“Unconventional CD147‐dependent platelet activation elicited by SARS‐CoV‐2 in COVID‐19”: Comment from Wada et al

Dear Editor,

We are very interested in the recently published report entitled “Unconventional CD147‐platelet activation elicited by SARS‐CoV‐2 in COVID‐19” by Maugeri et al.¹ Authors reported that early and intense platelet activation was reproduced in vitro by stimulating platelets with SARS‐CoV‐2, and that this was dependent on the CD147 receptor. The authors reported that platelets released soluble P‐selectin and HMGB1+ extracellular vesicles and that the early accumulation of platelet HMGB+ extracellular vesicles predicted worse clinical outcomes. Although these findings were markedly important, the methodology that they used to detect platelet activation was complicated for physicians. CD147 is a receptor for SARS‐CoV‐2 that is well‐known to play an important role in COVID‐19 infection.²

Coronavirus disease 2019 (COVID‐19), which sometimes causes acute respiratory distress syndrome, coagulopathy, and poor outcomes, has now spread worldwide. Thus, several mechanisms underlying the worsening of the condition of COVID‐19 patients have been proposed.³ Soluble C‐type lectin‐like receptor 2 (sCLEC‐2) has been introduced as a new biomarker of platelet activation⁴ and elevated plasma levels of sCLEC‐2 have been reported in patients with thrombotic microangiopathy,⁵ disseminated intravascular coagulation,⁶ and acute cerebral infarction.⁷ Elevated plasma levels of sCLEC‐2 were recently reported in patients with COVID‐19 infection and those were correlated with the severity of COVID‐19.⁸ Platelets in patients with COVID‐19 infection may release large amounts of sCLEC‐2 into the blood without microthrombus formation through CD147‐dependent platelet activation.

Regarding the further analysis, which included additional cases,⁸ plasma sCLEC‐2 levels in patients with COVID‐19 infection (median 25‐75th percentile, 491 μg/L; 363–651 μg/L) were significantly higher (p < .001, respectively) in comparison to patients with other pneumonia (276 μg/L; 183–459 μg/L), upper respiratory infection (247 μg/L; 173–355 μg/L) and unidentified clinical syndrome (178 μg/L; 134–207 μg/L) (Figure 1 ). There was no significant difference in the plasma sCLEC‐2 levels among COVID‐19 patients with mild, moderate, severe, and critical illness. These findings suggest that elevated plasma sCLEC‐2 levels may not be related to pneumonia.

FIGURE 1.

Plasma levels of sCLEC2 and sCLEC‐2/D‐dimer ratio in patients with COVID‐19 infection and those with other infections. #p < .001, #p < .01 and #p < .05; p < .001, p < .01, and p < .05 in comparison to unidentified clinical syndrome, respectively.

The platelet counts of patients with COVID‐19 infection, other pneumonia, upper respiratory infection, and unidentified clinical syndrome did not differ to a statistically significant extent. Plasma D‐dimer levels in patients with other pneumonia (3.4 mg/L; 1.8–8.7 mg/L) were significantly higher (p < .001, respectively) in comparison to patients with COVID‐19 infection (0.8 μg/L; 0.4–1.5 mg/L), upper respiratory infection (1.2 mg/L; 0.6–2.2 mg/L), and unidentified clinical syndrome (0.5 mg/L; 0.4–1.6 mg/L). These findings suggest that a hypercoagulable state is more predominant in patients with other pneumonia than in patients with COVID‐19 infection. The sCLEC‐2/D‐dimer ratio in patients with COVID‐19 (650/335–1274) was significantly higher in comparison to patients with other pneumonia (61.7; 36.1–210), upper respiratory infection (224; 87.8–472), and unidentified clinical syndrome (331; 87.7–490) (all p < .01). The sCLEC‐2/D‐dimer ratio in COVID‐19 patients with critical illness (241/73.5–594) was significantly lower in comparison to COVID‐19 patients with mild illness (837; 519–1423) or moderate illness (660; 284–1584) (Figure 1). These findings suggest that patients with early‐stage COVID‐19 infection shows only platelet activation, and that severe COVID‐19 infection causes hypercoagulability. Low‐dose aspirin was reported to be useful for managing COVID‐19 infection.⁹ The administration of aspirin may be useful for patients with early‐stage COVID‐19.

In conclusion, the sCLEC‐2 assay is an easy and rapid assay that can measure many samples, and is useful to measure platelet activation in patients with COVID‐19 infection.

AUTHOR CONTRIBUTIONS

H.W. wrote the manuscript and K.S. and K.S.‐I. discussed and revised the manuscript.

CONFLICT OF INTEREST

The measurement of sCLEC‐2 and D‐dimer levels were partially supported by LSI Medience. The authors declare no other conflicts of interest in association with the present study.

ETHICAL APPROVAL

The study protocol (2020‐S25) was approved by the Human Ethics Review committees of Mie Prefectural General Medical Center, and informed consent was obtained from each patient.