One of the main mechanical forces that influences blood clotting has been identified. New research demonstrates how proteins called “integrins” — receptors in the outer membranes of cells that facilitate how cells bind to one another and interact with their environment — form an intermediate state between their active and inactive forms that promotes the aggregation of platelets, the blood cells that form clots.
Coagulation of platelets is key to stopping blood loss from a cut or wound, but overactivation of this process — thrombosis — can lead to deadly blood clots, heart attack or stroke. The new findings take researchers one step closer to developing new anti-thrombotic drugs without the serious side effects that can cause fatal bleeding.
The research, by an international team of biomedical researchers and data scientists from Penn State, the Scripps Institute, Georgia Tech and the University of Sydney in Australia, appears in the March 25 issue of the journal Nature Materials and is built on the research team’s prior work that was published in eLife and featured as a Top Story by the U.S. National Science Foundation Science360 News in 2016.
“We want to understand the mystery behind blood clots, using innovative biomedical engineering and novel statistical tools,” said Lingzhou Xue, assistant professor in the Department of Statistics at Penn State and an author of the paper. “We’ve been working together for a long time to study how mechanical force triggers blood clotting at the molecular scale.”
When you nick yourself shaving, or slice your thumb while cutting sheetrock, you can be thankful for integrins. These specialized proteins play a critical role in stopping the bleeding that ensues as a result of the wound. Following a wound, your platelets swarm the wound and clump together, forming a plug, or clot, to stop blood loss. This first stage of wound healing is called hemostasis.
“Of course, the other side of the coin is thrombosis, which is what kills people who have cardiovascular disease,” said Cheng Zhu, Regents Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and an author of the paper.
Integrins also are vital to basic cellular biological processes, such as growth and development. Cell attachment to each other and to the extracellular matrix that surround them is a basic requirement in building a multicellular organism, for instance.
“Integrins basically facilitate how cells bind to and respond to their mechanical environment,” said Arnold Lining Ju, co-lead author from the University of Sydney’s School of Aerospace, Mechanical and Mechatronic Engineering, Heart Research Institute, and Charles Perkins Centre. “They allow cells to cling to each other, and are great communicators, transmitting bi-directional signals to activate the binding function; and outside-in, allowing the cell to sense and react to the extracellular environment. The integrin can instruct the platelet cells’ clotting behaviors.”
But the mechanisms behind these important processes remain poorly understood. In order to begin to understand these processes, the researchers used a microfluidic channel, which could mimic the narrowing of vessels that cause blood clots, to observe the activation of platelets at the single-molecule level. The researchers demonstrated that blood flow disturbances could lead to the activation of the previously unrecognized intermediate form of integrins.
The researchers also developed a single-molecule biomechanical nanotool called a “dual biomembrance force probe (BFP)” to observe how platelets harness mechanical force in blood flow to exert adhesive clotting functions.
The researchers say the finding — that biomechanical thrombus growth is mainly mediated by an intermediate state triggered by a unique integrin biomechanical activation pathway — has the potential to guide the development of new anti-thrombotic strategies.
“Our finding may also offer help to diabetic patients since diabetic platelets are more resistant to conventional anti-clotting drugs,” said Ju. “Targeting biomechanical pathways may also have the advantage of preventing deadly clots without bleeding side effects.”
In addition to Xue, Zhu, and Ju, the research team includes Yunfeng Chen from the Scripps Institute; Fangyuan Zhou, Jiexi Liao, and Hang Lu at Georgia Tech; Qian Peter Su and Dayong Jin at the University of Technology Sydney, Australia; and Shaun Jackson and Yuping Yuan at the University of Sydney.
This research was supported by grants from the U.S. National Institutes of Health (and under its umbrella, the National Institute on Drug Abuse), the U.S. National Science Foundation, the Australian Research Council, the University of Technology Sydney, the Diabetes Australia Research Program, the University of Sydney, the Royal College of Pathologists of Australasia, and the Cardiac Society of Australia and New Zealand.