2B or not 2B? Disparate discrimination of functional VWF discordance using different assay panels or methodologies may lead to success or failure in the early identification of type 2B VWD

2007 ◽  
Vol 98 (08) ◽  
pp. 346-358 ◽  
Author(s):  
Roslyn Bonar ◽  
Muriel Meiring ◽  
Alison Street ◽  
Katherine Marsden ◽  
Emmanuel Favaloro ◽  
...  
Keyword(s):  
Early Identification ◽  
Correct Diagnosis ◽  
Diagnostic Errors ◽  
Von Willebrand Disease ◽  
External Quality ◽  
Platelet Aggregometry ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryLaboratory proficiency in the identification of functional von Willebrand factor (VWF) discordance in type 2B von Willebrand disease (VWD) was assessed by external quality assurance surveys conducted by the RCPA Haematology QAP, and using six different type 2B VWD plasma samples (three historical and three previously unpublished) tested by up to 52 laboratories. For the three most recent samples, functional VWF discordance was either not identified in testing or by interpretation with misidentification as ‘normal’ or ‘type 1 VWD’, on average for 25.7% of test occasions when laboratories performed VWF:Ag and VWF:RCo as their primary VWF test panel, but somewhat fewer occasions (10.9%) for laboratories that incorporated VWF:CB as an additional functional VWF assay. VWF assay sub-methodologies also influenced the appropriate identification of samples as potentially type 2 VWD, and VWF functional discordance was more consistently identified when laboratories used (i) automated platelet agglutination for VWF:RCo compared to classical platelet aggregometry, (ii) inhouse VWF:CB assays compared to commercial kit methods, and (iii) automated LIA-based ‘VWF:Activity’ assays compared to ELISA based assays.We conclude that:(i) laboratories are generally proficient in tests for VWD but interpretative diagnostic errors do occur; (ii) correct diagnosis is more likely when test panels are more comprehensive and include the VWF:CB; (iii) sub-methodology influences the appropriate identification of VWF functional discordance. On the basis of these findings, we provide a series of recommendations to enable the appropriate laboratory identification of VWD, in particular type 2B VWD.

Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

2021 ◽  
Vol 47 (02) ◽  
pp. 192-200
Author(s):  
James S. O'Donnell
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Risk ◽  
Von Willebrand Disease ◽  
Personalized Treatment ◽  
Treatment Plans ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractThe biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

Identification of Type 2 von Willebrand Disease in Previously Diagnosed Type 1 Patients: a Reappraisal Using Phenotypes, Genotypes and Molecular Modelling

2000 ◽  
Vol 84 (12) ◽  
pp. 998-1004 ◽  
Author(s):  
Ioana Nitu-Whalley ◽  
Anne Riddell ◽  
K. Pasi ◽  
Dale Owens ◽  
M. Enayat ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Single Amino Acid ◽  
Elisa Assay ◽  
Modelling Analysis ◽  
A1 Domain ◽  
Von Willebrand

SummaryIn order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Limitations of Current Plasma VonWillebrand Factor (VWF) Activity Tests: A Comprehensive Comparison of Five VWF Activity Assays.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3376-3376
Author(s):  
Dong Chen ◽  
Rajiv Pruthi ◽  
William L. Nichols ◽  
John A. Heit
Keyword(s):  
Activity Ratio ◽  
Light Transmission ◽  
Von Willebrand Disease ◽  
Assay Method ◽  
Type I ◽  
Platelet Activity ◽  
Platelet Aggregometry ◽  
Von Willebrand

