Blood clots are thought to occur in as many as a third of patients hospitalized with COVID-19. In many cases these clots can be deadly, such as pulmonary embolisms—blood clots that travel to the lungs. In fact, in nearly one third of patients with COVID-19, these clots led to death.
An abnormal immune response is thought to be the major driver of severe COVID-19. One protein, called soluble urokinase plasminogen activator receptor, or suPAR, circulates in the blood and originates from immune cells and has been shown to play a major role in complications of COVID-19.
Salim Hayek, M.D., Medical Director of the University of Michigan Frankel Cardiovascular Center Clinics, Shengyuan Luo, M.D., internal medicine resident physician at Rush University Medical Center and a team of researchers from around the world have been studying suPAR and its relationship to critical outcomes in COVID-19 cases.
In a publication by the International Study of Inflammation in COVID-19, a multinational observational study of patients hospitalized for COVID-19, researchers found that higher suPAR levels were associated with increased risk of blood clot formation.
Their new findings, published in the Journal of the American Heart Association, suggest that suPAR levels in hospitalized COVID patients were associated with venous thromboembolism including pulmonary embolism independently from a marker of blood clot formation called D-dimer.
“Traditionally, clinicians utilize D-dimer, a blood clot breakdown product, to assess VTE activity,” Luo said. “However, this marker has proven to be less predictive in COVID-19, as blood clot formation is in large part caused by a uniquely abnormal immune response to the virus.”
The authors therefore conceived that combining suPAR, a marker of the immune system, and D-dimer could improve the reliability of determining who is at high or low risk of blood clot formation among COVID hospitalized patients.
“Even before the pandemic, before COVID-19, we had this idea about suPAR,” Hayek said. “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.”
When researchers discovered the severity of blood clots forming in COVID-19 patients early in the pandemic, they turned to suPAR for more insight. Earlier studies showed that suPAR levels were three to five times higher in COVID-19 patients and often associated with disease complications.
“We had previously shown that patients with high suPAR levels are at much higher risk of death, kidney injury, respiratory failure needing mechanical ventilation and now venous thromboembolism,” said Hayek.
In the study, researchers compiled data from 1,960 adults who were hospitalized for COVID-19 and who had their suPAR levels measured at the time of admission to the hospital. All patients were monitored until they were either discharged, or in some cases, until death.
Important attributes for patients in this study included: age, sex, race, and body mass index. Additional medical conditions assessed upon admission included: diabetes, hypertension, congestive heart failure, stroke and other critical cardiology and inflammatory diseases.
Researchers measured D-dimer and suPAR levels over a 30-day period during patients’ hospitalizations and diagnosed VTE (deep vein thrombosis and pulmonary embolism) using ultrasounds of the lower extremities and scans of the lungs.
Results showed that VTE occurred in 163 patients, and of those, 65 patients developed deep vein thrombosis, 88 patients developed a pulmonary embolus, and 10 patients developed both. Patients who developed blood clots had suPAR levels nearly 50% higher than those who did not develop clots. And, when suPAR levels were combined with D-dimer, researchers could classify 41% of study participants to have low-risk for occurrence of VTE.
“There is a modest positive correlation between suPAR and D-dimer levels; they both tend to trend in the same direction,” explained Hayek.
Now that the association is made between suPAR levels and blood clot formation, clinicians could assess who is at high or low risk, which will help them decide what therapies to use to treat them. For example, someone at high risk could be given medications before blood clot formation.
Studying suPAR and its link to the immune system has positive implications within critical COVID-19 patients, and beyond.
“In the background, there’s been a lot of work showing that this molecule (suPAR) is doing something bad to the body when levels are high,” Hayek said. “Companies are developing drugs to target suPAR, and so we might be measuring this on a regular basis.”
Hayek is optimistic about preventing critical outcomes within COVID-19 and other infectious diseases, and what the Michigan Medicine COVID-19 Cohort and the International Study of Inflammation in COVID-19 have been able to accomplish since the start of the pandemic.
Current studies are underway to test anti-suPAR therapies in patients with COVID-19.
“In the next year or so, we might be able to impact critical care in several other populations with implications that go beyond COVID,” said Hayek.
The present study confirms but also contributes with new knowledge of suPAR as an independent predictor of organ damage, in this case pneumonia with respiratory failure, and length of hospital stay for patients with different severity of COVID-19 in a Swedish setting. suPAR was significantly elevated at inclusion in patients who later developed severe or critical illness with increased oxygen demand and subsequently had a longer stay at the hospital.
