Increased serum transferrin receptor 1 (sTFR1) levels are associated with severity of acute ischemic stroke and pneumonia in COVID-19 patients, suggesting TFR1 as a potential role player in both COVID-19 pneumonia and arterial thrombosis associated with COVID-19 infection.
Key Findings
Results
COVID-19 patients with and without AIS showed significantly increased serum sTFR1 levels compared to AIS patients without COVID-19.
Three groups were compared: 29 COVID-19+ pneumonia patients with AIS due to MCA occlusion, 25 COVID-19+ pneumonia patients without AIS, and 26 AIS patients without COVID-19 infection.
Serum sTFR1 levels were elevated in both COVID-19 groups regardless of AIS status.
sTFR1 levels were measured by ELISA.
This finding suggests sTFR1 elevation is related to COVID-19 infection itself rather than solely to stroke.
Results
COVID-19 patients with AIS showed significantly decreased serum DPP4 levels compared to other groups.
Dipeptidylpeptidase-4 (DPP4) was measured as a ferroptosis marker by ELISA.
Decreased DPP4 levels were specific to the COVID-19 + AIS group.
DPP4 levels showed a negative correlation with D-dimer and/or C-reactive protein (CRP) in COVID-19 patients with AIS.
This pattern distinguished COVID-19-associated AIS from AIS without COVID-19.
Results
Serum GPX4 levels were comparable among all three groups.
Glutathione peroxidase 4 (GPX4) was measured by ELISA as a ferroptosis marker.
No significant differences in GPX4 levels were detected across COVID-19+AIS, COVID-19 without AIS, and AIS without COVID-19 groups.
GPX4 did not correlate with clinical or prognostic features of pneumonia or AIS.
Results
In COVID-19 patients with AIS, sTFR1 levels showed a positive correlation with D-dimer and/or CRP levels.
sTFR1 demonstrated positive correlation with inflammatory and coagulation markers D-dimer and/or CRP.
DPP4 showed the opposite pattern, with negative correlation with D-dimer and/or CRP in the same group.
These correlations were observed specifically in the COVID-19 + AIS patient group.
Neither ferroptosis marker correlated with clinical or prognostic features of pneumonia or AIS severity scales directly in correlation analyses.
Results
COVID-19 patients with sTFR1 levels ≥131 pg/ml were more likely to exhibit severe pneumonia, increased clinical severity of AIS, and elevated D-dimer/CRP levels.
A threshold of ≥131 pg/ml was identified for sTFR1 as a discriminating value.
AIS severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).
Patients above this threshold showed associations with severe pneumonia, higher NIHSS/mRS scores, and elevated D-dimer/CRP.
This suggests potential biomarker utility of sTFR1 for risk stratification in COVID-19 patients.
Discussion
The study suggests that AIS associated with COVID-19 has a different pathogenesis compared to AIS without COVID-19.
The distinct ferroptosis marker profile (elevated sTFR1, decreased DPP4) in COVID-19+AIS patients compared to non-COVID-19 AIS patients supports a different underlying mechanism.
Authors propose TFR1 as a potential role player in both COVID-19 pneumonia and arterial thrombosis associated with COVID-19.
The biomarker utility of sTFR1 in these disorders was recommended for further evaluation.
Ferroptosis involvement is implicated based on the pattern of marker changes observed.
What This Means
This research examined whether markers of a cell death process called ferroptosis could be detected in the blood of COVID-19 patients who suffered strokes, and whether these markers were linked to how severe their condition was. The researchers measured three ferroptosis-related proteins — GPX4, DPP4, and soluble transferrin receptor 1 (sTFR1) — in three groups: COVID-19 pneumonia patients who had a stroke, COVID-19 pneumonia patients who did not have a stroke, and stroke patients without COVID-19. They found that sTFR1 levels were elevated in COVID-19 patients regardless of whether they had a stroke, while DPP4 levels were specifically reduced only in COVID-19 patients who also had a stroke. GPX4 levels did not differ meaningfully between the groups.
A key practical finding was that COVID-19 patients with sTFR1 blood levels at or above 131 pg/ml were more likely to have severe pneumonia, more severe strokes (based on standard clinical scales), and higher levels of inflammation and clotting markers (CRP and D-dimer). This suggests that measuring sTFR1 in the blood might help identify COVID-19 patients who are at greater risk for worse outcomes from both pneumonia and stroke.
This research suggests that strokes occurring in the context of COVID-19 may have a distinct biological mechanism compared to strokes in people without COVID-19, possibly involving ferroptosis and iron metabolism pathways. The protein sTFR1 appears to be a promising biomarker for disease severity in COVID-19 complicated by stroke, though the authors note that larger studies are needed to confirm its usefulness in clinical practice.
Memiş Z, Soylu S, Duran Bayar M, Büşra Şişman A, Sancar N, Tüzün E, et al.. (2026). [Increased serum transferrin receptor 1 levels are associated with severity of acute ischemic stroke in patients with Covid-19 pneumonia].. Ideggyogyaszati szemle. https://doi.org/10.18071/isz.79.0181