How life-threatening blood
clots take hold
Thursday, April 16,
2009
When plaques coating blood vessel walls rupture and expose
collagen, platelets spring into action to form a blood clot at the
damaged site. Now, a new report in the April 17th issue of the
journal Cell, a Cell Press publication, reveals how those
life-threatening clots—a leading cause of death in the United
States, Europe and other industrialized countries--get an early
grip. The discovery might offer a new way to fight clot formation
before it can even begin, according to the researchers.
"Compared to other diseases, blood clotting has been very well
understood," said Athan Kuliopulos of Tufts Medical Center and
Tufts University School of Medicine. Nevertheless, he continued,
many people still suffer from heart attacks, ischemic stroke and
death as a result of clot formation.
"Drugs designed to inhibit clots through known pathways are widely
used by millions. They work well, but not perfectly. There is still
an unmet need." Those drugs include aspirin and the so-called
thienopyridines, including Clopidogrel (trade name Plavix).
Scientists have known that a protein called thrombin plays an
important role in clot formation as a potent activator of
platelets. It also cuts fibrinogen into fibrin, a fibrous protein
that works together with platelets to form a clot.
But thrombin isn't the whole story. Enzymes known as matrix
metalloproteases have recently emerged as important players in
platelet function and the biology of blood vessels. Two of those
enzymes, MMP-1 and MMP-2 can actually encourage platelet
activation, according to earlier studies, although the means were
unknown. In cancer cells too, MMP-1 activates a receptor known as
PAR1 – the same receptor that is also responsible for receiving the
thrombin signal on human platelets.
"There is abundant proMMP-1 coating platelets," Kuliopulos said.
"We thought maybe it was on the outside waiting to be activated by
something. Maybe it could be involved in an early event in blood
clotting, before thrombin is around."
Indeed, Kuliopulos' team has now connected those dots. They show
that exposure of platelets to collagen activates MMP-1, which in
turn directly cut PAR1 on the surface of platelets. Collagen is the
first thing a platelet "sees" when a blood vessel ruptures or is
cut.
The MMP-1-PAR1 pathway activates another set of molecular players
known to be involved in early clot formation, he said. Those
activated platelets change their shape, sending out spikes and
membrane sheets. "Within seconds, they become more sticky,"
adhering to the vessel surface and then other platelets.
Moreover, they show that treatments that block the MMP1-PAR1
pathway prevent blood clots from forming in the presence of
collagen, suggesting that drugs targeting this
metalloprotease-receptor system could offer a new way to treat
patients with acute coronary syndromes.
According to the new results, PAR1 inhibitors already being tested
in clinical trials might have an added benefit, Kuliopulos said.
It's also possible they might work a little too well, since there
is a careful balance between the risk of dangerous blood clots and
the risk of bleeding. "An MMP-1 inhibitor might be better
tolerated," he said.
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Cell Press
Thanks to Cell Press for this
article.