Abstract Accurate measurement of plasma von Willebrand factor (VWF) activity is essential for the laboratory diagnosis and treatment monitoring of von Willebrand disease (VWD). Currently available VWF activity assays include VWF ristocetin cofactor activity by manual light transmission platelet aggregometry (VWF:RCo–Agg) or flow cytometry (VWF:RCo–FL), collagen I and III binding activity (VWF:Co–I and –III) (Technozym), and platelet activity by latex agglutination (VWF:Lx) (Instrumental Laboratory). In this study we evaluated and compared the accuracy and precision of these 5 assay methods. Plasma samples from 11 normal donors and 41 patients categorized as type 1 (n=20) or type 2 (n=21) VWD based on clinical evaluation, fVIII:C activity, VWF:RCo–Agg, VWF antigen (VWF:Ag) level and plasma VWF multimer analysis by agarose gel electrophoresis were assayed for VWF activity by VWF:RCo–FL, VWF:Co–I, VWF:Co–III and VWF:Lx methods. The VWF:Ag/VWF activity ratio by VWF activity assay method was calculated for each sample. For normal donors and type I VWD patients, VWF:RCo–FL and VWF:Lx correlated well with VWF:RCo–Agg (R2=0.87, and 0.97, respectively), while VWF:Co–I and –III were lower compared to VWF:RCo-Agg. For type 2 VWD patients, different VWF:Ag/VWF activity ratio cutoffs (range 0.3–0.7) were used (Figure). Both VWF:RCo–Agg and –FL were sensitive (95%) and specific (97%) for type 2 VWD while the VWF:Lx was slightly less sensitive (81%) but was very specific (100%). VWF:Co–I and –III were the least sensitive (<90%) and specific (<90%); both methods had high false positive and negative rates for type 2 VWD. In Summary, for normals and type 1 VWD patients, VWF:RCo–FL and VWF:Lx correlate well with VWF:RCo–Agg and have similar sensitivities and specificities for type 2 VWD. VWF:Co–I and –III are unreliable for assessing plasma VWF activity.

PFA-100 monitoring of von Willebrand factor (VWF) responses to desmopressin (DDAVP) and factor VIII/VWF concentrate substitution in von Willebrand disease type 1 and 2

2008 ◽  
Vol 100 (09) ◽  
pp. 462-468 ◽  
Author(s):  
Huub H. D. M. van Vliet ◽  
Mies C. Kappers-Klunne ◽  
Jan J. Michiels ◽  
Frank W. G. Leebeek
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Before And After ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryDose-response relationship was studied between PFA-100 closure times (PFA CTs) and factor (F)VIII-von Willebrand factor (VWF) parameters in patients with von Willebrand disease (VWD) type 1 and type 2 before and after treatment with DDAVP (n=84) or FVIII/VWF concentrate (n=38). DDAVP treatment of patients with VWD type 1 normalised the PFA CTs by increasing VWF levels to normal. Of the 14 patients with VWD type 2, PFA CTs did not normalize in eight. Haemate-P substitution in patients with VWD type 1 induced a less favourable response as compared to DDAVP, because PFA CTs did not correct in all patients. Of 12 patients with VWD type 2 treated with Haemate-P, six showed a correction of PFA CTs (<250 sec), which correlated with the normalisation of the VWF CB/ Ag ratio. In-vitro studies were performed by using whole blood of patients with VWD and adding various amounts of FVIII/VWF concentrate. Addition of Haemate-P induced an increase of the VWF CB/Ag ratio from 0.30 to 0.70 in blood of patients with VWD type 2 with correction of the PFA CTs. Immunate did not result in an increase of VWF CB/Ag ratio in blood of VWD type 2 patients, and the PFA CTs remained prolonged. We conclude that PFA-100 might be an adequate instrument not only for diagnosis but also for monitoring of DDAVP responses and FVIII/ VWF substitution of patients with VWD type 1 and 2,but this is dependent upon the type of VWD and the concentrate used.

Analysis of von Willebrand Disease in the South Moravian Population (Czech Republic): Results from the BRNO-VWD Study

2019 ◽  
Vol 119 (04) ◽  
pp. 594-605 ◽  
Author(s):  
Inge Vangenechten ◽  
Petr Smejkal ◽  
Ondrej Zapletal ◽  
Jan Jacques Michiels ◽  
Zwi Berneman ◽  
...  
Keyword(s):  
Czech Republic ◽  
Von Willebrand Disease ◽  
University Hospital ◽  
Cross Sectional ◽  
Mutation Database ◽  
Family Based ◽  
Von Willebrand ◽  
Willebrand Factor

