scholarly journals Applying diagnostic criteria for type 1 von Willebrand disease to a pediatric population

2009 ◽  
Vol 52 (1) ◽  
pp. 102-107 ◽  
Author(s):  
Sarah A. Hyatt ◽  
Wei Wang ◽  
Bryce A. Kerlin ◽  
Sarah H. O'Brien
Keyword(s):  
Diagnostic Criteria ◽  
Pediatric Population ◽  
Von Willebrand Disease ◽  
Von Willebrand

Applying Diagnostic Criteria for Type 1 von Willebrand Disease to a Pediatric Population.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2138-2138
Author(s):  
Sarah A. Hyatt ◽  
Wei Wang ◽  
Bryce A. Kerlin ◽  
Sarah H. O’Brien
Keyword(s):  
Diagnostic Criteria ◽  
Pediatric Population ◽  
Von Willebrand Disease ◽  
Abnormal Laboratory ◽  
Laboratory Values ◽  
Bleeding Score ◽  
Definition Of ◽  
Von Willebrand ◽  
Mucocutaneous Bleeding

Abstract Background: Although type 1 von Willebrand disease (VWD) is the most common bleeding disorder seen by pediatric hematologists, making a definitive diagnosis continues to be a challenge in clinical practice. Both the International Society on Thrombosis and Haemostasis (ISTH) and the Hospital for Sick Children in Toronto (HSC) have proposed diagnostic criteria for type 1 VWD. These include abnormal laboratory values, significant mucocutaneous bleeding, and/or a positive family history. Most recently, the ISTH published updated recommendations, which differed only in the requirement of more abnormal laboratory results (VWF:Ag 5–20 IU/ml). We applied ISTH and HSC criteria, as well as updated ISTH criteria, to a large population of pediatric patients diagnosed with type 1 VWD. We hypothesized that a substantial number of patients would not meet either HSC or ISTH diagnostic criteria. Methods: We performed a retrospective medical record review of all type 1 VWD patients at our Hemostasis and Thrombosis Center. We evaluated each record for bleeding history, family history, and laboratory values. Frequencies of fit for HSC, ISTH and updated ISTH criteria were calculated. Mean VWF:Ag, VWF:RCo, and bleeding scores (Rodeghiero et al, J Thromb Haemost, 2006) were compared across populations meeting each proposed criteria. Results: Of 201 patients, 33.9% met the HSC definition of “definitive” type 1 VWD, 4.5% met ISTH definition, and 0% met updated ISTH definition. An additional 56.2% (HSC), 15.4% (ISTH), and 6% (updated ISTH) met definitions of “possible” type 1 VWD. For each proposed definition, criteria for significant mucocutaneous bleeding were most likely to be met, while criteria for abnormal laboratory values were least likely. In fact, 74% of patients had significant bleeding as defined by the HSC (56% as defined by ISTH). We did find significant clinical and laboratory differences between patients labeled as definite, possible, and normal by ISTH and HSC criteria. For example, patients meeting criteria for definite disease by HSC criteria had a mean bleeding score of 3.5 and mean VWF:Ag of 31 IU/ml, compared to 2.6 and 47 IU/ml in patients labeled as possible, and 2.2 and 68 IU/ml in patients labeled as normal (p=0.001 bleeding score, <0.001 mean VWF:Ag). Regardless of whether they met any set of criteria, most patients (94%) received some type of medical intervention (pre-operative or therapeutic desmopressin or VWF replacement). Discussion: We found that the majority of our pediatric type 1 VWD patients did not meet the original ISTH definition of definite or even possible type 1 VWD, thus confirming in a larger population the findings of HSC investigators (Dean et al, Thromb Haemost, 2000). In addition, we have demonstrated that the new ISTH criteria are even more inappropriate for clinical practice in a pediatric population, with 0% of patients meeting criteria for definite disease. Therefore, these criteria failed to identify a substantial number of children and adolescents who presented to medical attention, had significant mucocutaneous bleeding, and required therapeutic interventions. The new ISTH criteria may be an excellent scientific tool for identifying a narrow, severely affected population of patients likely to have autosomal dominant VWD mutations. However, they do not appear to have clinical validity in the pediatric setting.

scholarly journals Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease

2011 ◽  
Vol 9 (9) ◽  
pp. 1752-1760 ◽  
Author(s):  
J. D. ROBERTSON ◽  
P. R. YENSON ◽  
M. L. RAND ◽  
V. S. BLANCHETTE ◽  
M. D. CARCAO ◽  
...  
Keyword(s):  
Pediatric Population ◽  
Von Willebrand Disease ◽  
Von Willebrand

von Willebrand Disease in a Pediatric-based Population - Comparison of Type 1 Diagnostic Criteria and Use of the PFA-100® and a von Willebrand Factor/Collagen-binding Assay

