key: cord-0999714-umwshl3l
authors: Bilgin, Emre; Ertenli, Ali İhsan
title: Proposal of a new nomenclature for the underlying pathogenetic mechanism of severe Coronavirus Disease-19: “Inflammatory Thrombosis with Immune Endotheliitis—ITIE”
date: 2021-01-03
journal: Rheumatol Int
DOI: 10.1007/s00296-020-04768-1
sha: 51838d7bece1a8fa1652d8be9deebf4d7023ff85
doc_id: 999714
cord_uid: umwshl3l

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level is low in classical MAS suggesting the development of disseminated intravascular coagulation (DIC); however, fibrinogen level is extremely high in COVID-19-related hyper-inflammation, supporting the hypothesis of pulmonary intravascular coagulopathy is prominant in COVID-19 patients rather than DIC [4] .

Laboratory surrogate of possible thrombotic process (d-Dimer) is also extremely high in COVID-19-related hyper-inflammation state in contrast to classical MAS [5] . "Cytokine release syndrome (CRS)" was another proposed term for the process occurred in COVID-19. However, cytokine profile and laboratory values are somehow different in two entities. Ferritin, interleukin-6 and soluble interleukin-2 receptor-alpha levels are extremely higher in CRS compared to COVID-19-related hyper-inflammation [5] . On the other hand; d-dimer and fibrinogen levels are extremely higher in COVID-19-related hyper-inflammation compared to CRS [5] . Another overlapping but differing situation is the typical acute respiratory distress syndrome (ARDS), and in ARDS, cytokine levels, IL-6,8 and tumor necrosis alpha, are extremely high compared to COVID-19-related hyperinflammation [6] . Also, necropathological examination of patient with COVID-19 revealed a much higher rate of microvascular injury and microthrombi compared to ARDS related to other infections, and accelerated thrombosis plays a central role in COVID-19 [7, 8] . Besides the cytokine and laboratory parameter differences between COVID-19 and other clinical entities, pulmonary endothelialitis plays a central role in COVID-19. Endotheliitis leads to disruption of vascular integrity and remaining subendothelial substances activate coagulation cascade; VEGF-A, PDGF-AA, PDGF-AB/BB, angiopoietin-2, FLT-3L and PAI-1 are several biomoleculs proposed as a biomarker for endotheliitis [9, 10] . This injury may explain the microthrombi formation and elevation of d-dimer. Also, another clue of the endotheliitis and its involvement in the COVID-19 is the high prevalence of Kawasaki disease in children. Current nomenclature of the process occuring in COVID-19 is highly confusing. In clinical aspect, "inflammation"oriented definitions have promoted anti-cytokine-based treatments and have left aside the treatments targeting coagulation process. However, none of the anti-cytokine-based treatments have been shown to reduce mortality, yet.

Regarding all these data, we are proposing a new name for the COVID-19-related hyper-inflammation "Inflammatory thrombosis with immune endotheliitis [ITIE] " that implicates the underlying process more clearly and combines the pathways that should be targeted with medical therapies.

Funding None.

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Conflict of ınterest None.