The panel was concerned that a decision to remove a VWD diagnosis might result in a patient not receiving appropriate treatment of a bleed or prior to a procedure, in addition to the patient not having appropriate clinical follow-up and monitoring. For policy makers: Policy making will require substantial debate and involvement of various stakeholders. von Willebrand disease is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Von Willebrand's disease represents the most common of the inherited bleeding disorders, with a prevalence as great as 1% of the population. Prolonged bleeding from trivial wounds, oral cavity bleeding, and. The guideline panel determined that there is low-certainty evidence for a net health benefit from using newer assays that measure the platelet-binding activity of VWF (eg, VWF:GPIbM, VWF:GPIbR) over VWF:RCo for patients suspected of having VWD. The panel suggests targeted genetic testing over low-dose ristocetin-induced platelet agglutination (RIPA) to diagnose type 2B VWD for patients suspected of type 2A or 2B in need of additional testing (Figure 2) (conditional recommendation based on low certainty in the evidence from diagnostic accuracy studies ). Multiple published guidelines recommend a cutoff of <0.30 IU/mL for a definite diagnosis of type 1 VWD, with the US National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) guidelines stating that this recommendation does not preclude the diagnosis of VWD in individuals with VWF:RCo of 30 to 50 IU/dL if there is supporting clinical evidence and/or family evidence for VWD.75 The recommendation of the United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) states: Patients with an appropriate bleeding history and VWF activity 0.30-0.50 IU/mL should be regarded as having primary hemostatic bleeding with reduced VWF as a risk factor rather than VWD. Types of VWD Type 1 This is the most common and mildest form of VWD, in which a person has lower-than-normal levels of VWF. For patients suspected of type 2N VWD in need of additional testing, should VWF:FVIIIB or targeted genetic testing be used to diagnose type 2N VWD? For new reviews, risk of bias was assessed at the health outcome level using the Cochrane Collaborations risk-of-bias tool for nonrandomized studies and the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for test-accuracy studies.36 In addition to conducting systematic reviews of test accuracy, the researchers searched for evidence related to baseline risks, values, preferences, and costs, and summarized findings within the EtD frameworks.4,5,30 Subsequently, the certainty in the body of evidence (also known as quality of the evidence or confidence in the estimated effects) was assessed for test-accuracy outcomes following the GRADE approach based on the following domains: risk of bias; precision, consistency, and magnitude of the estimates of effects; directness of the evidence; and risk of publication bias. Drugs used to treat von Willebrand Disease The following list of medications are in some way related to or used in the treatment of this condition. Ten experienced >1 bleeding symptom.71 The EtD framework for this recommendation is available online at https://guidelines.ash.gradepro.org/profile/Ckc7oThe8q0. Thromb Haemost 2000 Dec;84 (6):998-1004. wrote the first draft of the manuscript and revised the manuscript based on authors suggestions; guideline panel members B.A., J.D.P., J.E., N.G., S.H., V.J.-P., B.K., C.M., S.M., R.R.M., J.S.O., N.S., and R.S. What are others saying and what is new in these guidelines? Specificity was assumed to be 100% for <0.5 but was not directly available from the published studies. The guideline panel determined that there is low-certainty evidence for a net health benefit from using a VWF:RCo/VWF:Ag cutoff of <0.7 over a lower cutoff of <0.5 for patients suspected of type 2 VWD. A survey was developed by the KUMC methods team to prioritize these questions, and it was then translated from English into French and Spanish and widely publicized. doi: https://doi.org/10.1182/bloodadvances.2020003265. Regardless, clear communication and shared decision-making in this critical aspect of patient management is key, and one must keep in mind the physical and psychosocial impact on the patient. Select drug class All drug classes Miscellaneous coagulation modifiers (6) Antidiuretic hormones (2) The panel was less concerned about false positives for this question, as additional testing, such as VWF multimer analysis, the VWF:CB assay, and/or genotyping, is typically performed for type 2 VWD, providing further clarification of the subtype. As science advances and new evidence becomes available, recommendations may become outdated. Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function, Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels, Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease, Outgrowing the laboratory diagnosis of type 1 von Willebrand disease: a two decade study, The effect of ABO blood group on the diagnosis of von Willebrand disease, Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States, The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study, Predictors of von Willebrand disease diagnosis in individuals with borderline von Willebrand factor plasma levels, Impact of plasma von Willebrand factor levels in the diagnosis of type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1VWD), Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD) [published correction appears in, Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease, Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines, A number of factors explain why WHO guideline developers make strong recommendations inconsistent with GRADE guidance, Reduced von Willebrand factor survival in type Vicenza von Willebrand disease, Von Willebrand factor propeptide makes it easy to identify the shorter Von Willebrand factor survival in patients with type 1 and type Vicenza von Willebrand disease, Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD), Evaluation of the utility of von Willebrand factor propeptide in the differential diagnosis of von Willebrand disease and acquired von Willebrand syndrome, Performance of two new automated assays for measuring von Willebrand activity: HemosIL AcuStar and Innovance, Validation of an automated latex particle-enhanced immunoturbidimetric von Willebrand factor activity assay, Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study, Measurement of von Willebrand factor binding to a recombinant fragment of glycoprotein Ibalpha in an enzyme-linked immunosorbent assay-based method: performances in patients with type 2B von Willebrand disease, Diagnosing von Willebrand disease: a large reference laboratorys perspective, Establishment and characterization of a new and stable collagen-binding assay for the assessment of von Willebrand factor activity, Role of multimeric analysis of von Willebrand factor (VWF) in von Willebrand disease (VWD) diagnosis: lessons from the PCM-EVW-ES Spanish project, Performance and clinical utility of a commercial von Willebrand factor collagen binding assay for laboratory diagnosis of von Willebrand disease, Comparison of an automated chemiluminescent assay to a manual ELISA assay for determination of von Willebrand Factor collagen binding activity on VWD plasma patients previously diagnosed through molecular analysis of VWF, Evaluation of a semi-automated von Willebrand factor multimer assay, the Hydragel 5 von Willebrand multimer, by two European centers, Ristocetin cofactor and collagen binding activities normalized to antigen levels for a rapid diagnosis of type 2 von Willebrand diseasesingle center comparison of four different assays, Collagen binding provides a sensitive screen for variant von Willebrand disease, Use of the collagen-binding assay for von Willebrand factor in the analysis of type 2M von Willebrand disease: a comparison with the ristocetin cofactor assay, Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients, Genetic variants of VWF gene in type 2 von Willebrand disease, Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants, The molecular defect in type IIB von Willebrand disease. The numbers in the yellow circles correspond to guideline questions. Additionally, the methodology to perform a RIPA is not standardized, and different concentrations of ristocetin have been proposed as indicating a positive test (eg, 0.5 mg/mL and 0.25 mg/mL). Research priorities were identified including detailed data (including outcomes for bleeding with procedures and prevalence of a concomitant bleeding disorder) for patients with VWF levels between 0.30 and 0.60 IU/mL as well as the correlation with bleeding symptoms and information about family members of patients with type 1 VWD. To ensure that recent studies were not missed, searches (presented in supplemental File 4) were updated on 8 January 2020, and panel members were asked to suggest any studies that might have been considered missed that fulfilled the inclusion criteria for the individual questions. Additionally, removal of a diagnosis could have significant effects on insurance coverage in some countries. The panel also included a clinical vice-chair who served on both the diagnosis and management panels to ensure that their efforts were coordinated. The accurate identification of patients who have type 1C VWD has management implications, as these patients may require VWF concentrate to treat/prevent bleeds. Click here to read the guidelines in full, or scroll to the bottom of this page for more information. A desmopressin trial, in addition to identifying patients with increased VWF clearance, also provides very useful information to the clinician about the utility of that treatment of an individual patient. 