Blood, 1 April 2003, Vol. 101, No. 7, pp. 2450-2450
Von Willebrand factor: a matrix protein that tries to
be soluble
Platelet adhesion and aggregation onto vascular wall lesions
contribute to the arrest of posttraumatic bleeding but may also cause
arterial occlusion leading to complications such as myocardial infarction and stroke (Ruggeri, Nat Med. 2002;8:1227-1234). The interaction between the membrane glycoprotein (GP) Ib
and von Willebrand factor (VWF) is required to support platelet adhesion and
aggregation in areas of the vasculature with rapid blood flow, a
hemodynamic condition that reaches pathologic extremes at sites of
arterial stenosis. VWF is a large multimeric protein assembled from
disulfide-linked identical subunits. Endothelial cells secrete VWF as
an insoluble constituent of the extracellular matrix or as a soluble
plasma component; megakaryocytes package VWF into granules for
release by platelets upon activation. Plasma VWF multimers exceed a
mass of 1 × 107 Da but may derive from even
larger forms that are cleaved by ADAMTS-13, a recently identified
metalloproteinase (Levy et al, Nature. 2001;413:488-494). Previous
evidence had indicated that plasma VWF multimers can self-associate on
a surface exposed to flowing blood (Savage et al, Proc Nat Acad
Sci U S A. 2002;99:425-430).
In this issue Shankaran and coworkers (page 2637) extend this concept
and show that self-association can also occur with VWF multimers in
solution. These new results are presented in the context of studies
that, with a remarkable effort to numerical accuracy, contribute to
clarify the mechanisms of shear-induced platelet activation, a process
that depends on the binding of VWF to GP Ib and may contribute to
pathologic thrombosis. It is generally accepted that the prothrombotic
functions of VWF are directly related to multimer size. This and
previous studies demonstrate that shear forces generated by flowing
blood can cause the noncovalent but relatively stable assembly of very
large VWF polymers from plasma multimers and, thus, enhance platelet
adhesion and activation. The cleavage by ADAMTS-13 of very large
VWF released from endothelial cells, and presumably platelets, may be
necessary to limit the size of circulating VWF multimers and reduce the risk of unwarranted platelet activation and aggregation. Indeed, when
this mechanism is deficient, thrombotic disorders develop. Size,
however, is of the essence for VWF function, and shear-mediated reassembly into larger structures may represent an efficient way to
allow locally the presence of molecular species needed for thrombus
formation but whose systemic appearance would not be desirable. Through
such a mechanism, ultralarge VWF may be made available even where it
cannot be released as such by endothelial cells. Reassembled large VWF
polymers are probably subjected to size-limiting cleavage by ADAMTS-13,
delineating a tightly regulated mechanism that controls the proadhesive
properties of VWF through polymer size and may become a contributing
cause of arterial thrombosis if unregulated.
Zaverio M. Ruggeri
The Scripps Research
Institute
