Herunterregulation des Thrombomodulin-Thrombin-aktivierten-Protein-C-Signalwegs als Mechanismus der SARS-CoV-2-induzierten Endotheliopathie und mikrovaskulären Thrombose

There is emerging evidence of microvascular thrombosis and thrombotic microangiopathy (TMA) induced by COVID-19, presumably from endothelial injury. Thrombomodulin (TM) is an endothelial glycoprotein that plays a dual role in maintaining healthy endothelium-as a natural anticoagulant by binding thrombin to activate protein C (APC) and a negative regulator of the alternate complement pathway (AP). TM is shed into the plasma as soluble TM (sTM) during endothelial injury. We hypothesize that SARS-CoV-2 spike proteins cause direct microvascular endothelial injury, leading to TM shedding, decreased activation of PC, and consequently, microvascular thrombosis in COVID-19. We conducted this study twofold: 1) in vivo, we assessed endothelial injury (by measuring sTM) and AP activation by quantifying Ba (cleavage product of AP component Factor B) in a cohort of critically ill COVID-19 pediatric patients and the implications on clinical outcomes; and 2)in vitro, we investigated endothelial injury (TM shedding) by SARS-COV-2 spike proteins and the subsequent functional consequence in activated PC (APC) levels and Ba levels. sTM and Ba in plasma samples from SARS-CoV-2 positive patients admitted to Texas Children's Hospital Pediatric Intensive Care Unit (n = 33) and from healthy controls (n = 38) were measured by ELISA. In vitro, confluent glomerular microvascular endothelial cells (GMVECs) were incubated for 48 h in the presence or absence (control) of purified SARS-CoV-2 spike proteins, S1 and S2. TM from the cell lysates while Ba and APC from the cell supernatants were measured by ELISA. sTM and Ba levels were significantly higher in the COVID-19 pediatric patients compared to healthy controls (p < 0.01 and p < 0.001, respectively). Among the COVID-19 patients, elevated sTM was associated with increased vasopressor use (p = 0.01) and elevated Ba was associated with increased duration of mechanical ventilation (p = 0.04). In vitro, surface bound TM and soluble APC were significantly lower in GMVECs after addition of spike proteins (p < 0.05), while Ba was undetectable in both control and spike proteins exposed GMVECs. In conclusion, we provide evidence of endothelial injury in COVID-19 pediatric patients and demonstrate a potential pathway of SARS-CoV-2 induced thrombosis. Decreased surface-bound TM results in lower amount of thrombin-TM complex, hence lesser activation of PC, likely leading to a pro-thrombotic state. These findings in GMVECs could explain the vulnerability of kidneys to COVID-19-induced TMA.

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Bei 33 kritisch kranken Kindern mit COVID-19 waren lösliches Thrombomodulin (sTM) und Ba (Faktor-B-Spaltprodukt) im Plasma gegenüber 38 gesunden Kontrollen signifikant erhöht (p < 0,01 bzw. p < 0,001); erhöhtes sTM war mit vermehrtem Vasopressorgebrauch (p = 0,01), erhöhtes Ba mit längerer Beatmungsdauer (p = 0,04) assoziiert. Nach 48-stündiger Inkubation glomerulärer mikrovaskulärer Endothelzellen mit Spike-Proteinen S1 und S2 waren oberflächenständiges TM und lösliches APC vermindert (p < 0,05). Die Autoren sehen darin einen potenziellen Weg der SARS-CoV-2-induzierten Thrombose.

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