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1644
(page 1662) used friendlier starting material
than plasma, factor VIII/vWF concentrates,
and employed conventional chromatography
on heparin, ion exchange, and size exclusion columns. From the products of these
independent purification methods, both
groups obtained the same protein sequence.
The vWF protease is a 150-kd singlechain glycoprotein that requires divalent
metal ions. Exploring the human genomic
database, Fujikawa and colleagues found a
match between their N-terminal protein sequence and an EST cluster from chromosome 9q34. This composite cDNA sequence
encodes a metalloprotease belonging to the
ADAMTS subfamily, although the expected
thrombospondin domain is not part of this
partial sequence. ADAMTS proteases typically contain both zinc and calcium ions,
and the congruence between the known
properties of the vWF protease and
ADAMTS proteases provides additional
compelling evidence that the vWF protease
has been identified.
To what use might this initial information be applied? It is likely that polyclonal
and monoclonal antibodies can be prepared
against the deduced protein sequence,
making quantitation of plasma protease
antigen and a rapid diagnostic test for TTP
no more than a clinical ELISA away. But a
significant fraction of patients with microangiopathy have normal levels of this protease, and new tools based on this new pro-
tease should facilitate the dissection of these
potentially distinct entities that converge on
a common TTP-like phenotype. Ultimately,
completion of the cDNA sequence will lead
to production of recombinant protein, which
could enable specific therapy for the rare
patient with congenital TTP and possibly for
patients with low-titer autoantibodies. Eventually we should be able to prove or refute
the UL-vWF multimer theory of TTP,
thereby moving us one step closer to a cure.
—Kenneth Kaushansky
University of Washington
Endothelial cells: they
only look all alike
In this issue, Morigi and colleagues (page
1828) provide experimental evidence that
delineates a pathogenetic mechanism for the
postdiarrheal hemolytic uremic syndrome of
children. Their findings suggest that the localization of platelet thrombi in the arteriolar circulation and capillaries, as typically
seen in the disease, is the consequence of a
distinct response of microvascular endothelial cells to verotoxin produced by E coli.
These results illustrate 2 concepts that may
prove of general significance in our understanding of the causes that trigger arterial
thrombosis.
First, the paper provides a welldocumented example of the heterogeneity
of endothelial cells, based on the variable
BLOOD, 15 SEPTEMBER 2001 䡠 VOLUME 98, NUMBER 6
expression of specific molecules that determine a distinct response to stimuli.
Evidence is accumulating that the genetic
programming of endothelial cells not only
differs in arteries and veins, as well as in
larger and smaller vessels, but also defines
unique environments in the vascular bed of
organs that may explain the preferential localization of disease processes. Thus the
same event in different vessels may lead to
variable outcomes. Second, the proposed
explanation for the effect of verotoxin is a
further demonstration of the link between
infections and arterial thrombosis. Epidemiologic and experimental studies have called
attention to the fact that bacteria and bacterial
products may be involved in precipitating
acute occlusive incidents on the background
of chronic degenerative alterations, such as
seen in atherosclerosis.
Morigi and colleagues’ results add
support to the hypothesis that infections or
other stimuli may induce specific changes in
gene expression that, for example, could
alter the make up of proadhesive molecules
in the extracellular matrix and enhance the
likelihood of platelet deposition on a ruptured plaque. We have known for some time
that endothelial cells are not just a passive
barrier to flowing blood. Now we are
learning with increasing clarity that their
dynamic responses may have a remarkable
variety of regional flavors.
—Zaverio M. Ruggeri
Scripps Research Institute
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2001 98: 1644
doi:10.1182/blood.V98.6.1644
Endothelial cells: they only look all alike
Zaverio M. Ruggeri
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