2000 ◽  
Vol 84 (09) ◽  
pp. 401-409 ◽  
Author(s):  
J.A. Dean ◽  
V. S. Blanchette ◽  
M. D. Carcao ◽  
A. M. Stain ◽  
C. R. Sparling ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Von Willebrand Factor ◽  
Screening Test ◽  
Binding Assay ◽  
Von Willebrand Disease ◽  
Consensus Guidelines ◽  
Collagen Binding ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryDefinitive diagnosis of type 1 von Willebrand Disease (VWD) remains a problem. Provisional consensus guidelines for the diagnosis of definite and possible type 1 VWD were prepared by the Scientific Subcommittee on von Willebrand factor (VWF) of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) during the 1996 annual meeting for the specific purpose of further evaluation in retrospective and prospective studies by a Working Party on Diagnostic Criteria (1996 Annual Report of the SSC/ISTH Subcommittee on VWF). In the first phase of this study, we compared 2 definitions of type 1 VWD, each with 3 criteria: significant bleeding history, laboratory investigations, and family history. Using the ISTH consensus guidelines for type 1 VWD definition, significantly fewer patients were diagnosed with definite type 1 disease as compared to our “in house” Hospital for Sick Children (HSC) criteria (4 vs. 31). While we recognize that the provisional ISTH consensus guidelines were not intended for clinical use, we believe that the results of our studies are of interest and will assist in any future refinements to the ISTH guidelines.In the second phase of this study, we investigated the utility of 2 new tests, a laboratory screening test and a functional test, for VWD in our well characterized, pediatric-based population. The Platelet Function Analyzer (PFA-100®) provides an in vitro measure of primary hemostasis under conditions of high shear, using disposable cartridges containing collagen and either epinephrine or ADP. All tested subjects with types 2 or 3 VWD had prolonged PFA-100 closure times (CTs) with both cartridge types (n = 17) and prolonged bleeding times (n = 14). In subjects with definite type 1 VWD, 20/24 (83%) had prolonged CTs with the collagen/ADP cartridge (19/24 (79%) with collagen/epinephrine), compared with 7/26 (27%) with prolonged bleeding times. In subjects with definite types 1, 2, or 3 VWD, collagen/ADP CTs were abnormal in 37/41 subjects, giving an overall sensitivity of 90%. With this high sensitivity, the PFA-100 is a better screening test for VWD than the bleeding time.We also tested a VWF collagen-binding assay (VWF:CBA) as a functional test for VWF, in comparison with the more routinely-used ristocetin cofactor assay (VWF:RCo). The VWF:CBA is based on an ELISA technique, which has the potential to be more reproducible than the VWF:RCo. We found that the VWF:CBA detected 43/49 (88%) subjects with definite types 1, 2, or 3 VWD, performing as well as the VWF:RCo, that detected 42/48 (88%). We also showed that, used in conjunction with VWF antigen levels, the VWF:CBA may be useful in classification of VWD subtypes.

Characterisation of Type 2N von Willebrand Disease Using Phenotypic and Molecular Techniques

1996 ◽  
Vol 75 (06) ◽  
pp. 959-964 ◽  
Author(s):  
I M Nesbitt ◽  
A C Goodeve ◽  
A M Guilliatt ◽  
M Makris ◽  
F E Preston ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Von Willebrand Disease ◽  
Molecular Techniques ◽  
Haemophilia A ◽  
Binding Region ◽  
Gene Encoding ◽  
Covalently Linked ◽  
Von Willebrand ◽  
Willebrand Factor

Summaryvon Willebrand factor (vWF) is a multimeric glycoprotein found in plasma non covalently linked to factor VIII (FVIII). Type 2N von Willebrand disease (vWD) is caused by a mutation in the vWF gene that results in vWF with a normal multimeric pattern, but with reduced binding to FVIII.We have utilised methods for the phenotypic and genotypic detection of type 2N vWD. The binding of FVIII to vWF in 69 patients, 36 with type 1 vWD, 32 with mild haemophilia A and one possible haemophilia A carrier with low FVIII levels was studied. Of these, six were found to have reduced binding (five type 1 vWD, one possible haemophilia A carrier), DNA was extracted from these patients and exons 18-23 of the vWF gene encoding the FVIII binding region of vWF were analysed. After direct sequencing and chemical cleavage mismatch detection, a Thr28Met mutation was detected in two unrelated individuals, one of whom appears to be a compound heterozygote for the mutation and a null allele. No mutations were found in the region of the vWF gene encoding the FVIII binding region of vWF in the other four patients

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.

Recessive von Willebrand Disease Type 2 Normandy: Variable Expression of Mild Hemophilia and VWD Type 1

2009 ◽  
Vol 121 (2-3) ◽  
pp. 119-127 ◽  
Author(s):  
Jan Jacques Michiels ◽  
Alain Gadisseur ◽  
Inge Vangenegten ◽  
Wilfried Schroyens ◽  
Zwi Berneman
Keyword(s):  
Disease Type ◽  
Von Willebrand Disease ◽  
Variable Expression ◽  
Von Willebrand

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.

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