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