Optimizing treatment of von Willebrand disease by using phenotypic and molecular data

Abstract

The wide clinical spectrum of von Willebrand disease (VWD), its complex pathophysiology and its classification into distinct quantitative (type 1 or type 3) and qualitative (type 2) types with further subtle distinctions have prevented most clinicians from establishing a straightforward approach to diagnosing and treating this inherited bleeding disorder. The results of studies involving large cohorts of patients with a wide range of bleeding manifestations and variable von Willebrand factor (VWF) reduction have recently become available. These data have allowed the proposal of minimal criteria for a clinically useful diagnosis and for differentiating patients with mild VWD from subjects with borderline or only slightly reduced VWF levels who will not benefit from a specific diagnosis. These criteria are based on measurement of VWF ristocetin cofactor (VWF:RCo), VWF antigen (VWF:Ag), factor VIII and a standardized bleeding score (BS). Demonstration of the inheritance of the disorder could help to classify patients for whom insufficient hemostatic challenges may produce a falsely reassuring BS (like in children). Using this approach, mild VWD appears to be mostly composed of type 1 cases. Complemented by the results of desmopressin trial infusion, these parameters form the basis for a clinically oriented classification of all forms of VWD and may be useful for selecting the best treatment according to the severity of the disease. Although few molecular data have revealed practical utility, there is no doubt that the clarification of the molecular pathophysiology of VWD has allowed the unification of this complex disorder into a simple conceptual framework. This framework underlies the proposed utilization of simple phenotypic markers for optimizing treatments in individual patients.

New treatment approaches to von Willebrand disease

“…In addition, adequate hemostasis must be maintained during dental or surgical interventions, and around the time of delivery. Suggested management strategies for these common scenarios have been described in a number of recent reviews 8,10,[22][23][24] and are summarized in Table 2. In addition to tranexamic acid, DDAVP, and VWF-containing concentrates, several other adjunctive therapies can also be useful for specific indications.…”

Enfermedad de von Willebrand, biología molecular y diagnóstico

“…También es importante tomar en cuenta diferentes factores, algunos de los cuales aumentan la concentración del VWF: embarazo, ejercicio, trauma, cirugía, edad; y su nivel es mayor en individuos del grupo sanguíneo A, que en el O. En cambio, otros causan su disminución: hipertiroidismo, falla renal, enfermedad hepá-tica, aterosclerosis, estados inflamatorios, cáncer, diabetes e hipotiroidismo 24,25 .…”

“…Los multímeros son vistos mediante autorradiografía después de la incubación con anticuerpo contra el VWF marcados con inmunoperoxidasa o fosfatasa alcalina. Esta técnica permite el diagnóstico con certeza de los diferentes tipos de la enfermedad de von Willebrand según su patrón de multímeros y tiene lugar solo en los laboratorios de referencia 24,25,30,31 .…”

Diagnosis and classification of von Willebrand disease

“…In contrast, in type 2 VWD there is a loss of VWF function (often also coincident to a quantitative loss of VWF) and, hence, a potentially greater risk of severe bleeding. In type 1 VWD, desmopressin ('DDAVP') is often an effective treatment, representing a nontransfusional therapy that acts to release VWF stored in endothelial cells [1,12]. In type 2 VWD, desmopressin is typically less effective, given that this leads to release of 'dysfunctional' VWF; hence, VWF replacement or alternate therapies are usually applied [1,12].…”