Researchers at Oregon Health & Science University have uncovered how a molecule found on certain bacteria may drive blood clotting in sepsis, a life-threatening condition that causes about 8 million deaths per year.
The team in the cardiovascular engineering lab at OHSU has focused on the role of specific blood clotting mechanisms in sepsis, with hopes of improving treatments for critically ill patients.
Owen McCarty, Ph.D., senior author of the paper and professor of biomedical engineering in the OHSU School of Medicine, said the immune system's response to bacteria can spiral out of control.
"Your blood normally forms tiny clots to contain certain bacteria to clear them from the bloodstream," McCarty said. "But if there are too many bacteria, the system gets overwhelmed, using up all the platelets and clotting factors. The result is catastrophic — you can't stop clotting or bleeding."
The team's newest study, published in this month's issue of the Journal of Biological Chemistry, focused on lipopolysaccharide, or LPS, a molecule found on the surface of certain bacteria like E. coli. The researchers found that LPS can directly activate proteins in the blood that trigger clotting, which can block blood flow and damage vital organs.
This process, known as the "contact pathway," involves a chain reaction where proteins in the blood work together to form clots. The researchers showed that one specific type of LPS, called O26:B6, is particularly good at setting off this reaction, making it more likely to cause clotting problems.
Sepsis is a dangerous condition where the body's response to an infection spirals out of control, leading to widespread inflammation, organ failure and problems like excessive blood clotting. Gram-negative bacteria, such as E. coli, are common culprits in sepsis because they release LPS when they invade the bloodstream.
"Sepsis can be incredibly challenging to treat," said Joseph Shatzel, M.D., a physician-scientist at OHSU who specializes in clotting and bleeding disorders, along with a host of other hematologic disorders. Shatzel is an associate professor of biomedical engineering in the OHSU School of Medicine and holds an appointment in the OHSU Knight Cancer Institute.
"The systems that control blood clotting and bleeding become dangerously unbalanced. Our group has focused on part of the clotting system, the contact activation system, that traditionally has been ignored," Shatzel said. "My personal work has been to take the innovation from this lab and bring it directly to the patients, or take samples from patients and bring it back to the lab."
Spanning lab research, patient care
The study, conducted in nonhuman primates, found that when bacteria containing LPS entered the bloodstream, it quickly activated the clotting system. This included coagulating proteins like factor XII, which seems to initiate the clotting process, causing a chain reaction.
"People who are born without factor XII are healthy and don't bleed abnormally," Shatzel said. "That makes it a great target for therapies — blocking it might help stop dangerous clots without causing bleeding."
André L. Lira, Ph.D., a postdoctoral scholar and lead author of the study, said his research focuses on how the physical properties of bacterial surfaces trigger the clotting system. Sepsis can arise from bacterial, viral or fungal infections.
"Even when we know the bacteria causing the infection, different strains can behave differently," he said. "By understanding this, we hope to develop precision therapies."
The team is working on experimental treatments targeting factor XII, including antibodies designed to block its activity. This expands on their work developing treatments for the protein factor XI in human clinical trials published in 2023.
"We're optimistic that this approach could prevent dangerous clots in sepsis patients without increasing their risk of bleeding," McCarty said.
These antibodies, created at OHSU, have already been tested in early stage clinical trials and animal models.
"We've seen promising results," Lira said. "The antibodies seem to stop the clotting caused by certain bacterial infections without harming the patient's ability to heal."
Shatzel said the need for new therapies for sepsis is critical. The disease kills millions of people annually, and little progress has been made on treatments.
"The mortality rate of sepsis in the United States can be as high as 50%, and there haven't been major breakthroughs in decades," he said. "We're still treating it with antibiotics, supportive care, maybe steroids to modulate the immune system, but it is not developed like oncology. We don't have targeted therapies that really improve outcomes. This research could be a game-changer."
The researchers credit OHSU's collaborative environment for enabling their work.
"This is one of the rare programs that truly spans the gap between lab research and patient care," Shatzel said. "We're working from test tubes to animal models to clinical trials — it's all happening here."
McCarty highlighted the interdisciplinary nature of the team as a key reason for their innovative work.
"We have basic scientists like André, who think about the physics of how bacteria interact with blood, and clinicians like Joe, who see the real-world challenges in the ICU," he said. "That kind of collaboration is what makes breakthroughs possible."
The team continues with ongoing studies and grant applications to fund further research and clinical trials.
"We're excited about the potential impact this could have," Lira said. "There's a long way to go, but the possibility of helping patients drives us forward."
In addition to Lira, McCarty and Shatzel, coauthors include Berk Taskin, B.S., Cristina Puy Garcia, Ph.D., Jiaqing Pang, M.S., Joseph E. Aslan, Ph.D., FAHA, Christina U. Lorentz, Ph.D., and Erik I. Tucker, Ph.D., with OHSU; Ravi S. Keshari, Ph.D., Robert Silasi, Ph.D., and Florea Lupu, Ph.D. with Oklahoma Medical Research Foundation; Alvin H. Schmaier, M.D., with Case Western Reserve University; and David Gailani, M.D., with Vanderbilt University Medical Center.
In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to this research, Christina U. Lorentz and Erik I. Tucker are employees of Aronora, Inc., and Joseph Shatzel serves as a medical consultant for Aronora, Inc., a company that may have a commercial interest in the results of this research and technology. Review details of OHSU's conflict of interest program to find out more about how we manage these business relationships.
The research was supported by the National Heart, Lung, and Blood Institute awards R01HL144113, R01HL101972, R01HL151367, R01HL157405, and R35HL140025, and the National Institute of Allergy and Infectious Diseases, award R01AI157037, both of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