Background von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative (type 1 and 3) or qualitative (type 2) defect of von Willebrand factor (VWF). The heterogeneity of laboratory phenotyping makes diagnosing difficult. Objective A cross-sectional, family-based VWD study in a collaboration between University Hospital Brno (Czech Republic) and Antwerp University Hospital (Belgium) to improve the understanding of laboratory phenotype/genotype correlation. Patients and Methods A total of 205 patients with suspected VWD were identified from historical records. Complete laboratory analysis was established using all available VWD assays including VWF multimers and genetic analysis. Results Based on the current International Society of Thrombosis and Haemostasis (ISTH) – Scientific and Standardization Committee VWD classification and type 2A sub-division into 2A/IIA, IID, IIC and IIE, the majority was characterized as a type 1 VWD, followed by type 2. Proposed laboratory phenotypes were confirmed by their multimeric pattern within 98% of this cohort. All type 2, 3 and 75% of type 1 VWD patients were confirmed by underlying causative mutations. Forty-six different causal mutations (117 not previously described in the literature) could be identified. Fifty per cent of all cases was represented by eight individual mutations, mainly p.Pro812ArgfsX31. Thirteen patients had a large heterozygous gene alteration. Conclusion Although an extensive panel of tests was used, VWD classification and (sub)typing remains difficult and fluid. This study provides a cross-sectional overview of the VWD population in the Czech Republic and provides important data to the ISTH/European Association for Haemophilia and Allied Disorders VWD mutation database in linking causal mutations with unique VWD (sub)types. It also identifies new, as not previously described in the literature, causal mutations.

Desmopressin parenteral bei VWD 1, VWD 2A und Thrombozytopathie

2011 ◽  
Vol 31 (S 01) ◽  
pp. S29-S33 ◽  
Author(s):  
H. Pollmann ◽  
B. Siegmund
Keyword(s):  
Side Effects ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Occlusion Time ◽  
Almost All ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

SummaryDesmopressin (DDAVP, Minirin® parenteral), which induces the release of von-Willebrand factor from endogenous stores, is indicated in von Willebrand disease type 1 (VWD 1). In the present study effectiveness of DDAVP was tested and side effects were recorded in patients with VWD 1, von Willebrand disease type 2 (VWD 2) or thrombocytopathy (TCP). Patients, methods Subjects were analysed prior to and after Minirin parenteral infusion (0.4 μg/kg body weight (b.w.) over 60 minutes) for partial thromboplastin time (PTT, seconds), ADP/epinephrine triggered plateletfunction analyzer (PFA-100) occlusion time (seconds), factor VIII activity (FVIII, %), VWF as ristocetin cofactor activity (VWF:RCo, %) and VWF antigen (VWF:Ag, %). Side effects of DDAVP during operative interventions were recorded per questionnaires by the patients. Results The mean ± standard deviation dose (n = 165 patients) of Minirin parenteral administered was 0.37 ± 0.02 μg/kg b.w., most often upcoming dental operations (57%) necessitated testing. Coagulation parameters of patients with VWD 1 or TCP normalised in almost all patients, but only in approximately 50% of patients with VWD 2 respectively. Appraisal of effectiveness of Minirin parenteral as good was 96% in case of VWD 1 and 95 % in case of TCP. During minor surgeries (n = 23) in 91% of the patients no complications and in 2 patients (9%) postoperative haemorrhages without need for further interventions occurred, but 83% of the patients reported adverse reactions in the questionnaires, although Minirin parenteral was well tolerated by all patients during DDAVP efficacy tests. Conclusion Desmopressin is well tolerated and affective in patients with VWD 1 and thrombocytopathy.

Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients

2012 ◽  
Vol 108 (10) ◽  
pp. 662-671 ◽  
Author(s):  
Hamideh Yadegari ◽  
Julia Driesen ◽  
Anna Pavlova ◽  
Arijit Biswas ◽  
Hans-Jörg Hertfelder ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Splice Site ◽  
Von Willebrand Disease ◽  
Missense Mutations ◽  
Large Deletions ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryVon Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects of the von Willebrand factor (VWF). VWD is classified into three types – type 1 (partial quantitative deficiencies), type 2 (qualitative defects) and type 3 (complete deficiency of VWF). In this study we explored genotype and phenotype characteristics of patients with VWD with the aim of dissecting the distribution of mutations in different types of VWD. One hundred fourteen patients belonging to 78 families diagnosed to have VWD were studied. Mutation analysis was performed by direct sequencing of the VWF. Large deletions were investigated by multiplex ligation-dependent probe amplification (MLPA) analysis. The impact of novel candidate missense mutations and potential splice site mutations was predicted by in silico assessments. We identified mutations in 66 index patients (IPs) (84.6%). Mutation detection rate was 68%, 94% and 94% for VWD type 1, 2 and 3, respectively. In total, 68 different putative mutations were detected comprising 37 missense mutations (54.4%), 10 small deletions (14.7%), two small insertions (2.9%), seven nonsense mutations (10.3%), five splice-site mutations (7.4%), six large deletions (8.8%) and one silent mutation (1.5%). Twenty-six of these mutations were novel. Furthermore, in type 1 and type 2 VWD, the majority of identified mutations (74% vs. 88.1%) were missense substitutions while mutations in type 3 VWD mostly caused null alleles (82%). Genotyping in VWD is a helpful tool to further elucidate the pathogenesis of VWD and to establish the relationship between genotype and phenotype.

