Targeting inflammation could be important to reducing morbidity and mortality in venous thromboembolism, a serious diagnosis that up to 900,000 Americans will receive annually, according to a Michigan Medicine team.

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Thomas Wakefield, M.D., and Sumi Sood, M.D., recently tested a selectin inhibitor in normal volunteers and then treated calf vein thrombosis (deep vein thrombosis found below the knee) with the selectin inhibitor strategy to target inflammation. It's a global first, and the next step in their longtime National Institutes of Health-funded research.

"This has been a 25-year odyssey from the basic concept to the first-in-human clinical usage of the drug, and it worked well in the first patients," says Wakefield, head of vascular surgery and a director of Michigan Medicine's Frankel Cardiovascular Center.

Patients with DVT, or blood clots in the veins, are at risk of pulmonary embolism, in which a piece of the clot breaks loose and travels to the lungs, as well as recurrent DVT, extension of their DVT, and pain and swelling in the leg after DVT, the so-called post-thrombotic syndrome. They are typically put on blood thinners, but blood thinners also come with a bleeding risk.

"Our goal was to stop clotting without increasing the bleeding complications," says Sood, a Michigan Medicine hematologist and assistant professor in internal medicine and surgery.

Wakefield says the interplay between inflammation and thrombosis is significant.

"We now know it's a vicious cycle: The clots in the veins lead to inflammation, which leads to more clotting and then vein wall changes," he says.

The 25-year odyssey

Wakefield and his team started studying different formulations of P-selectin inhibitors in the early 1990s, finding they worked well to inhibit thrombosis in rodent and primate models.

In 2008, Wakefield and Denisa Wagner, M.D., of Harvard University, shared a five-year, $3.7 million grant from the NIH to partner with biopharmaceutical company Archemix to work toward clinical application of VTE treatment, starting with basic laboratory studies to understand the biology of the condition and identify which drugs had potential.

"We found P-selectin inhibitors are a way to inhibit the clotting and the inflammation that occurs in the vein," Wakefield says.

And in 2014, Wakefield and Sood received NIH funding through the National Heart, Lung, and Blood Institute's VITA program to treat clinical DVT for the first time with this anti-inflammatory approach. VITA, short for vascular interventions/innovations and therapeutic advances, helps accelerate promising therapies for underserved medical needs.

"We found an E-selectin inhibitor that was ready for trial and confirmed it worked as well as the P-selectin inhibitors," Wakefield says.

Calf vein DVT

Wakefield and Sood's team selected subjects with calf vein DVT, based on the current clinical approach.

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"Not all physicians feel all patients with calf vein DVT should be treated with anticoagulants, as the incidence of post-thrombotic syndrome is less when below the knee," Wakefield says.

Sood says calf vein DVT was also a good choice because more than half of DVTs involve the calf to some degree.

"It was a safer population to study than those with clots from the knee up, but a good population for studying venous thrombosis," Sood says. "Patients develop pain and swelling in their leg and are at risk of developing post-thrombotic syndrome."

Continuing the process

The patients treated so far have had positive results. Researchers hope the next step will be a multicenter trial with a combination of the selectin inhibitor strategy and standard therapy or this drug alone.

"Our contract has now ended with this proof of concept and initial foray into understanding how these drugs could work," Wakefield says. The next contract, VITA 2, will last until 2018 and is co-headed by Daniel D. Myers, DVM, MPH, and Wakefield. "Being able to reduce bleeding events could eventually be important to all sorts of clinical situations where you need an anticoagulant."

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosure: Wakefield: Decision Resources Group