von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We... Show morevon Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD. Show less
von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these... Show morevon Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD. Show less
Abdi, A.; Eckhardt, C.L.; Velzen, A.S. van; Vuong, C.; Coppens, M.; Castaman, G.; ... ; INSIGHT Study Grp 2021
Background Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs).... Show moreBackground Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). Objectives This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. Patients/Methods Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. Results Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. Conclusions Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course. Show less
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... Show moreBackground: 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. Show less
Velzen, A.S. van; Eckhardt, C.L.; Peters, M.; Oldenburg, J.; Cnossen, M.; Liesner, R.; ... ; INSIGHT Consortium 2020
Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates... Show moreInhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case-control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case-control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2-40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma-derived FVIII concentrates (adjusted odds ratio 0 center dot 96, 95% confidence interval (CI) 0 center dot 36-2 center dot 52) or for specific types of FVIII concentrates. Show less
Velzen, A.S. van; Eckhardt, C.L.; Streefkerk, N.; Peters, M.; Astermark, J.; Brons, P.P.; ... ; INSIGHT Study Grp 2014
