Electrically stimulating the vagus nerve — the main set of nerve fibers that control involuntary bodily functions — significantly reduced blood loss and sped up clot formation after injury in a mouse model of hemophilia A, according to a recent study.

Controlling bleeding by stimulating the vagus nerve was just as effective as factor VIII (FVIII) replacement therapy, the current gold standard treatment for treating hemophilia.

“From the delivery room to the operating room and the military battlefield, bleeding is too often fatal and we do not have one universal therapy or technology to help reduce it, or even better, prevent it from occurring,” Jared Huston, MD,  an assistant professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes of Medicine, and the study’s senior author, said in a press release. “This research is an important step toward discovering improvements in patient care, not only for those living with hemophilia, but also for any patient or individual facing a high-bleeding risk scenario.”

Huston is also an associate professor of surgery and science education at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

The study, “Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice,” was published in Nature Communications.

Patients with hemophilia have excessive, uncontrolled bleeding that stems from a lack of certain proteins needed for clotting. In hemophilia A, where the FVIII protein is absent, patients are usually treated with replacement therapy to supply the body with a lab-made version of FVIII.

Some patients will develop inhibitors, a type of neutralizing antibody against the proteins, that can render treatment less effective.

The vagus nerve, which runs through the neck, acts as a means of communication between the brain and the body. By interacting with all the major organs, it controls essential involuntary bodily functions, such as heart rate, breathing, and immune function. Not much was known about its role in blood clotting before this study, however.

“The vagus nerve is the main communication line between the brain and the body’s organs, but no one before suspected it can control blood clotting,”  said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes.

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An illustration of a lab scientist.

Stimulating the vagus nerve to control bleeding

The researchers found that five minutes of vagus nerve stimulation before a tail injury led to up to 75% less blood loss, which was comparable to the 64% reduction seen with preventive FVIII replacement therapy. The time it took for a clot to form in the hemophilia A mice was also significantly shorter after stimulating the vagus nerve, reaching rates similar to healthy mice.

Vagus nerve stimulation wasn’t able to control bleeding in mice whose spleens had been removed, however. The spleen stores about a third of the body’s platelets, the cell fragments involved in blood clotting.

Controlling bleeding by stimulating the vagus nerve was found to be dependent on a population of immune T-cells in the spleen that increase the levels of acetylcholine, a nerve signaling chemical. The process requires acetylcholine to bind to a family of proteins called alpha-7 nicotinic acetylcholine receptors (alpha-7 nAChRs) on the surface of platelets. In turn, the receptors increased calcium levels inside platelets, priming their activation and promoting blood clotting in an area where there’s been an injury.

The researchers said it’s still not clear “how long circulating platelets remain in a primed state after vagus nerve stimulation or if repeated stimulation is required to maintain enhanced platelet function.”

Stimulating the vagus nerve appeared to only promote local clot formation around an injury and didn’t induce systemic blood clotting that could affect blood flow throughout the body or cause tissue damage.

Vagus nerve stimulation has been in use for depression and epilepsy for decades. Implantable pulse generator devices have been deemed safe and well tolerated by regulatory agencies. Other noninvasive approaches are also under development. Researchers believe such devices could be effective alternatives to medications that may be costly or have unwanted side effects.

“Because hemophilia A affects hundreds of thousands of individuals and causes significant morbidity and mortality, it will be interesting to further study the role of vagus nerve signaling for this and other bleeding disorders,” the researchers wrote.

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