von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

Abstract

von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.

How I treat type 2 variant forms of von Willebrand disease

“…14 Apart from a strikingly different RIPA pattern, type 2B VWD closely resembles type 2A in terms of VWF assays and multimeric structure. 15 Mild-to-moderate thrombocytopenia is present in about 40% of patients because of in vivo platelet clumping. 16 Thrombocytopenia may further aggravate the bleeding risk in these patients.…”

Efficacy and safety of a VWF/FVIII concentrate (wilate®) in inherited von Willebrand disease patients undergoing surgical procedures

“…von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence estimated to range from 1 to 100 in 10 000 [1]. VWD is caused by quantitative (Types 1 and 3) or qualitative (Type 2) deficiency in von Willebrand factor (VWF) and is markedly heterogeneous in type and severity [1][2][3][4].…”

“…VWD is caused by quantitative (Types 1 and 3) or qualitative (Type 2) deficiency in von Willebrand factor (VWF) and is markedly heterogeneous in type and severity [1][2][3][4]. Surgical procedures in patients with VWD can be associated with a life-threatening risk of excessive bleeding and may require prophylactic treatment with a combined VWF/FVIII concentrate [5].…”

Management of VWD

“…It is characterized primarily by mucocutaneous bleeding, excessive hemorrhage after invasive procedures, and, less commonly, by soft tissue hematomas and joint bleeding in the more severe types. 1 There are excellent clinical guidelines published to facilitate the diagnosis and management of the various types of VWD. 2 The general approach to management of VWD depends upon increasing the circulating concentration of functional VWF and/ or using adjunctive therapies to preserve or enhance clot formation.…”