Elevated levels of soluble urokinase plasminogen activator receptor (suPAR) — a protein produced by the immune system in response to SARS-CoV-2 infection — may predict the formation of clots in patients hospitalized with COVID-19, even those with low levels of D-dimer, new research suggests.
Investigators analyzed data from close to 2000 adults hospitalized for COVID-19 who had their suPAR levels measured at admission. All patients were monitored until discharge or death and their D-dimer and suPAR levels were measured over a 30-day period during the hospitalization.
Patients who developed blood clots had suPAR levels nearly 50% higher than those who did not. Moreover, combining suPAR levels with D-dimer enabled the investigators to classify 41% of study participants as having a low risk for occurrence of venous thromboembolism (VTE).
"Clinicians should be aware that patients with severe disease are at higher risk of clots, regardless as to whether the D-dimer levels on presentation are low," Salim Hayek, MD, medical director, University of Michigan Frankel Cardiovascular Center Clinics, Ann Arbor, told theheart.org | Medscape Cardiology.
"SuPAR is not currently available for measurement in a clinic setting but will be soon and can help identify the patients at risk for COVID-19-related complications," said Hayek, who is also assistant professor of internal medicine and assistant professor of cardiovascular medicine, University of Michigan.
The study was published online August 4 in the Journal of the American Heart Association.
VTE is a "highly prevalent COVID-19 complication, estimated to occur in as many as 26% of patients hospitalized for the disease," the authors write.
Moreover, pulmonary embolism (PE) "remained prevalent, despite certain immunomodulators effective at stalling the progression of respiratory illness," and was the "direct cause of death" in almost one-third of patients with COVID-19, despite anticoagulant prophylaxis.
The "excessive thromboembolic risk" is attributable to immunothrombosis — "a condition where viral infection induces immune dysregulation and significant vascular inflammation, ultimately resulting in microangiopathy and macroangiopathy," they explain.
D-dimer, the most commonly used biomarker for VTE, has been shown to be less reliable in COVID-19, but combining it with markers of immune dysregulation might refine risk stratification in patients with COVID-19, the authors note.
The urokinase plasminogen activator (uPA)/urokinase plasminogen activator receptor (uPAR) system is a "key regulator" in cross-reactions between vascular inflammation, immunity, and coagulopathy, they write.
In fact, previous research has shown suPAR levels to be three- to fivefold higher in patients with COVID-19 and strongly associated with COVID-19-related complications. Thus, suPAR may be an "ideal biomarker to quantify hyperinflammation in COVID-19."
To investigate whether suPAR levels were associated with VTE risk in COVID-19, independent of D-dimer, and to see whether a role might exist for suPAR in the stratification of VTE risk in COVID-19 patients, the researchers turned to the International Study of Inflammation in COVID-19 (ISIC), a multinational observational study assessing the role of various inflammatory biomarkers in COVID-19-related adverse outcomes.
Patients (n = 1960; mean age, 58 ± 17 years; 57% male; 20% Black) hospitalized specifically with COVID-19 who had a blood sample collected within 48 hours of hospitalization, were included in the study,
Baseline variables collected included age, race, body mass index (BMI), anticoagulation therapy before hospital admission, comorbidities, and laboratory values (particularly creatinine, D-dimer, and suPAR).
The researchers applied logistic regression and Fine-Gray modeling that accounted for the competing risk for death.
Strongest Risk Factor
The median plasma D-dimer was 1.0 mg/L (interquartile range [IQR], 0.6 - 2.6), whereas the median plasma suPAR was 6.7 ng/mL (IQR, 4.5 - 10.1).
VTE occurred in 163 patients (8.7%), 65 of whom experienced incident deep venous thrombosis (DVT), 88 of whom experienced PE, and 10 of whom experienced both.
Patients who developed VTE were more likely than those who did not to be male (75% vs 55%) and more likely to be Black (30% vs 20%).
They also had higher median D-dimer and higher median suPAR than those without VTE (2.1 vs 1.0 mg/mL and 9.7 vs 6.5 ng/mL, respectively).
