpartum hemorrhage (PPH) was self-reported in 63.5% of parous women (n = 74); 21.6% required transfusion, critical care, radiological, or surgical intervention. Our data demonstrate that gynecological bleeding is frequently reported in women with low VWF; despite pregnancy-related increases in plasma VWF levels, these women may experience PPH. Defining the optimal management approach for these patients requires further research. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

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To cite this article: Alb anez S, Ogiwara K, Michels A, Hopman W, Grabell J, James P, Lillicrap D. Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms. J Thromb Haemost 2016; 14: 953-63. Essentialsvon Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms. Summary. Background:The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives: To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods: A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results: Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (b = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (b = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (b = À0.15; 95% CI, À0.25, À0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions: Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly influenced by the presence of the other.

Summary Background Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion. Objectives The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Patients/Methods 34 families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values, and anti-VWF inhibitor status were included as well as sequence analysis. Results We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense, and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS=22) than those with mutations elsewhere in VWF (BS=13). 62 of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified. Conclusions We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In ~50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.