The length of hospital stay in this cohort of COVID-19 patients was mainly determined by the need for oxygen supplementation with gradual phasing out and not the need for rehabilitation, since rehabilitation primarily was carried out at another department. Our results are consistent with previous studies (16, 47), but to our knowledge, suPAR has previously not been shown to independently reflect the cohesive length of hospital stay.
Nevertheless, suPAR has previously been shown to correlate with a prolonged stay at hospital due to other serious conditions with excessive inflammation, such as cardiac surgery, pneumonia in children, and burn injuries (48–50). Besides this, the significance of elevated suPAR levels in viral infections such as human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and hantavirus, has been established before the SARS-CoV-2 pandemic. Like its importance in COVID-19, elevated suPAR was demonstrated to significantly correlate with severity and mortality in these conditions (51–55).
The concentration of suPAR in sera correlated with the degree of COVID-19 severity, which has been shown previously (47). In SARS-CoV-2 infected individuals with low admission levels of suPAR (<4 ng/ml), the risk of needing mechanical ventilation and the 14-day mortality was almost non-existent, while levels between 4–6 ng/ml and especially >6 ng/ml were associated with a significantly increased risk. Similar outcomes of stratification of suPAR levels in relation to COVID-19 disease classification were obtained in this study. Interestingly, the cut-off level for severe/critical disease obtained from our study population (5.9 ng/mL) was very close to the manufacturer’s cut-off level for the recommendation of hospitalisation (6 ng/mL).
The study cohort reflects the well described characteristics of hospitalised patients with COVID-19, with a male dominance, middle-aged and older individuals, presence of co-morbidities such as CVD, chronic pulmonary disease, obesity, and diabetes (56–58). Although these conditions are known risk factors for severe COVID-19, somewhat surprisingly, we did not find a significant association of co-morbidities, besides obesity, with disease severity. This is partly explained by the limited number of patients in each group.
Approximately one tenth of the cohort had an immunosuppressive disorder, whereof two patients became critically ill and one with a newly diagnosed haematological malignancy deceased during the hospital stay. These findings are consistent with prior observations indicating a relatively low risk, compared to the general population, of severe COVID-19 due to immunosuppression (59–63).
However, since not all patients with COVID-19 at the hospital were included in this study, definite conclusions cannot be drawn from the proportion of immunosuppressed relative to immunocompetent patients in the cohort. Most of the patients were classified as moderately to severely ill, i.e., needed non-invasive ventilation support mainly in the form of HFNOT.
All of them received dexamethasone to reduce the inflammation in the lungs. Sixty percent of the patients were already prescribed corticosteroids at inclusion, which might have influenced the suPAR levels. In fact, corticosteroids have a suppressive effect on suPAR (21, 64). However, among patients in this study, suPAR levels were higher in corticosteroid treated patients, probably indicating dexamethasone treatment as a surrogate marker of severe disease.
Similarly, suPAR levels were higher in patients who received remdesivir at inclusion, reflecting severe inflammation and lung involvement of COVID-19 in these patients already early in the course of the disease. Remdesivir treatment was, however, not associated with disease severity, but rather with length of hospital stay.
A similar association was in fact made in studies by Anderson et al. (65) and Spinner et al. (66), in which length of hospital stay was shown to be affected by remdesivir treatment and a peak in discharge rates was observed upon completion of the intravenous therapy, suggesting that physicians actually delayed discharge to complete treatment. The small cohort in this study does not allow any definite conclusions to be drawn regarding possible beneficial effects of remdesivir on disease severity.
The main strengths of the study were the prospective design, the well-characterised patient cohort, and that the assessment of clinical variables and review of medical records in all patients was done by one, experienced infectious disease specialist (J.S.). However, some limitations deserve to be mentioned.
The range of symptom duration was wide, explained by the fact that some patients were initially receiving care at another pandemic department at the hospital and were not included until they were transferred to the Department of Infectious Diseases. Many elderly patients were excluded because of acute or chronic cognitive impairment, which resulted in a relatively limited study population. For practical reasons, only Swedish and English-speaking patients were included, which might have ruled out patients known to have an increased risk of developing severe COVID-19 (67, 68).
reference link : https://www.frontiersin.org/articles/10.3389/fmed.2021.791716/full
More information: Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19, Journal of the American Heart Association (2022). DOI: 10.1161/JAHA.122.025198