Exploring the Molecular Origin
of Blood Clot Flexibility
Well-Known Protein Structure Acts as a Molecular Spring
(PHILADELPHIA) – How do blood
clots maintain that precise balance of stiffness for wound healing
and flexibility to go with the flow? Researchers at the University
of Pennsylvania School of Medicine and the School
of Arts and Sciences have shown that a well-known protein structure
acts as a molecular spring, explaining one way that clots may stretch
and bend under such physical stresses as blood flow. They report their
findings in a Letter in the latest online edition of the Biophysical
Journal. This knowledge will inform researchers about clot physiology
in such conditions as wound healing, stroke,
Clots are a three-dimensional network of fibers, made up primarily of
the blood protein fibrinogen,
which is converted to fibrin
during clotting. A blood clot needs to have the right degree of stiffness
and plasticity to stem the flow of blood when tissue is damaged, yet be
flexible enough so that it does not block blood flow and cause heart
attacks and strokes.
In previous research, senior author John
W. Weisel, PhD, Professor of Cell
and Developmental Biology, measured the elastic properties of individual
fibers and found that the fibers, which are long and very thin, bend much
more easily than they stretch, suggesting that clots deform in flowing
blood or under other stresses, primarily by the bending of their fibers.
The current research extends those earlier findings to the molecular level,
suggesting a way that individual fibers flex - by the unraveling of the
three, tightly twisted rod-like regions within fibrinogen molecules, called
coiled-coils. The researchers measured this change by pulling engineered
strands of fibrinogen molecules using an atomic
force microscope. This alpha-helical coiled-coil “spring”
is a common motif in protein structure, first identified more than 50
years ago and so its stretchiness may have broader implications in biology
By understanding mechanical processes at the molecular level, it may eventually
be possible to see how they relate to the mechanical properties of single
fibers and a whole clot. This knowledge may enable researchers to make
predictions about the function of differently formed fibrin clots in the
circulating blood or in a wound. For example, when clots are not stiff
enough, problems with bleeding arise, and when clots are too stiff, there
may be problems with thrombosis,
which results when clots block the flow of blood. First author André
Brown, a physics graduate student at Penn,
notes that this research is a first step towards understanding the mechanics
of the relationship between clot elasticity and disease.
Recent research by other scientists showed that a fibrin fiber could stretch
four to five times its original length before snapping. "This is
among the most extensible, or stretchy, of polymers that anyone has ever
found," says Weisel. "But, how is the stretching happening at
a molecular level? We think part of it has to be the unfolding of certain
parts of the fibrin molecule, otherwise how can it stretch so much?"
Previous research from senior coauthor Dennis
Discher, PhD, Professor in the Physics
& Molecular Biology graduate groups, suggested the possibility
that alpha-helical structures in some blood-cell proteins unfold at low
levels of mechanical force. But "it wasn't known before that the
coiled coil region of the fibrinogen molecule would be the part to unfold
under the stress induced by the atomic force microscope," notes Brown.
Once the origins of the mechanical properties of clots are well understood,
it may be possible to modulate those properties, note the study authors.
"If we can change a certain parameter perhaps we can make a clot
that's more or less stiff," explains Weisel. For example, various
or proteins, such as antibodies,
bind specifically to fibrin, affecting clot structure. The idea would
be to use such compounds in people to alter the properties of the clot,
so it can be less obstructive and more easily dissolved.
In the future, the researchers will examine other processes at the molecular
and fiber levels that may be responsible for the mechanical properties
of clots to eventually develop a model that can then be used to predict
the effect of changes at one scale on clot properties at other scales.
Such a model should be useful for developing prophylactic
and therapeutic treatments for many aspects of cardiovascular disease
and stroke, suggest the investigators.
I. Litvinov is also from Penn. This research was funded by the National
Institutes of Health and the Natural
Sciences and Engineering Research Council of Canada.
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