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02.16 Collaborative Clots
Collaborative Clots    
 

Highlights

  • Blood clotting is essential to stop bleeding and repair wounds.
  • PolySTAT is a newly developed polymer that becomes integrated into the blood clot as it forms.
  • In animal models PolySTAT demonstrated improvement in the time needed to create a blood clot and the strength of the blood clot formed. Applications for this new technology include the ambulance, the hospital and the battlefield.

Do you know how much blood you have in your body? The answer will depend on your height, weight and other factors. The average person has one to two gallons of blood running through them at any given time. And the blood is really flowing—carrying oxygen and nutrients through the bloodstream from the lungs to all of our organs and carrying the excess carbon dioxide back to the lungs.



The Circulatory System video


How much of that gallon or two of blood do you really need? The typical blood donation is one pint (two cups) of blood, which takes about 24 hours for the body to replace. The needle prick to draw the blood is quickly closed up by the immune system so the body doesn’t lose any more. Even after a pint of blood has been removed, there is still plenty left over for the occasional cut, scratch, or scrape. After the body loses twenty percent of blood volume, though, blood loss can become life-threatening. This is a condition known as hypovolemic shock. This is not something most of us see on a daily basis—unless we happen to work in emergency medicine.

Dr. Nathan White is an emergency medicine doctor at the University of Washington. He sees patients on a regular basis who have lost lots of blood but managed to survive. Violence, car crashes and other situations are the most common reasons for such extreme blood loss. While Dr. White helps many people, he can’t help those who do not make it to the emergency room alive because they have lost too much blood.

One day several years ago, Dr. White mentioned this to Dr. Suzie Pun, a colleague in bioengineering. At the time, Dr. Pun was developing targeted polymers to be used for drug delivery. In the course of the discussion, Dr. Pun realized that the polymers from her lab might be useful for trauma patients. That conversation began a collaboration between Dr. White, the emergency medicine doctor, and Dr. Pun, the bioengineer. The result of this collaboration is polymers that strengthen blood clots and stop bleeding.

Blood Clot Formation

To understand how this new technology works, let’s first address the basics of blood clot formation. Bleeding occurs when a blood vessel is damaged and blood flows out of the blood vessels. This can occur both externally (whenever we see blood) or internally, inside our organs. Damaged blood vessels send signals to cells of the immune system to activate the response for blood clot formation. Proteins in the blood vessel walls act as the glue that bind red blood cells together into clots that plug the hole and stop the bleeding while the blood vessels are repaired.



How Blood Clots


Patients who end up dying from blood loss had wounds too big for their bodies to repair in time.

The larger the wound, the larger and stronger the clots must be to stop the bleeding. Patients who end up dying from blood loss had wounds too big for their bodies to repair in time. This is where the polymers come in. The polymers that Drs. Pun, White and their team developed, known as PolySTAT, bind to proteins released by the walls of the blood vessel and integrate into the clot as it forms. The resulting clots are a fusion of natural and synthetic molecules. Testing in animal models has shown that PolySTAT polymers effectively strengthen blood clots with the potential to save lives.



A 3-D rendering of fibrin forming a blood clot, with PolySTAT (in blue) binding strands together.
Credit: William Walker, University of Washington


Designing a Polymer

The polymer was designed based on the needs for a rapidly acting but highly specific material. It needed a chemical structure that would allow it to travel throughout the bloodstream and find sites of injury without sticking to other cells or interacting with other parts of the body. In addition, the polymer had to stay in the bloodstream for just the right amount of time before dissolving, as natural blood clots do.

The polymer itself consists of a water-soluble backbone with ‘tags’ that bind to fibrin, the fibers that form in blood clots. These tags allow the polymers to identify clots in the bloodstream and integrate into them.

The polymer design was tested using a machine to measure the properties of blood clots, known as a thrombelastography machine. The machine consists of a rotating cup that holds the blood, with a pin in the middle that is also capable of rotation. As unclotted fluid rotates in the cup, the center pin stays in place. As the clot forms, however, it sticks to the center pin, which begins to rotate as well. “You can think of clots as having the consistency of jello,” explains Dr. Pun. This system allows the researchers to measure how long it takes for a blood clot to form, the maximum strength of the blood clot, and how long it takes for the clot to dissolve.



A ROTEM thrombelastography machine


The scientists tested the polymers in multiple experiments using the thrombelastography machine. They conducted experiments to determine the appropriate protein markers inside the polymers, to optimize the concentration of the polymer coating needed to stay in the bloodstream for about an hour, and to optimize the number of polymers needed to form a clot of certain strength.

Applications for this new technology are not limited to the ambulance or hospital setting. PolySTAT is also a candidate for use on the battlefield, particularly because it does not need to be refrigerated.

Dr. Pun and her team tested the polymers in mouse models. The researchers observed significant improvement in the time needed to create a blood clot and the strength of the blood clot formed. “These are really exciting results,” comments Dr. Pun.

Polymer development can often be a matter of trial and error, with researchers experimenting with multiple molecules before identifying one that works. For Dr. Pun, PolySTAT was the very first polymer she tried. “We have lots of years of experience in polymer development, and we designed the materials really well on paper before going in,” explains Dr. Pun. “But this is really rare. It’s something we’re all proud of.”

Applications for this new technology are not limited to the ambulance or hospital setting. PolySTAT is also a candidate for use on the battlefield, particularly because it does not need to be refrigerated. “But we’re not there yet,” cautions Dr. Pun. PolySTAT must first be tested in larger animal models. If the results of those experiments are positive, only then can PolySTAT move into clinical trials for testing on human patients.

“We were two researchers, two teams, with very different backgrounds,” concludes Dr. Pun. “We were able to use our respective expertise to make a product that will one day, I hope, save lives.”

Dr. Suzie Pun is the Robert F. Rushmer Professor of Bioengineering and Adjunct Professor of Chemical Engineering at the University of Washington. Her research focuses on the development of synthetic molecules for drug delivery including her work on blood clot formation. Dr. Pun chose engineering because of her interest in music. “I was interested in either engineering or chemistry,” recalls Dr. Pun. “The engineering department had a program to support my music lessons, so I went with that. And I never looked back.” When not in the laboratory, Dr. Pun enjoys spending time with her family.

Dr. Nathan White is Assistant Professor of Emergency Medicine at the University of Washington.

For More Information:

  1. Chan, L. et al. 2015. “A synthetic fibrin cross-linking polymer for modulating clot properties and inducing hemostasis.” Science Translational Medicine, 7(277): 1-11.

To Learn More:

  1. Pun laboratory http://faculty.washington.edu/spun/
  2. How the Blood Clots. https://www.youtube.com/watch?v=fAOti396K_4
  3. Brohi K. Make the bleeding stop. Science Translational Medicine, 7, 277fs10.
  4. National Trauma Institute. http://www.nationaltraumainstitute.org/home/hemorrhage.html
  5. Diagram of the Human Circulatory System http://www.livescience.com/27585-human-body-system-circulation-infographic.html

Written by Rebecca Kranz with Andrea Gwosdow, PhD at www.gwosdow.com



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L to R: Robert Lamm, Xu Wang, Suzie Pun, Leslie Chan, Nathan White



Susie Pun and Leslie Chan



Leslie Chan





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