Diagnosis of type 2B von Willebrand disease in children

Even though von Willebrand disease (vWD) is a common bleeding disorder, it comprises some rare types as well. Type 2B vWD is usually diagnosed in 3-5% of all vWD cases. The important diagnostic markers of this disease subtype include thrombocytopenia, decreased von Willebrand factor (vWF) activity, increased low-dose ristocetin-induced platelet aggregation, and identification of mutations in exon 28 of the vWF gene. The purpose of this study was to highlight challenges associated with the differential diagnosis of vWD as well as to demonstrate heterogeneous clinical and laboratory signs of type 2B vWD. Here, we retrospectively analyzed all the cases of type 2B vWD diagnosed at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. For the analysis, we used de-identified data collected during routine clinical care and hence did not need an approval from the Local Ethics Committee. All the patients had undergone medical history assessment and laboratory investigations and had been evaluated for bleeding disorders using the Pediatric Bleeding Questionnaire. Type 2B vWD was diagnosed based on the following criteria: bleeding symptoms, thrombocytopenia, significantly decreased vWF ristocetin-cofactor activity, normal or decreased vWF antigen levels, ristocetin-cofactor activity/vWF antigen ratio < 0.7; increased low-dose ristocetin-induced platelet aggregation. Type 2B vWD was diagnosed in 7 patients. Out of these, 5 had bleeding symptoms and 2 had a family history of vWD. All the children had been diagnosed with thrombocytopenia during their first year of life. Five patients had been initially diagnosed with immune thrombocytopenia, with one girl having a family history of vWD. All the patients with diagnosed immune thrombocytopenia had been treated with intravenous immunoglobulins, and one child had also undergone treatment with corticosteroids. Three patients had had to be admitted to hospital for major bleeding before they were diagnosed with vWD. All the patients had the typical laboratory phenotype, and five out of them demonstrated decreased vWF collagen-binding activity. In two patients with positive family history, the diagnosis was genetically verified, with both of them harboring mutations in exons 20 and 28 of the vWF gene. Our findings are consistent with the literature suggesting how challenging differential diagnosis of this vWD type is. Still, a low-dose ristocetin-induced platelet aggregation test along with other laboratory investigations can be used to effectively identify the type 2B vWD phenotype. In Russia, factor replacement therapy remains the primary treatment option for patients with any type of vWD.