Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Penn researchers show that protein unfolding is key for understanding blood clot mechanics

Implications for cardiovascular medicine as well as polymer and materials science

Fibrin, the chief ingredient of blood clots, is a remarkably versatile polymer. On one hand, it forms a network of fibers -- a blood clot -- that stems the loss of blood at an injury site while remaining pliable and flexible.

On the other hand, fibrin provides a scaffold for thrombi, clots that block blood vessels and cause tissue damage, leading to myocardial infarction, ischemic stroke, and other cardiovascular diseases. How does fibrin manage to be so strong and yet so extensible under the stresses of healing and blood flow?

The answer is a process known as protein unfolding, report Penn researchers in Science this week. An interdisciplinary team, composed of investigators from the University of Pennsylvania School of Medicine, the School of Arts and Sciences, and the School of Engineering and Applied Science, has revealed how protein unfolding allows fibrin to maintain its remarkable and contradictory characteristics. Understanding blood clot mechanics could help in the design of new treatments not only to prevent or remove clots that cause heart attacks and strokes but also to enhance blood clotting in people with bleeding disorders. Fibrin's unusual characteristics may also lead to applications in designing new synthetic materials based on its biology.

Building on previous work examining the properties of fibrin, senior author John Weisel, PhD, Professor of Cell and Developmental Biology, and his collaborators studied the mechanics of fibrin clots under stress from the macroscopic scale down to the molecular level. The results were achieved by joint efforts of scientists with different skills, knowledge, and backgrounds: A graduate student Andre E. X. Brown and his adviser Professor Dennis E. Discher brought physics and biomedical engineering; Senior Investigator Rustem I. Litvinov provided his expertise in protein chemistry and medicine; and Prashant K. Purohit, an Assistant Professor of Mechanical Engineering, joined the team to perform theoretical analyses of the experimental data and construct mathematical models of what was happening.

The researchers found that individual fibers in a fibrin blood clot are normally randomly oriented in an intricate meshwork pattern. But when the clot is stretched, the fibers begin to align with each other in the direction of the stress. As the strain continues, the clot stretches and gets longer -- but its volume actually decreases, which surprised the scientists. "That's very unusual," notes Weisel. "It's a property that's been found in a few other materials but it's very rare."

This was a sure sign that something unexpected was going on. "Slipping past each other between or within fibers was not a possibility that could give rise to such high unusual extensions because these fibers were cross-linked. This research provides evidence, both in terms of the mathematical model and with x-ray scattering data, that there is indeed unfolding going on," Purohit says."

The team used a variety of techniques from simple controlled stretching to electron microscopy, X-ray diffraction, atomic force microscopy, and mathematical modeling, to provide a coherent picture of how fibrin clots behave from the centimeter to the nanometer scale. This multi-scale strategy was vital: "You have to examine events at different spatial scales with various methodologies to understand how fibrin behaves," explains Weisel.

Protein unfolding explains how the volume of the fibers decreases as they're stretched. "When you unfold proteins, you're exposing parts that are normally buried in the middle of the molecule," Weisel says. "And these are hydrophobic; they don't want to be near water. So the unfolded protein structures interact with each other through those hydrophobic parts and water is expelled from the molecule. We see this when we stretch the fibrin and that's how the whole clot volume decreases about tenfold with threefold stretching." This great extensibility of fibrin on the molecular scale allows a fibrin clot to undergo the stretching and pulling that occurs during wound healing, while remaining permeable enough to allow itself to be broken down by enzymes when it's no longer needed.

That expulsion of water was a surprise, Weisel says. "The volume change, the fact that it's so extensible, that wasn't known previously. At the molecular level this unfolding is necessary for the mechanical properties."

The work has opened up new avenues of research that the researchers are eager to pursue. "The more we know about the mechanism of blood clotting, the greater the possibilities for learning how to control and modulate it, which may lead to new treatments of thrombotic and bleeding problems," surmises Weisel.

Beyond the obvious medical benefits, the team's interdisciplinary approach highlights the relevance of the research to other fields, such as biomedical engineering and materials science.

The study was funded by the National Heart Lung and Blood Institute, the National Science Foundation, and the Natural Sciences and Engineering Research Council of Canada.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in 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 currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 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 (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center, named one of the nation's "100 Top Hospitals" for cardiovascular care by Thomson Reuters. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Karen Kreeger | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>