By Randolph Fillmore
Since the beginning of the COVID-19 pandemic, one of the most alarming and confounding aspects of the complex SARS-CoV-2 virus has been that people who become seriously ill with COVID-19, including children, are at increased risk for blood clots. The clots can appear in blood vessels both large and small, often with serious (and sometimes fatal) results.
The increased risk of blood clots (also called “thromboembolism”) appears to be related, at least in part, to the high levels of inflammation that the virus causes. The massive inflammatory response to COVID-19 can raise clotting factors in the blood and can cause blockage of blood vessels; when this occurs in arteries (which carry blood that nourishes healthy tissues with critical nutrients and oxygen). Deprived of oxygen, the tissue becomes injured or dies. In pediatric patients, the condition of high inflammation can affect tissues throughout the body — particularly the heart — and is called “multisystem inflammatory syndrome” (MIS-C).
Preventing COVID-19-related Blood Clots
Reducing the risk for blood clots is referred to in medical terms as “thromboprophylaxis,” which means using blood “thinners,” or anticoagulants (anti-clotting medications), to reduce the possibility of blood clots forming. Evidence regarding the safety and efficacy of using anticoagulants for thromboprophylaxis among pediatric patients hospitalized for COVID-19 has been limited—until recently, there have been no clinical trials performed that focused on this issue.
Responding to this critical need, a team of researchers at Johns Hopkins All Children’s Hospital, and their colleagues at medical institutions across the nation, initiated a clinical trial in the early months of the COVID-19 pandemic, focused on the safety and efficacy of using the drug “enoxaparin” to prevent blood clots in hospitalized pediatric patients with COVID-19 and MIS-C.
According to Anthony A. Sochet, M.D., MHSc, of the Pediatric Critical Care Medicine Division at Johns Hopkins All Children’s and the study’s principal investigator, determining the safety of using thromboprophylaxis for children with serious COVID-19 or MIS-C was a critical “endpoint” (or outcome) in the study because the main side effect of anti-clotting medications (based on their mode of action in the blood) is bleeding.
“Physicians routinely use anti-clotting medications for adults who are at risk for blood clots, but there remains little evidence for their safe use in hospitalized children at increased risk for clot development,” Sochet explains. “In children who are ill, just being on a ventilator raises the risk of getting blood clots.”
John Morrison, M.D., Ph.D., also an investigator on the study and a pediatric hospitalist in the Department of Medicine at Johns Hopkins All Children’s, described the study as “born of necessity,” given the lack of data on using thromboprophylaxis with children at risk for blood clots and the seriousness of their inflammation.
After the study completed enrollment from the eight participating children’s hospitals, the first step was to describe just how at risk for blood clot development these children were. To do so, they looked at markers in the blood of normal clot development and breakdown, including a test called a D-dimer.
“The D-dimer levels show fragments of degrading blood clots, often microscopic ones in patients who don’t have overt blood clots,” Sochet explains. “Patients with MIS-C and primary COVID-19 infection have significantly elevated D-dimer levels compared to those with other illnesses that lead to hospitalization.”
Sochet added that, “Adults with the highest risk of developing blood clots have markedly elevated D-dimer levels just like our pediatric patients do.” He went on to say that coming up with the right dose of enoxaparin for children — administered twice daily by injection just under the skin — was an important next step. They found that dose requirements did not differ for children over vs. under age 12, but that patients with MIS-C may require a slightly higher dose to achieve therapeutic drug levels.
The results of Sochet’s multicenter study, titled “Enoxaparin Thromboprophylaxis in Children Hospitalized for COVID-19: A Phase 2 Trial,” were recently published in the journal Pediatrics, the official journal of the American Academy of Pediatrics.
Sochet and colleagues concluded that “enoxaparin as primary thromboprophylaxis among children hospitalized for symptomatic COVID-19-related illness is safe without evidence of clinically relevant bleeding or other serious adverse events.”
The authors added, “Further investigation is warranted to definitively assess clinical efficacy.”
“The beauty of our finding that enoxaparin was safe for children is that this result could be immediately transferrable to the bedside,” Morrison says. “Our findings will improve the care of kids with COVID-19 across the nation.”
He added that since the study’s publication, clinicians are already putting their findings to work with potentially life-saving results.
While multicenter studies are always more challenging than ones performed at a single hospital or academic medical center, this one required the team to clear several extraordinary hurdles. Among those hurdles were conducting the study under pandemic conditions, maintaining close communication and contact among the researchers and clinicians from eight participating institutions, and getting the critical data so quickly.
According to Sochet, a lot of “sweat equity” went into completing the study as quickly as possible, while exercising the great care that goes into documentation and high levels of patient observation and critical care.
Neil Goldenberg, M.D., Ph.D., who served as senior mentor on the team, emphasized, “The unprecedented rapid launch of the trial would not have been achieved without the collaborative team effort of a multidisciplinary team of faculty physician-researchers and professional research staff in the Clinical Coordinating Center and Data Coordinating Center for Pediatric Multicenter Studies at the Johns Hopkins All Children’s Institute for Clinical & Translational Research, as well as their colleagues at the Johns Hopkins All Children’s Pediatric Biorepository.”
“Although there are so many colleagues to thank,” Morrison concludes, “we’re most grateful to the children and their families who participated in the study, who (through their participation) have benefited other children hospitalized with COVID-19 in the U.S. and around the world.”
Generating More Data to Determine Blood Clot Risk
Although the main study has been completed, the researchers are still investigating blood clotting mechanisms and blood clot risks in pediatric patients who become ill with COVID-19. To do so, they are continuing to generate laboratory data from the additional blood samples provided by the same 38 pediatric patients, which they hope will aid in their ongoing efforts to develop thromboembolism risk models that could improve outcomes for hospitalized children who have severe inflammation due to COVID-19 or other illnesses.
According to William Schleif, M.S., M.T., manager of the Johns Hopkins All Children’s Pediatric Biorepository, the blood samples collected for research are being used to find “biomarkers” that can help identify blood clot risks for pediatric patients with elevated levels of inflammation. That means looking at a great variety of biological clues and evidence, such as “peripheral blood mononuclear cells” (PBMCs).
“The study team placed a special emphasis on developing a robust biospecimen collection strategy that supported the isolation of PBMCs at many pediatric hospitals, so that we can fully investigate questions regarding genetic risk and inflammatory contributions from these specialized immune cells in relation to the presence of virus in the blood,” Schleif explains.
As COVID-19 mutates and new variants of the virus emerge, physicians hope new data will allow them to keep pace with the demands of treating ill children in an ever-changing COVID-19 variant landscape, or even get several steps ahead of the virus as it changes.
Children and COVID-19 Vaccines
Morrison, who as a pediatric hospitalist works so closely with young patients with COVID-19, emphasizes the need to vaccinate children against COVID-19, especially since the U.S. Food and Drug Administration (FDA) in October 2021 approved vaccination for children ages 5-12.
In another step, on May 17, 2022, the FDA added that vaccine effectiveness against COVID-19 “wanes after the second dose in all authorized populations.” The FDA subsequently determined that the “known and potential benefits” of a single booster dose at least five months after completion of a primary series of vaccinations “outweighs its known and potential risks” and that “a booster dose can help provide continued protection against COVID-19” for children as well as those in older age groups.