A nanoparticle therapy developed by researchers at University Hospitals (UH) and Case Western Reserve University targets overactive neutrophils, a specific type of white blood cell, to prevent almost all types of blood clots without increase the risk of bleeding. The preclinical results, published in Science Translational Medicinecould help find safer ways to treat patients with blood clots. According to the Centers for Disease Control and Prevention (CDC), approximately 900,000 people in the United States suffer life-threatening blood clots each year.
“What we are showing for the first time is that neutrophils are the primary drivers of arterial and venous thrombosis. And when you target a neutrophil, you don’t increase the risk of bleeding, you just decrease the risk of clotting,” said Lalitha Nayak, MD, lead study author, hematologist/oncologist at the Seidman Cancer Center in UH, a member of the Developmental Therapeutics Program at the Case Comprehensive Cancer Center, and an associate professor at the Case Western Reserve School of Medicine.
Historically, arterial and venous thrombosis have been considered distinct molecular events requiring separate treatment paradigms. Arterial thrombosis (a clot in an artery), which can cause a heart attack or stroke, is usually treated with antiplatelet drugs such as aspirin, while blood thinners are used to treat venous thrombosis (a clot in an vein), which can cause 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 exploited as new therapeutic targets.
In the new study, Nayak and his colleagues use animal models to show that hyperactive neutrophils participate in both arterial and venous thrombosis by increasing their ability 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 order to stop the process, the researchers identified a group of receptors unique to activated neutrophils and developed antibody-coated nanoparticles that specifically target these groups.
“Because neutrophils play an important role in innate immune function, if we target all neutrophils, we will increase our risk of infections. But here we are starting to say that we can identify activated neutrophils and only prevent them from participating in the clot,” Nayak said.
Other therapeutic mechanisms for targeting activated neutrophils could revolve around Krüppel-like factor 2 (KLF2), a transcription factor that researchers have identified as central in neutrophil activation.
“Interestingly, we change a single transcription factor in the neutrophil and it does all of this,” Nayak said. “Can we consider therapies that simply increase KLF2 to keep neutrophils quiescent? We have so many avenues for therapy here. »
Nayak points out that while this research is likely to have an impact on the field of thrombosis in general, these findings may have particular impact for patients with pancreatic cancer or other cancers for which blood clots are a complication. current. According to the CDC, blood clots are the leading cause of death in people with cancer, after the cancer itself.
“About 40% of pancreatic cancer patients can develop a clot before they die,” she said. “The next steps in our research are to use a mouse model of cancer-associated thrombosis to see if we could use nanoparticles as a targeted therapy in this case. »
Cleveland University Hospitals Medical Center
Nayak, L., et al. Targetable pathway in neutrophils attenuates arterial and venous thrombosis. Science Translational Medicine (2022). DOI:10.1126/scitranslmed.abj7465