SFLT‐1 levels in COVID‐19 patients: Association with outcome and thrombosis
Authors: Aurelio Negro, Angelo Fama, Domenico Penna, Lucia Belloni, Alessandro Zerbini, Pasquale Gianluca Giuri
Journal: American Journal of Hematology (2020)

We read with great interest the recent paper by Giardini et al. (2020) regarding endothelial dysfunction in coronavirus disease 2019 (Covid-19) patients and appreciate that the authors recognize similarities with the pre-eclampsia syndrome model.1 The article addresses a very timely and important topic with a high impact on clinical practice and management of the patients. Covid-19 is not only a worldwide emergency but also an insidious disease. The virus accesses host cells via the angiotensin-converting enzyme 2, which is very abundant in the alveolar epithelial cells and other cell types, including endothelial cells. The clinical spectrum ranges from asymptomatic to critically ill cases, characterized by pneumonia, which can worsen rapidly to respiratory failure and acute respiratory distress syndrome.2 The mortality rate is high, and over 50% of severe cases die due to complications. In this context, early identification of high-risk patients could facilitate appropriate supportive care and reduce the mortality rate. Therefore, it is crucial to identify reliable biomarkers associated with shortened survival. A growing number of data shows that Covid-19 mortality is partially due to a severe form of coagulopathy. Furthermore, the most common comorbidities with a significant impact on survival are hypertension, diabetes, and obesity, all conditions characterized by chronic endothelial dysfunction.3 Varga et al. recently demonstrated histologically diffuse endothelial inflammation in various organs due to direct viral infection.4 Therefore, it is essential to study better the role of angiogenic and anti-angiogenic factors in the onset of endothelial dysfunction. As pointed out in the article, pre-eclampsia syndrome is a well-known model of angiotensin II-mediated endothelial dysfunction. For this reason, we recently conducted a single-center study focused directly on the vascular damage impact on survival with a similar approach to Giardini's group; however, our primary goal was to assess factors associated with survival in patients with moderate/severe Covid-19. The study was approved by the institutional review board and conducted according to the Declaration of Helsinki principles. All patients provided written, informed consent, and data were collected and analyzed by the investigators. The study population included 105 inpatients with Covid-19 diagnosis, confirmed by RT-PCR SARS-CoV-2 assay on nasopharyngeal and oropharyngeal swabs, and followed to death or until recovery. The variables evaluated included standard clinical and laboratory variables, placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and interleukin-6 (IL-6). The blood samples were collected 5 to 8 days from admission to the hospital. The Cobas Roche platform was used to determine IL-6, PlGF, and sFlt-1 levels. Significant differences among groups in the distribution of continuous or nominal variables were determined with standard statistical methods. A significant P value was <.05. Univariate analysis (Table 1) showed significant differences in distribution of eight variables between the survivors and the deceased: age (P = .001), white blood cell count (P = .005), and the levels of N-terminal prohormone of brain natriuretic peptide (P = .039), albumin (P = .003), ferritin (P = .043), lactate dehydrogenase (P = .020), procalcitonin (P = .033), and sFLT-1 (P = .001). Notably, neither PlGF nor sFlt-1/PlGF ratio were significantly different between the two groups of the patients. In multivariable analysis only three risk factors retained significance: age (P = .018), white blood cell count (P = .022), and sFlt-1 levels (P = .003). The best threshold for each variable was determined with logistic regression: sFlt-1 > 165 pg/mL; Age > 65 years; WBC > 10 000 cells/μL. The predictive accuracy of the three new binomial categories combined was evaluated with the ROC curve: AUC 0.87. To better understand the endothelial damage role, we decided to rerun the analysis using only sFLT-1 > 165 pg/mL category: AUC = 0.75, OR = 11.61 (3.74-39.67). The same threshold was used to analyze the rate of major thrombotic events (deep vein thrombosis, pulmonary embolism, stroke) during hospitalization in the study population (data not shown). The results (TableS1-S3) showed that elevated sFlt-1 levels are significantly associated with thrombosis (P = .020), especially in the subgroup not treated with anticoagulant therapy (P = .023). Whereas data from Giardini et al. propose sFlt-1/PlGF ratio as a tool to stratify the severity of angiotensin II-mediated endothelial dysfunction and discern the patients with Covid-19 associated pneumonia from patients with non-Covid-19 pneumonia, the utility of the sFlt-1/PlGF ratio for stratification of endothelial dysfunction among Covid-19 patients only and outcome prediction is unclear. Our study, on a larger population, confirms the presence of endothelial damage in Covid-19 and furthers these results by showing that sFlt-1 is a more reliable biomarker than the sFlt-1/PlGF ratio to predict survival and thrombotic accidents in Covid-19 patients. Increased sFlt-1 levels are associated not only with pre-eclampsia, but also with other conditions characterized by severe endothelial dysfunction like sepsis, and acute pancreatitis.5, 6 The same severe endothelial dysfunction is likely present in Covid-19 patients with a significant impact on survival. Furthermore, the vascular dysfunction role most likely overarches the impact of inflammation on survival in Covid-19, as testified by the not significant association of poor outcome with IL-6 levels on multivariate analysis. The clinical implication is that up-regulated sFlt-1 levels may represent a useful marker for predicting and assessing Covid-19 progression to death. Moreover, the higher rate of thrombosis in the population with elevated sFlt-1 levels and not treated with anticoagulant therapy underscores the importance of starting anticoagulant therapy in this group of patients. In conclusion, sFlt-1 could be a reliable tool to monitor endothelial dysfunction in Covid-19 patients: increased biomarker levels could induce the clinicians to attempt a more aggressive treatment therapy or change the management of the patient to increase the chances of survival. The authors declare no conflict of interest. A.N. conceived the project. A.F. wrote the first draft of the paper. A.N. and A.F. supplied clinical material and collected samples. D.P. performed the statistical analysis. L.B. and A.Z. performed lab tests. P.G.G. supervised results. A.N. and D.P. finalized the manuscript. All authors approved the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1 Thrombotic accidents and anticoagulant therapy in the study population. Table S2. Thrombotic accidents in the population treated with anticoagulant therapy. Table S3. Thrombotic accidents in the population not treated with anticoagulant therapy. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.