Discovery of Blood-Clotting Disorder Suggests New Treatment
David Ginsburg, Beth McGee,
David Motto, Angela Young, David Siemieniak and Gallia Levy
Photo: Bill Wood
Researchers led by David Ginsburg, M.D.a Warner-Lambert/Parke-Davis
Professor of Medicine, professor of internal medicine and of
human genetics, and a Howard Hughes Medical Institute investigator
in the U-M Medical School have discovered the cause of
an inherited blood-clotting disorder, thrombotic thrombocytopenic
purpura or TTP, which can lead to deadly kidney failure or stroke.
In a paper published in the October 4, 2001, issue of Nature,
the research team reported that TTP is caused by mutations in
a gene that makes an important enzyme ineffective. Now that
the cause is known, it might be possible to treat people with
TTP by giving them an active form of the enzyme, in the same
way that people with hemophilia receive clotting factor.
The cause of the disease was a mystery, says Ginsburg.
Patients suddenly became very ill and the only treatment
was replacing their blood plasma.
Earlier studies had implicated a clotting-related protein known
as von Willebrand factor (VWF) in the disorder. These studies
found that the blood of TTP patients showed an abnormally large
form of the VWF protein. The protein had not been cut into two
smaller sizes, as is normally the case. According to Ginsburg,
this led scientists to believe that a defect in a protein-clipping
enzyme called a protease might be responsible for TTP.
An assay developed at the Montefiore Medical Center and Albert
Einstein College of Medicine was used to test blood samples
from four families with an inherited form of TTP. The assay
showed that family members with TTP had low VWF protease activity,
while carriers of the disease showed medium levels of activity
and unaffected individuals had normal levels.
The findings seemed too good to be true, says Ginsburg.
They clearly showed the presence of a recessive gene in
which all the carriers, who had one good copy and one bad copy
of the gene, had about half the level of protease activity.
Gallia G. Levy, a graduate student in the U-M Medical School
and lead author on the paper, then narrowed the area containing
the disease gene to one region of chromosome 9. When Levy studied
TTP patients for mutations in this target region, she found
the mutations in a gene for a protease called ADAMTS. According
to Ginsburg, Levys findings open the way to understanding
how and why this enzyme cleaves VWF and how the failure to cleave
the protein causes disease.
Our current hypothesis is that the large form of VWF is
too sticky. Unless the protease cuts it into two smaller forms,
it spontaneously sticks to blood platelets and clogs vessels,
It doesnt appear to take much of this protease to
treat the disease and it lasts for awhile in the blood,
Ginsburg adds. So it might be possible to give people
with TTP a periodic injection of the enzyme to maintain their
protease activity. Such treatment would work better and be safer
than plasma exchange, because of the risk of complications from
The research was supported by the National Institutes of Health
and the Howard Hughes Medical Institute. Kenneth R. Start, M.D.,
Ph.D., a U-M house officer in internal medicine collaborated
in the study, along with Howard Hughes Medical Institute research
specialists Angela Y. Yang and David R. Siemieniak and Beth
M. McGee, research technician.
Adapted by Sally Pobojewski from
information provided by Howard Hughes Medical Institute
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