1: Introduction, GRADE guidelines: 2. Through the Outcomes and Implementation Research Unit at KUMC, some researchers who contributed to the systematic evidence reviews received salary or grant support. These recommendations take into consideration cost and cost-effectiveness, resource requirements, impact on health equity, acceptability, and feasibility. The potential harms that could be caused by the use of a BAT include the possibility of missing affected individuals who have not manifested bleeding symptoms, such as men and children. The EtD frameworks for these recommendations are available online at https://guidelines.ash.gradepro.org/profile/RBzFDJwKapc and https://guidelines.ash.gradepro.org/profile/aVdJ7pZVxu4. The algorithm says VWF level 30 to 50 for simplicity; this refers to VWF levels of 0.30 to 0.50 IU/mL, with the caveat that the lower limit of the normal range as determined by the local laboratory should be used if it is <0.50 IU/mL. Additionally, it was recognized that family structures vary widely and might influence the possibility of a diagnosis, for example, if someone had many female relatives who have heavy menstrual bleeding. *Men and children, referred to a hematologist and/or first-degree relative affected with VWD. Decisions about reconsidering or removing the diagnosis should consider the patients values and preferences and be informed by a shared decision-making process. Von Willebrand disease is a lifelong bleeding disorder in which your blood doesn't clot properly. 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. Patients with this subtype typically have a more severe bleeding phenotype compared with other type 2 and type 1 VWD patients, and the bleeding risk has been shown to correlate with the degree of thrombocytopenia.94 Additionally, desmopressin is relatively contraindicated because it can worsen the thrombocytopenia. Platelet-type von Willebrand disease and type 2B von Willebrand disease: a story of nonidentical twins when two different genetic abnormalities evolve into similar phenotypes Semin Thromb Hemost. The panel suggests against a platelet-dependent VWF activity/VWF:Ag ratio <0.5 cutoff, and rather using a higher cutoff of <0.7 to confirm type 2 VWD (2A, 2B, or 2M) for patients with an abnormal initial VWD screen (conditional recommendation based on very low certainty in the evidence from diagnostic studies ). Repeated blood draws are required, which could decrease acceptability for some patients. The panel considered recommending that patients with VWF levels between 0.30 and 0.50 IU/mL and a positive family history should also be diagnosed with type 1 VWD (regardless of bleeding symptoms); however, the risk of an inaccurate diagnosis in a family member was felt to be a significant concern. The possibility that changes in the ability of laboratories to measure VWF:RCo could be playing a role was considered; however, in 1987, Gill et al published a cross-sectional study of blood donors that showed a 0.01 IU/mL annual increase in VWF levels between 20 and 60 years of age, suggesting that the levels truly do increase with age.68 Whether that is in relation to comorbidities or independent of them remains unclear. Lastly, not all tests are available in all laboratories, and decisions to switch from one assay to another must take into account local circumstances. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms. Overall, the panel determined that there is low certainty for a net health benefit from the use of a desmopressin trial over the VWFpp/VWF:Ag ratio for the identification of type 1C VWD. Diagnosis of VWD is complex and requires (1) a personal history of bleeding symptoms, (2) family history of bleeding or VWD, and (3) confirmatory . Six observational studies were identified that addressed this question; all 6 evaluated diagnostic test accuracy,59,81-85 and 1 also looked at VWF mutations felt to be causative of type 2M VWD.83 The pooled sensitivity for the higher cutoff of <0.70 was 0.90 (95% CI, 0.83-0.94) compared with 0.58 to 0.79 for <0.5. Von Willebrand disease (vWD) is a common, inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein termed von Willebrand factor (vWF). Members of the guideline panel received travel reimbursement for attendance at in-person meetings. Additional research is needed to understand variability in the VWF:RCo in different ethnic groups. They should never be omitted when quoting or translating recommendations from these guidelines. The Evidence-to-Decision (EtD) framework for each recommendation describes which individuals were recused from making judgments about each recommendation. Policy making will require substantial debate and involvement of various stakeholders. Good practice statement: VWF activity assays should be performed in a laboratory with appropriate expertise. Diagnosing individuals with type 1 VWD who have VWF levels between 0.30 and 0.50 IU/mL might result in more repeat testing for those on the borderline. Trivial wounds, oral cavity bleeding, and should never be omitted when quoting or translating recommendations from these?!: RCo in different ethnic groups diagnosis could have significant effects on insurance coverage in some countries from the studies. 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