The recommendations are labeled as either strong or conditional according to the GRADE approach. Most laboratories that do the VWF:CB assay use type I and/or III collagen, which is known to be a surrogate for the presence of high-molecular-weight VWF. Likewise, RIPA is not available at all centers; however, that test requires a fresh sample; therefore, shipping is not possible, limiting accessibility to the test. The panels work was done using Web-based tools (www.surveymonkey.com and www.gradepro.org) and face-to-face and online meetings. These guidelines are based on updated and original systematic reviews of evidence conducted under the direction of the Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC). These recommendations place the highest value on not missing the diagnosis in affected patients in order to ensure access to care. 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. 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. A detailed review of validated BATs can be found at https://elearning.wfh.org/resource/compendium-of-assessment-tools/#bleeding_assessment_tools1a42-60ce78a1-2573f205-9a34. In type 2B and platelet-type, large multimers are absent due to increased interaction with platelets, resulting in clearance of large vWF and platelets. Type 2: This is the second most common form of inherited VWD. Multiple factors make a firm diagnosis of VWD difficult. Future critical research priorities are also identified. Lastly, not all tests are available in all laboratories, and decisions to switch from one assay to another must take into account local circumstances. Treatment for von Willebrand disease (VWD) is based on the type of VWD you have and how severe it is. The response to desmopressin can also identify these patients, if a 4-hour postinfusion time point is included and shows a >30% decrease from the peak VWF level.79 Five studies were reviewed to address this question, including 2 that evaluated the correlation between the VWFpp/VWF:Ag ratio and VWF half-life78,79 and 3 that reported on the correlation of the VWFpp/VWF:Ag ratio and VWF mutation.21,22,80 No test-accuracy results were presented in the included studies because of the lack of an accepted reference standard to define type 1C VWD. Ten addressed diagnostic test accuracy for types 2A and 2B59,85-93 and 6 for type 2M.87-90,92,93 For types 2A and 2B, the sensitivity of VWF:CB/VWF:Ag was 0.90 (95% CI, 0.78-0.96) and specificity was 0.95 (95% CI, 0.89-0.98), vs a sensitivity of 0.90 (95% CI, 0.90-0.99) and specificity of 0.97 (95% CI, 0.94-0.99) for multimers. 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. Blood. Collagen types I and III interact with the A3 domain of VWF and type IV collagen with the A1 domain; as noted, most laboratories that perform this assay use type I and/or III collagen. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences. This could have accessibility and feasibility implications, particularly for those who do not live in centers with specialized coagulation laboratories. Furthermore, BATs provide educational value to patients and clinical experts about bleeding symptoms and possible interventions, and offer validation to patients by recognizing symptoms of the disease. All completed disclosure-of-interest forms, which were reviewed by ASH and are available as supplemental Files 2 and 3. These issues led to debate about the cause of bleeding in someone with milder reductions in VWF; however, these patients are still likely to benefit from the many treatments that are given for VWD, although they may suffer harms from side effects. Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder caused by changes in von Willebrand factor (VWF) that enhance binding of VWF to GPIb on platelets. The recommendation can be adopted as policy in most situations. False negatives were judged to be of greater importance by both clinical and patient experts because of the concern of missing patients who would benefit from treatment. Similarities and differences were analysed in 33 type 2B patients, 12 with a normal and 21 with an abnormal multimer pattern, to see whether they should be considered separately. Additionally, if an F8 variant is identified as opposed to a VWF variant, then the diagnosis can be confirmed as hemophilia A with appropriate treatment and genetic counseling for X-linked inheritance.120. ASH, ISTH, NHF, and WFH do not warrant or guarantee any products described in these guidelines. Patients with type 2 VWD generally have more significant bleeding than those with type 1 VWD, and the family histories are clearly autosomal dominant, without the issues of incomplete penetrance or variable expressivity that complicate milder forms of type 1 VWD.45 Desmopressin is relatively contraindicated in type 2B VWD, as it may cause thrombocytopenia due to increased platelet binding; however, patients suspected of having this subtype would usually have additional testing performed, such as genetic testing, that would