Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques

Abstract

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

“…Microvascular thrombosis is characteristic of severe COVID-19 [ 10 , 14 , 15 , 16 , 28 ] and it has been proposed that a virus-induced prothrombotic state culminates with hyperinflammatory effectors and platelets to form immunothrombotic clots [ 152 , 153 ]. Reports of microangiopathic complications in severe COVID-19—including disseminated intravascular coagulation (DIC), venous thromboembolism, and pulmonary embolism—support a role for immunothrombosis in viral pathogenesis [ 22 , 23 , 154 ].…”

“…As previously described, induction of the RAAS by SARS-CoV-2-mediated ACE2 downregulation and/or shedding promotes hypofibrinolysis [ 97 ]. Hypercoagulation and hypofibrinolysis simultaneously foster a pro-thrombotic state, which with the addition of immune effectors and platelets, forms a highly pathogenic immunothrombotic clot in COVID-19 [ 152 , 153 ].…”

“…Severe COVID-19 is associated with thrombotic complications due to hypercoagulation and hypofibrinolysis [ 97 , 153 ]. These processes have therefore been designated as therapeutic targets for COVID-19.…”

Immunology of COVID‐19

“…This upregulation of inflammatory and complement pathways leads to recruitment of macrophages and neutrophils, activation of platelets, and triggering of the coagulation cascade, explaining the microthrombi in the alveolar septa of SARS‐CoV‐2 infected animals and increased fibrin and blood clotting factors deposition in the lungs. The researchers described in the animals vascular intimal thickening with lymphocytic infiltrates, features of inflammation of blood endothelia that have also been observed in SARS‐CoV‐2‐infected human (Aid et al ., 2020).…”

Perkembangan Terkini Terapi Antikoagulan Pada Pasien Covid-19 Bergejala Berat

“…Penelitian baru-baru ini yang dilakukan oleh Aid et al mempelajari mekanisme penyakit COVID-19 baik pada hewan percobaan (Rhesus macaques) maupun pada manusia yang menunjukkan bahwa COVID-19 menyebabkan inflamasi dan trombosis vaskuler. Dalam penemuan tersebut dilaporkan bahwa SARS-CoV-2 menyebabkan terjadinya peningkatan kadar beberapa komponen komplemen maupun kaskade, diantaranya C1R, C1QC, C3b/C4b reseptor 1 (CR1), C3, faktor koagulasi II, V, IX, dan X. Selain itu juga terdapat gambaran aktivasi trombosit, agregasi, dan adhesi serta didapatkan peningkatan sel megakariosit [30] [33].…”