After controlling for age, sex, Black race, BMI, comorbidities, and estimated glomerular filtration rate (EGFR), with each doubling of plasma suPAR, the D-dimer level was found to be 7.34 times higher (β = 7.34; 95% CI, 1.49 - 13.2; P = .002).
After adjustment for baseline age, sex, Black race, BMI, anticoagulation therapy, comorbidities, and kidney function, the third tertile of suPAR was associated with a 168% higher odds of VTE (adjusted odds ratio [aOR], 2.68; 95% CI, 1.51 - 4.75; P < .001), compared with the first tertile of suPAR. However, this association was "mildly attenuated" after additional adjustment for D-dimer level (aOR, 1.98; 95% CI, 1.08 - 3.66; P = .028).
Of the incident VTE events that took place during 30 days of hospitalization, the cumulative incidence of VTE was 3.5%, 6.0%, and 12.6% for the first, second, and third tertiles of suPAR, respectively (log-rank P < .001)
In survival analyses, and after adjustment for covariates (including D-dimer), the risk for VTE within 30 days was 3% lower (adjusted hazard ratio [aHR], 0.97; 95% CI, 0.48 - 1.58; P = .15) and 52% higher (aHR, 1.52; 95% CI, 0.86 - 2.68; P = .32) for the second and third tertiles of suPAR, respectively, when compared with the first tertile.
These findings remained consistent when stratified by D-dimer levels and in a survival analysis that accounted for death as a competing risk.
Moreover, on the basis of predicted probabilities from random forest, a decision tree identified a subgroup of patients with a combined D-dimer of less than 1 mg/L and suPAR of less than 11 ng/mL who had a 3.6% probability of incident VTE during a COVID-19 hospitalization. This particular subgroup at low risk for VTE represented 41% of the entire study population.
"No other suPAR and D-dimer cutoff combinations yielded a <5% probability of the outcome," the authors state.
"Even before the pandemic, before COVID-19, we had this idea about suPAR," Hayek said in press release. "We were seeing levels of the suPAR marker as the strongest risk factor for bad outcomes in other viral infections and in heart and kidney disease."
"Companies are developing drugs to target suPAR, and so we might be measuring this on a regular basis," he added.
Commenting for theheart.org | Medscape Cardiology, Geoffrey Barnes, MD, MSc, assistant professor of internal, vascular, and cardiovascular medicine, Frankel Cardiovascular Center, University of Michigan, noted that randomized trials have defined the potential impact of treatment-dose anticoagulation for thromboprophylaxis in patients hospitalized with COVID-19.
However, many clinicians and expert groups "have been reticent to apply this treatment to all patients hospitalized with COVID-19 given the risk of bleeding associated with treatment-dose anticoagulation," said Barnes, who was not involved with the study.
These findings suggest that the combination of suPAR and D-dimer levels, measured at hospital admission, "might be useful in determining which patients are at sufficiently low risk of VTE that they can receive standard thromboprophylaxis instead of treatment-dose thromboprophylaxis," he said.
Further "mechanistic studies linking suPAR with VTE in COVID-19 and prospective trials evaluating this risk-stratification approach are needed before this becomes routinely applied in clinical practice," he added.
Additionally, "how suPAR and D-dimer predict VTE in the more recent waves of COVID-19 also warrant evaluation, as the risk of VTE seems to be shifting with each COVID-19 variant."
The study was funded by grants to individual investigators from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Frankel Cardiovascular Center, the Hellenic Institute for the Study of Sepsis, Charité – Universitätsmedizin Berlin, and the Berlin Institute of Health. Hayek and coauthor Jochen Reiser are members of the scientific advisory board of Walden Biosciences. The other authors' disclosures are listed in the publication. Barnes, a colleague of Hayek at the University of Michigan but not involved with this study, has done consulting work for Pfizer, Bristol-Myers Squib, and Janssen, each of which are involved in anticoagulant sales.
J Am Heart Assoc. Published online August 4, 2022. Full text
Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
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