clarify the subtype.94 Patients with type 2A or 2M are less likely to respond to desmopressin, but this would be identified at the time of a desmopressin trial.95 Other treatment decisions are not likely to vary significantly between subtypes. Development of these guidelines was wholly funded by the 4 collaborating organizations: ASH, ISTH, NHF, and WFH. The current classification includes types 1 and 3, which are characterized by quantitative deficiencies of von Willebrand factor (VWF), as well as types 2A, 2B, 2M, and 2N, which are qualitative variants. Decisions about reconsidering or removing the diagnosis should consider the patients values and preferences and be informed by a shared decision-making process. The panel considered not missing an affected patient an important benefit, in addition to identifying patients in a timely manner and decreasing unnecessary blood testing. Additionally, removal of a diagnosis could have significant effects on insurance coverage in some countries. Other researchers participated to fulfill requirements of an academic degree or program. 111 patients who had type 1 VWD at the Royal Free Haemophilia Centre; subgroup of 30 identified with VWF:RCo/VWF:Ag<0.7. These guidelines are primarily intended to help clinicians make decisions about diagnostic and treatment alternatives. Performance measures about the suggested course of action should focus on whether an appropriate decision-making process is fully documented. 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. However, it should be noted that this question applies to patients with abnormal initial VWD testing, making it more likely that a patient would be misclassified as having type 1 VWD than missed altogether. Slide 12: As discussed on slide 9, type 1 vWD results from a vWF deficiency and results in concordant decreases in vWF antigen and activity. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences. No specific resources would be required to remove a VWD diagnosis; however, the panel acknowledges that the necessary discussion between physician and patient is likely to be complicated and require adequate time. The recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. VWD results from quantitative or qualitative deficiencies in von Willebrand factor. Recommendation 1 is intended for primary care practitioners assuming a relatively low VWD prevalence in their clinic population, based on literature that shows an 3% prevalence of bleeding disorders in a population with abnormal laboratory tests (eg, prolonged aPTT).40 Recommendation 2 assumes a 20% VWD prevalence and is based on studies of consecutive patients referred to a hematology clinic, typically because of a personal history of bleeding/bruising and/or because of abnormal initial laboratory tests (eg, prolonged aPTT).41 Recommendation 3 assumes a 50% prevalence and is based on individuals with an affected first-degree relative, in keeping with the autosomal-dominant inheritance of most subtypes of the disease, regardless of bleeding symptoms or the results of initial laboratory tests.42,43 For these recommendations, 7 cohort studies that included 112 patients with a pooled sensitivity of 0.75 (95% confidence interval [CI], 0.66-0.83) were assessed and judged to be highly accurate; the sensitivity data were strongest for adult women. For most patients who have type 1 von Willebrand's disease or who are classified as having a low level of von Willebrand factor or possible type 1 von Willebrand's disease, and for some . The panel used the GRADEpro guideline-development tool (www.gradepro.org)35 and SurveyMonkey (www.surveymonkey.com) to brainstorm and then prioritize the questions described in Table 1. The purpose of these guidelines is to provide evidence-based recommendations on the diagnosis of VWD. The certainty was categorized into 4 levels: very low (), low (), moderate (), and high ().7,8,29,30,37-39. Patients with a historic diagnosis of type 1 VWD but who now have normal VWF levels, Patients with abnormal initial VWD screen (low VWF:Ag and/or platelet-dependent VWF activity) and suspected type 1 VWD, Diagnosis of type 1 VWD at VWF:Ag and/or platelet-dependent VWF activity <0.30 IU/mL, Diagnosis of type 1 VWD at VWF:Ag and/or platelet-dependent VWF activity <0.50 IU/mL, Accurate VWD diagnosis (to identify type 1 VWD), Desmopressin trial with 1- and 4-h blood work, Accurate VWD classification (to identify type 1C), Patients with abnormal initial screen (low VWF:Ag and/or platelet-dependent VWF activity) and suspected of type 2 VWD, Platelet-dependent VWF activity/VWF:Ag ratio <0.5, Accurate VWD classification (to identify those suspected of having type 2A, 2B, or 2M in need of additional testing), Patients suspected of type 2A, 2B, or 2M in need of additional testing, Accurate VWD classification (to identify type 2A, 2B, or 2M), Accurate VWD classification (to identify type 2B), Patients suspected of type 2N in need of additional testing, Accurate VWD classification (to identify type 2N). The work of the panel was coordinated by ASH and the Outcomes and Implementation Research Unit at KUMC (funded by the collaborating organizations, under a paid agreement). 