Laboratory Diagnosis of von Willebrand Disease

2009 ◽  
Vol 03 (01) ◽  
pp. 33 ◽  
Author(s):  
Muriel Meiring ◽  
Philip N Badenhorst ◽  
Mareli Kelderman ◽  
◽  
◽  
...  
Keyword(s):  
Factor Viii ◽  
Correct Diagnosis ◽  
Laboratory Diagnosis ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Coagulant Activity ◽  
Low Sensitivity ◽  
Von Willebrand ◽  
Willebrand Factor

von Willebrand disease (VWD) is a bleeding disorder caused by either quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). No single available test provides appropriate information about the various functions of VWF, and the laboratory diagnosis of VWD is based on a panel of tests, including the measurement of factor VIII coagulant activity (FVIIIC), VWF antigen levels (VWF:Ag), VWF activity as measured by the ristocetin co-factor activity (VWF:RCo), the collagen-binding activity of VWF (VWF:CB), VWF multimer analysis, ristocetininduced platelet agglutination (RIPA), the factor-VIII-binding assay of plasma VWF and VWF propeptide levels. Due to the heterogeneity of VWF defects and the variables that interfere with VWF levels, a correct diagnosis of types and subtypes may sometimes be difficult, but is very important for therapy. Furthermore, the RCo assay and the RIPA test are based on platelet agglutination in reaction with the non-physiological antibiotic ristocetin. These tests also have low sensitivity and are difficult to standardise. Therefore, several analyses (tests) are required to diagnose VWD and it is important to be aware of the pitfalls to which these tests are subjected in terms of the diagnosis. In this article, the laboratory diagnosis of patients with type 1, 2A, 2B, 2M, 2N and 3 VWD will be explained by using a modified algorithm that was first proposed by the guidelines for diagnosis and treatment of VWD in Italy.

Response of von Willebrand Factor Parameters to Desmopressin in Patients with Type 1 and Type 2 Congenital von Willebrand Disease: Diagnostic and Therapeutic Implications

2002 ◽  
Vol 28 (2) ◽  
pp. 111-132 ◽  
Author(s):  
Jan J. Michiels ◽  
Ann van de Velde ◽  
Huub H.D.M. van Vliet ◽  
Marc van der Planken ◽  
Wilfried Schroyens ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Therapeutic Implications ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Bleeding Symptoms and von Willebrand Factor Levels: 30-Year Experience in a Tertiary Care Center

2019 ◽  
Vol 25 ◽  
pp. 107602961986691
Author(s):  
Chatphatai Moonla ◽  
Benjaporn Akkawat ◽  
Yaowaree Kittikalayawong ◽  
Autcharaporn Sukperm ◽  
Mukmanee Meesanun ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Care Center ◽  
Tertiary Care ◽  
Bleeding Risk ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Correlations between bleeding symptoms and von Willebrand factor (VWF) levels may help to predict hemorrhagic severity in the Westerners with von Willebrand disease (VWD), but data in Asians are lacking. In this study, Thai patients with VWF levels <50 IU/dL without any secondary causes were enrolled from 1988 to 2018 to determine the relationship between VWF levels and hemorrhagic manifestations. According to the current concept, we reclassified VWD and low VWF by VWF levels ≤30 and 30 to 50 IU/dL, respectively. Type 2 VWD was diagnosed if VWF activity to antigen ratio was ≤0.6. Bleeding severity was determined by the condensed MCMDM-1VWD bleeding score (BS). Among 83 patients, VWF activities showed negative correlations with BS ( P = .001), which were higher in type 2 (median: 7, interquartile range [IQR]: 5-11) compared with type 1 VWD (median: 3, IQR: 2-4) and low VWF (median: 4, IQR: 2-8). Bleeding symptoms were indistinguishable between type 1 VWD and low VWF using the 30 IU/dL cutoff point. However, VWF ristocetin cofactor activity or gain-of-function mutant glycoprotein Ib binding activity <36.5 IU/dL and VWF collagen binding activity <34.5 IU/dL could predict increased bleeding risk (BS ≥3) by 92.3% specificity and 70.0% sensitivity ( P < .0001).

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