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Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection.
Carnevale, Roberto; Cammisotto, Vittoria; Bartimoccia, Simona; Nocella, Cristina; Castellani, Valentina; Bufano, Marianna; Loffredo, Lorenzo; Sciarretta, Sebastiano; Frati, Giacomo; Coluccia, Antonio; Silvestri, Romano; Ceccarelli, Giancarlo; Oliva, Alessandra; Venditti, Mario; Pugliese, Francesco; Maria Mastroianni, Claudio; Turriziani, Ombretta; Leopizzi, Martina; D'Amati, Giulia; Pignatelli, Pasquale; Violi, Francesco.
  • Carnevale R; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).
  • Cammisotto V; IRCCS Neuromed, Località Camerelle, Pozzilli (IS), Italy (R.C., S.S., G.F.).
  • Bartimoccia S; Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy.
  • Nocella C; Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy.
  • Castellani V; Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy.
  • Bufano M; Department of General Surgery and Surgical Speciality (V. Castellani, F.P.), Sapienza University of Rome, Italy.
  • Loffredo L; Laboratory affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies (M.B., A.C., R.S.), Sapienza University of Rome, Italy.
  • Sciarretta S; Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy.
  • Frati G; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).
  • Coluccia A; IRCCS Neuromed, Località Camerelle, Pozzilli (IS), Italy (R.C., S.S., G.F.).
  • Silvestri R; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).
  • Ceccarelli G; IRCCS Neuromed, Località Camerelle, Pozzilli (IS), Italy (R.C., S.S., G.F.).
  • Oliva A; Laboratory affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies (M.B., A.C., R.S.), Sapienza University of Rome, Italy.
  • Venditti M; Laboratory affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies (M.B., A.C., R.S.), Sapienza University of Rome, Italy.
  • Pugliese F; Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy.
  • Maria Mastroianni C; Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy.
  • Turriziani O; Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy.
  • Leopizzi M; Department of General Surgery and Surgical Speciality (V. Castellani, F.P.), Sapienza University of Rome, Italy.
  • D'Amati G; Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy.
  • Pignatelli P; Laboratory of Virology, Department of Molecular Medicine (O.T.), Sapienza University of Rome, Italy.
  • Violi F; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).
Circ Res ; 132(3): 290-305, 2023 02 03.
Article in English | MEDLINE | ID: covidwho-2194410
ABSTRACT

BACKGROUND:

SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear.

METHODS:

We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B2, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation.

RESULTS:

Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation.

CONCLUSIONS:

The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Thrombosis / COVID-19 Type of study: Observational study / Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Circ Res Year: 2023 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Thrombosis / COVID-19 Type of study: Observational study / Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Circ Res Year: 2023 Document Type: Article