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. A majority of the guideline panel, including the cochairs, had no such conflicts. There was significant concern that the term Low VWF creates an unintentional barrier to patients receiving appropriate care because of a lack of a clear diagnosis, particularly in countries without universal health care systems. Additionally, there was no consistent cutoff for the VWF:CB/VWF:Ag ratio. As science advances and new evidence becomes available, recommendations may become outdated. Type 2 The patient representatives received an honorarium of $200 dollars each. The EtD table addressed effects of interventions, resource utilization (cost-effectiveness), values and preferences (relative importance of outcomes), equity, acceptability, and feasibility. There was also serious patient-selection bias due to the case-control study design in all studies. Other purposes are to inform policy, education, and advocacy, and to state future research needs. Following synthesis, VWF is transported and stored in the Weibel--Palade bodies and platelet -granules. INTRODUCTION. The panel considered the following outcomes as critical for clinical decision-making across questions: major bleeding, transfusion and treatment, gastrointestinal bleeding, blood loss, symptom severity, minor bleeding, mortality, and unnecessary testing. 1. 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. Francesca Stufano for participating in guideline question prioritization and outcome selection. They may also be used by patients. 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? If you have VWD, there's a 15% to 30% chance you have Type 2. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences. Lastly, protocols for the completion of desmopressin trials and definitions of responsiveness vary widely. These considerations informed the panels deliberations, with a high value being placed on not missing affected patients. The panel suggests using either VWF:FVIIIB or targeted genetic testing (when available) for patients with suspected type 2N VWD in need of additional testing (Figure 3) (conditional recommendation based on low certainty in the evidence from diagnostic accuracy 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. 2008;111(6):3299-300]. Although estimates vary between countries, in general, the price is comparable between assays but payer systems and levels of insurability vary widely. BS, bleeding score; CBC, complete blood count; DDAVP, desmopressin; FVIII, factor FVIII; FVIII:C, FVIII coagulant activity; PT, prothrombin time; PTT, partial thromboplastin time; r/o, rule out; TT, thrombin time; VWF:CB/Ag, ratio of VWF collagen binding to antigen; VWF:FVIIIB, VWF FVIII binding. People with the disease have low levels of von Willebrand factor, a protein that helps blood clot, or the protein doesn't perform as it should. GPIb, glycoprotein Ib; RIPA, ristocetin-induced platelet agglutination. von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Search for other works by this author on: Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Clinical Practice Guidelines We Can Trust, Board of Trustees of the Guidelines International Network, Guidelines International Network: toward international standards for clinical practice guidelines, Guidelines International Network: principles for disclosure of interests and management of conflicts in guidelines, GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. We suggest referring to this as Low VWF.55 This guideline panel prioritized ensuring access to medical care and therefore recommends a level of <0.30 IU/mL regardless of bleeding and a VWF level of 0.30 to 0.50 IU/mL for patients with abnormal bleeding to confirm the diagnosis of type 1 VWD. These guidelines may not include all appropriate methods of care for the clinical scenarios described. Conflict-of-interest disclosure: Authors were members of the diagnosis guideline panel or members of the systematic review team or both, with the addition of V.H.F. For patients with an abnormal initial VWD screen (low VWF:Ag and/or platelet-dependent VWF activity) suspected of type 2 VWD, should a platelet-dependent VWF activity/VWF:Ag ratio cutoff of <0.5 or a higher cutoff of <0.7 be used to confirm type 2 VWD? 2007 Nov . Through the Outcomes and Implementation Research Unit at KUMC, some researchers who contributed to the systematic evidence reviews received salary or grant support. This recommendation addresses patients with an intermediate VWD pretest probability (20%) corresponding to those typically referred for hematology evaluation because of an abnormal personal bleeding history or abnormal initial laboratory tests (eg, prolonged aPTT) (including men and children). 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