A rationale for blocking thromboinflammation in COVID-19 with Btk inhibitors

Nicolson, Phillip Lr; Welsh, John D.; Chauhan, Abhishek; Thomas, Mark R.; Kahn, Mark L.; Watson, Steve P.

doi:10.1080/09537104.2020.1775189

Cited by 37 publications

(37 citation statements)

References 49 publications

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“…Several findings suggest the thrombi detected by CTPA in COVID-19 could – at least in part - be locally formed by the mechanism of thromboinflammation [ 16 ] SARS-CoV-2 is known to cause coagulopathy [ 8 , 17 , 18 ]. By mediating endothelial dysfunction and systemic inflammation, the coronavirus can cause a procoagulant state [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS

Müller-Peltzer

Krauß

Benndorf

et al. 2020

Respiratory Medicine

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Patients hospitalized for infection with SARS-CoV-2 typically present with pneumonia. The respiratory failure is frequently complicated by pulmonary embolism in segmental pulmonary arteries. The distribution of pulmonary embolism in regard to lung parenchymal opacifications has not been investigated yet. Methods: All patients with COVID-19 treated at a medical intensive care unit between March 8th and April 15th, 2020 undergoing computed tomography pulmonary angiography (CTPA) were included. All CTPA were assessed by two radiologists independently in respect to parenchymal changes and pulmonary embolism on a lung segment basis. Results: Out of 22 patients with severe COVID-19 treated within the observed time period, 16 (age 60.4 ± 10.2 years, 6 female SAPS2 score 49.2 ± 13.9) underwent CT. A total of 288 lung segment were analyzed. Thrombi were detectable in 9/16 (56.3%) patients, with 4.4 ± 2.9 segments occluded per patient and 40/288 (13.9%) segments affected in the whole cohort. Patients with thrombi had significantly worse segmental opacifications in CT (p < 0.05) and all thrombi were located in opacitated segments. There was no correlation between d-dimer level and number of occluded segmental arteries. Conclusions: Thrombi in segmental pulmonary arteries are common in COVID-19 and are located in opacitated lung segments. This might suggest local clot formation.

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Section: Discussionmentioning

confidence: 99%

Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS

Müller-Peltzer

Krauß

Benndorf

et al. 2020

Respiratory Medicine

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“…IL-6 circulating levels are elevated in severe COVID-19 [42]. Moreover, MAPK14 is an important signal transducer of IL-17 in endothelial cells [43], involved in neutrophilic inflammation, that may be important mediators of thrombosis in COVID-19 via the release of Neutrophil-Extracellular-Traps [20, 44]. MAPK14 is an important target of the potent corticosteroid dexamethasone [45], that was shown to decrease mortality in severe COVID-19 [46].…”

Section: Discussionmentioning

confidence: 99%

“…BMX has been shown to link both MYD88, another TLR-signaling adapter, and Focal Adhesion Kinases, a kinase associated with integrin activation to the synthesis of IL-6 [48]. The inhibition of genes in this family, and particularly BTK [41], has been proposed as a therapeutic approach to protect COVID-19 patients against pulmonary injury [42] and to block thrombo-inflammation [43]. Two potential downstream targets of BTK according to our regulatory networks (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of COVID-19-relevant transcriptional regulatory networks and associated kinases as potential therapeutic targets

Rousseau

Emad

2020

Preprint

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Identification of transcriptional regulatory mechanisms and signaling networks involved in the response of host to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, we combined a series of recently developed computational tools to identify transcriptional regulatory networks involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus. In addition, using network-guided analyses, we identified signaling pathways that are associated with these networks and kinases that may regulate them. The results identified classical antiviral response pathways including Interferon response factors (IRFs), interferons (IFNs), and JAK-STAT signaling as key elements upregulated by SARS-CoV-2 in comparison to mock-treated cells. In addition, comparing SARS-Cov-2 infection of airway epithelial cells to other respiratory viruses identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory networks identified herein reflect a combination of experimentally validated hits and novel pathways supporting the computational pipeline to quickly narrow down promising avenue of investigations when facing an emerging and novel disease such as COVID-19.

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“…In their letter [1] Nicolson et al propose a compelling concept of platelet CLEC-2 stimulation by podoplanin in microvascular thromboinflammation and venous thromboembolism that critically worsen the outcome in Coronavirus Disease 2019 [2,3,4,5] but might be amenable to inhibition of Bruton tyrosine kinase (Btk)-signaling downstream of CLEC-2 [6,7]. The Watson group had previously demonstrated the CLEC-2/podoplanin mechanism in murine venous thrombosis [6,8], salmonellosis caused murine hepatic thrombosis [9], and now reports high local podoplanin expression in valves of thrombosed human veins [1].…”

Section: Dear Sirmentioning

confidence: 99%