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Trauma surgeon Dr. Peggy Knudson of the CLOTT Study Group.

What do trauma patients have in common with people who are COVID-positive? It turns out that the incidence of blood clots in the lungs and deep vein thrombosis (DVT) is very high in both these patient populations.

“COVID is an inflammatory process,” explained Peggy Knudson, MD, FACS, leader of the CLOTT (Consortium of Leaders in the Study of Traumatic Thromboembolism) study group, a cross-country network of investigators that has been studying clots for more than a decade. “A lot of people have heart disease or renal failure after contracting COVID-19; and these conditions are associated with clots in the vascular system. It’s very similar to what we see in severely injured trauma patients.” Dr. Knudson is Professor of Surgery at the University of California San Francisco, a trauma surgeon at the San Francisco General Trauma Center and the Medical Director of the Military Health System Strategic Partnership with the American College of Surgeons (MHSSPACS).

Last year, just as the CLOTT group was beginning to explore the similarities between their trauma patients and their COVID patients, they were approached by the National Institutes of Health Accelerating COVID-Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership developing a coordinated research strategy for prioritizing and speeding development of treatments and vaccines. ACTIV works with multiple agencies, private companies and non-profit organizations to support Operation Warp Speed. Because of the success of the CLOTT network, Dr. Knudson and two of her colleagues were invited to join the steering committees for the three COVID-19 ACTIV-4 studies.

Lucy Kornblith, MD, Assistant Professor of Trauma and Surgical Critical Care at San Francisco General Hospital, participates on the steering committee for the first of the ACTIV studies to get underway (ACTIV-4a). Their work has already demonstrated that there is no apparent benefit in using full-dose anticoagulating medications in ICU patients with COVID-19 when compared to prophylactic doses, and they are now moving on to look at the role of anti-platelet agents in these patients. The speed with which that trial advanced from design to implementation (less than two months) and is already adapting to new data is truly remarkable and represents a new paradigm for the NIH.

Scott Brakenridge, MD, FACE, MSCS—another surgeon scientist, member of CLOTT, and Associate Professor of Surgery at the University of Florida, Gainesville—participated in the out-patient study panel (ACTIV-4c) investigating the role of anticoagulants in COVID-19 patients who do not require hospitalization. Dr. Knudson is on the steering committee for this study, which enrolled its first patient this month. The investigation is focused on the use of prophylactic anticoagulants in patients who are discharged from the hospital after treatment for COVID-19.

In the meantime, Dr. Knudson is also pouring through the CLOTT database of more than 8,000 patients prospectively enrolled at the 17 CLOTT centers and attempting to determine whether clots seen in the pulmonary arterial system are embolic (i.e., related to DVT) or inflammatory after injury, just like those in COVID-19 patients.

The Commitment of a Lifetime, Now Promising Pandemic Relief
When Knudson was a young surgeon, pulmonary embolism was the number three reason that people died after injury—just behind bleeding and brain injuries—and there were no guidelines directing physicians to an effective prophylaxis. “Three weeks after saving a trauma patient, I witnessed him get out of bed for the first time and drop dead in front of me from a pulmonary embolism,” she recalled. “I was shocked and wondered if I should have treated him differently. I went to the literature to search for how pulmonary embolism after injury could be prevented, but couldn’t find anything.” That incident led her to a lifetime interest in research related to the prevention of VTE (pulmonary embolism and venous thrombosis) in trauma patients.

Volunteering at the U.S. Military Hospital in Landstuhl, Germany, during the Afghanistan and Iraq conflicts, Dr. Knudson frequently saw clots in the lungs of injured soldiers on CT scans, but she and her colleagues didn’t know if the clots originated in the legs and pelvis and traveled to the lungs, or if they actually formed in the lungs directly. The military surgeons also wondered whether all clots seen on CT scans needed to be treated, especially in patients where the use of blood-thinners was risky, given their associated injuries and their need for prolonged transport back to the United States.

Her experience at the military hospital added to what she was seeing in civilian patients; and when she returned from that assignment, Dr. Knudson worked with the National Trauma Institute (now the Coalition for National Trauma Research (CNTR)) to secure Department of Defense funding for a study to determine the etiology of clots.

The study was conducted by the CLOTT study group—which by that time had already been active for more than 10 years. “We had been focused on preventing clots from forming in the extremities by using things like compression hose and anticoagulants, but we still saw a lot of clot despite those efforts,” she said. “So, the novel hypothesis was that at least some of these clots are formed as the result of inflammation and local trauma; they’re not all coming from abdominal veins and lower extremities.”

The CNTR-managed study is observational but contains detailed information on each patient including their trauma-related and pre-existing risk factors for VTE, the prophylactic measures utilized, and imaging procedures including duplex ultrasound exams and CT scans of the chest. This database is the largest in the world that focuses specifically on VTE after injury.

A Better Paradigm for Research Revealed
For her part, Dr. Knudson believes and hopes the ACTIV/Operation Warp Speed model and what it’s been able to achieve in such a short time will change research on the national level completely. “Clearly, research that quickly advances science takes much more resources and a more strategic and coordinated approach than has been historically committed.”

She also believes the experience showcases how you can leverage federally funded research. Original work funded by the Department of Defense has now become integral to the NIH; and the inclusion of these trauma investigators in ACTIV and Operation Warp Speed will help to propel medical advancements to mitigate the mortality and morbidity related to COVID-19. As Dr. Knudson put it, “We call it pivoting.”

Dr. Eileen Bulger, Chair of the Board of CNTR, noted, “The lifelong work of Dr. Knudson to advance our knowledge about the management of VTE events after injury, and now COVID, is a testament not only to her personal dedication, but to the value of supporting clinician-scientists who identify a problem that impacts their patients and can convene a team to investigate a solution.”

Traumatic injury remains the leading cause of death under the age of 44 years in the U.S., making it the most important problem facing our children. And yet the level of federal support for research in this area has lagged well behind many less common diseases. The mission of CNTR is to advocate for federal funding commensurate with the burden of injury in our society, coordinate research efforts among professional societies across the continuum of injury care, and strengthen the infrastructure to support multicenter clinical investigations, such as the work of the CLOTT network, to advance the care of our patients.