“What we are showing for the first time is that neutrophils are key drivers of both arterial and venous thrombosis. And when you target a neutrophil, you do not increase bleeding risk, you only decrease clotting risk,” said Lalitha Nayak, MD, study lead author, hematologist/oncologist at UH Seidman Cancer Center, member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center, and associate professor at Case Western Reserve School of Medicine.
Historically, arterial and venous thrombosis have been thought of as distinct molecular events that require separate treatment paradigms. Arterial thrombosis (an artery clot), which can cause heart attack or stroke, is commonly treated with antiplatelet agents like aspirin, while anticoagulants are used to treat venous thrombosis (a vein clot), a cause of pain or swelling in the legs or clots in the lungs.
More recently, however, experts have begun to suspect commonalities between the two events that could be leveraged as novel therapeutic targets.
In the new study, Nayak and colleagues use animal models to show that overactive neutrophils participate in both arterial and venous thrombosis through an increased capacity to migrate and adhere to sites of injury. They also show that overactive neutrophils increase the production of key factors used as building blocks for clots.
In seeking to halt the process, the researchers identified a cluster of receptors unique to activated neutrophils and developed antibody-coated nanoparticles that specifically target those clusters.
“Because neutrophils have an important role in innate immune function, if we target all neutrophils, we will increase our risk for infections. But here, we are beginning to say that we can identify activated neutrophils and only prevent them from participating in the clot,” said Nayak.
Other therapeutic mechanisms for targeting activated neutrophils may hinge on Krüppel-like factor 2 (KLF2), a transcription factor that the researchers identified as central to neutrophil activation.
“It was interesting that we change one transcription factor in the neutrophil, and it does all of this,” Nayak said. “Can we look at therapies that just increase KLF2 to keep neutrophils quiescent? We have so many avenues for therapy here.”
Nayak emphasizes that while this research is likely to impact the field of thrombosis at large, these findings may be especially impactful for patients with pancreatic cancer or other cancers for which blood clots are a common complication. Blood clots are a leading cause of death in people with cancer after the cancer itself, according to the CDC.
“About 40% of all pancreatic cancer patients can develop a clot before they die,” she said. “The next steps in our research involve using a mouse model of cancer-associated thrombosis to see whether we could use nanoparticles as targeted therapy in this case.”
Nayak, L., et al. A targetable pathway in neutrophils mitigates both arterial and venous thrombosis. Science Translational Medicine (2022). DOI:10.1126/scitranslmed.abj7465
To see a full copy of the study, copy & paste this link into a browser: https://www.science.org/doi/10.1126/scitranslmed.abj7465
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including five joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Northeast Ohio Medical University, Oxford University and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children’s Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women’s Hospital, Ohio’s only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.
About University Hospitals Seidman Cancer Center / Cleveland, Ohio
UH Seidman Cancer Center is the only freestanding cancer hospital in Northeast Ohio, where all clinicians and staff are dedicated to the prevention, diagnosis and treatment of cancer while researching new and innovative treatment options through clinical trials. Nationally ranked cancer care is also available to patients through the 11-county region at 16 community-based locations. Our UH Seidman specialists make up 14 cancer-specific teams focused on determining integrated care plans tailored to patient’s needs. UH Seidman Cancer Center is part of the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center at Case Western Reserve University, one of 53 comprehensive cancer centers in the country. Patients have access to advanced treatment options, ranging from a pioneering stem cell transplant program founded more than 40 years ago and a wide range of immunotherapy to the first and only proton therapy center in northern Ohio for adults and children. Go to UHhospitals.org/Seidman for more information.
About Case Western Reserve University
Case Western Reserve University is one of the country’s leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,800 undergraduate and 6,300 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.