Thrombocytopathy and type 2B von Willebrand disease

Abstract

The knowledge gained from "experiments of nature" has always been paramount in identifying key players in pathophysiologic pathways. This is well characterized by naturally occurring bleeding and thrombotic disorders. In most cases, it is the absence of a particular protein that leads to recognition of its importance for normal physiology. On the other hand, gain-of-function mutations highlight not only the presence of the protein, but also how it regulates a particular physiologic response. In this issue of the JCI, Casari and colleagues define a previously unrecognized consequence of variant type 2B von Willebrand factor (vWF) binding to blood platelets. More than 30 years after an initial description of type 2B variant vWF, the consequence of this spontaneous variant vWF binding to platelets is viewed as a dysregulation of platelet signaling pathways contributing to the type 2B bleeding phenotype.

Figure 1. Regulation of the vWF/Platelet axis.

(A) In response to endothelial cell damage, WT vWF binds to exposed extracellular matrix. This binding changes vWF affinity for the GP-Ib-IX, which promotes platelet adhesion. Platelet adhesion results in activation of integrins, including αIIbβ3, which in turn promotes platelet spreading, and aggregation. (B) A mutant vWF associated with vWD-type 2B has increased affinity for platelet GP-Ib-IX. Mutant vWF prevents activation of αIIbβ3, which reduces platelet adhesion, activation, and spreading in response to endothelial cell damage.