High Plasma Levels of Activated Factor VII-Antithrombin Complex Point to Increased Tissue Factor Expression in Patients with SARS-CoV-2 Pneumonia: A Potential Link with COVID-19 Prothrombotic Diathesis

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

Thymidine Phosphorylase Mediates SARS-CoV-2 Spike Protein Enhanced Thrombosis in K18-hACE2TGMice

“…These findings suggest that either a single injection of SP alone is not sufficient to initiate a change in the mRNA levels of TF, FVII, and other coagulation factors, or the increase of these factors is based on different mechanisms. Several studies also implicated that FVII is increased in the COVID-19 milieu, especially in severe patients 66,67 . In the FeCl 3 -induced thrombosis model, the entire vessel wall of the targeted segment is oxidatively damaged and the endothelial layer is denudated 35,36 .…”

COVID-19: Not a thrombotic disease but a thromboinflammatory disease

“…Likewise, Girard et al determined RNA sequencing in peripheral blood mononuclear cells, revealing a 5.2-fold enhancement in TF transcript expression for patients with severe COVID-19 compared to those with mild or moderate disease ( P < 0.05) ( 49 ). In addition, Martinelli et al reported that the complex of activated Factor VIIa (FVIIa) and antithrombin was elevated in COVID-19 pneumonia ( 50 ). This finding suggests a potential over-expression of TF indirectly because antithrombin specifically interacts with FVIIa only when FVIIa is bound to TF ( 51 , 52 ).…”

Tocilizumab for Severe COVID-19 Infection and Multisystem Inflammatory Syndrome in Adults and Children

“…Hypercytokinemia can also explain thromboinflammation and microthrombi associated with endotheliitis in patients with COVID-19. IL-6 has been shown to potentiate the coagulation cascade by causing platelet adhesion through increased production of selectins in endothelial cells, in addition to leading to the increased production of factor VIIa [10,11].…”

“…Since June 2021, the FDA enacted an emergency use authorization for tocilizumab for the treatment of COVID-19. Since there is inconsistent evidence of improvement in clinical outcomes and mortality, the FDA does not have approval for the use of tocilizumab and recommends careful consideration in specific patient populations [3,11]. While tocilizumab has a low side effect profile, it may serve as a useful adjunctive treatment with supportive care and corticosteroid use for severe COVID-19 pneumonia, MIS-C, and MIS-A [13].…”