Nav: Home

Exploring the molecular origin of blood clot flexibility

January 12, 2007

(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, and cardiovascular disease.

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 alpha-helical 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 and medicine.

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 and Cell & 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 peptides 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.
-end-
Co-author Rustem 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.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

University of Pennsylvania School of Medicine

Related Cardiovascular Disease Articles:

Is educational attainment associated with lifetime risk of cardiovascular disease?
Men and women with the lowest education level had higher lifetime risks of cardiovascular disease than those with the highest education level, according to a new study published by JAMA Internal Medicine.
Food policies could lower US cardiovascular disease rates
New research conducted by the University of Liverpool and partners shows that food policies, such as fruit and vegetable subsidies, taxes on sugar sweetened drinks, and mass media campaigns to change dietary habits, could avert hundreds of thousands of deaths from cardiovascular disease (CVD) in the United States.
Cardiovascular disease causes one-third of deaths worldwide
Cardiovascular diseases (CVD), including heart diseases and stroke, account for one-third of deaths throughout the world, according to a new scientific study that examined every country over the past 25 years.
Kidney disease is a major cause of cardiovascular deaths
In 2013, reduced kidney function was associated with 4 percent of deaths worldwide, or 2.2 million deaths.
Cardiovascular disease costs will exceed $1 trillion by 2035
A new study projects that by 2035, cardiovascular disease, the most costly and prevalent killer, if left unchecked, will place a crushing economic and health burden on the nation's financial and health care systems.
Prescribing drugs for cardiovascular disease prevention in the UK
Drugs such as statins that have the potential to prevent strokes and other types of cardiovascular disease have not been prescribed to a large proportion of people at risk in the UK, according to a research article by Grace Turner of the University of Birmingham, Birmingham, UK and colleagues published in PLOS Medicine.
Fatty liver disease contributes to cardiovascular disease and vice versa
For the first time, researchers have shown that a bi-directional relationship exists between fatty liver disease and cardiovascular disease.
More dietary calcium may lower risk of cardiovascular disease
In older people, higher dietary calcium intake may lower the risk of cardiovascular disease, but not of stroke and fracture, new research from South Korea suggests.
Renal hemodynamics and cardiovascular function in health and disease
The SRC will focus on unpublished work that is state-of-the-art in study of cardiovascular and renal disease and hypertension.
Cardiovascular disease in adult survivors of childhood cancer
For adult survivors of childhood cancer, cardiovascular disease presents at an earlier age, is associated with substantial morbidity, and is often asymptomatic.

Related Cardiovascular Disease Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#513 Dinosaur Tails
This week: dinosaurs! We're discussing dinosaur tails, bipedalism, paleontology public outreach, dinosaur MOOCs, and other neat dinosaur related things with Dr. Scott Persons from the University of Alberta, who is also the author of the book "Dinosaurs of the Alberta Badlands".