Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

Siess, Wolfgang; Hundelshausen, Philipp von; Lorenz, Reinhard

doi:10.1080/09537104.2020.1809647

Cited by 10 publications

(8 citation statements)

References 38 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our work demonstrates the importance of the immune activation and coagulatory disorders in COVID-19 and strengthens the possible use of therapies to control both inflammatory disorders [43] and also platelet-based treatments such as the use of Bruton tyrosine kinase (Btk) to curb platelet activation, immunothrombosis, and the formation of platelet-neutrophil aggregates [44].…”

Section: Discussionsupporting

confidence: 56%

Platelet-Based Biomarkers for Diagnosis and Prognosis in COVID-19 Patients

Alberca

Solis-Castro

et al. 2021

Life

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19) caused millions of deaths worldwide. COVID-19's clinical manifestations range from no symptoms to a severe acute respiratory syndrome, which can result in multiple organ failure, sepsis, and death. Severe COVID-19 patients develop pulmonary and extrapulmonary infections, with a hypercoagulable state. Several inflammatory or coagulatory biomarkers are currently used with predictive values for COVID-19 severity and prognosis. In this manuscript, we investigate if a combination of coagulatory and inflammatory biomarkers could provide a better biomarker with predictive value for COVID-19 patients, being able to distinguish between patients that would develop a moderate or severe COVID-19 and predict the disease outcome. We investigated 306 patients with COVID-19, confirmed by severe acute respiratory syndrome coronavirus 2 RNA detected in the nasopharyngeal swab, and retrospectively analyzed the laboratory data from the first day of hospitalization. In our cohort, biomarkers such as neutrophil count and neutrophil-to-lymphocyte ratio from the day of hospitalization could predict if the patient would need to be transferred to the intensive care unit but failed to identify the patients´ outcomes. The ratio between platelets and inflammatory markers such as creatinine, C-reactive protein, and urea levels is associated with patient outcomes. Finally, the platelet/neutrophil-to-lymphocyte ratio on the first day of hospitalization can be used with predictive value as a novel severity and lethality biomarker in COVID-19. These new biomarkers with predictive value could be used routinely to stratify the risk in COVID-19 patients since the first day of hospitalization.

show abstract

Section: Discussionsupporting

confidence: 56%

Platelet-Based Biomarkers for Diagnosis and Prognosis in COVID-19 Patients

Alberca

Solis-Castro

et al. 2021

Life

View full text Add to dashboard Cite

show abstract

“…31,32 Other non-antiplatelet drugs in trials for COVID-19 therapy target proteins also expressed in platelets and could therefore inhibit the contribution of platelets to thromboinflammation. The Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib has been evaluated in clinical trials on the basis of its potential to block macrophage activation, 33 however, the potential of Btk inhibitors to reduce the contribution of platelets to thrombosis in COVID-19 infection 34 and more generally in thomboinflammation 35 have also been noted.…”

Section: Discussionmentioning

confidence: 99%

Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets

Bye

Hoepel

Mitchell

et al. 2021

Blood

View full text Add to dashboard Cite

A subset of patients with COVID-19 become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill COVID-19 patients are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesised that platelets might be susceptible to activation by anti-SARS-CoV-2 antibodies and contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike IgG enhanced platelet-mediated thrombosis on von Willebrand Factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by therapeutic small molecules R406 (fostamatinib) and ibrutinib that inhibit tyrosine kinases Syk and Btk respectively or by the P2Y12 antagonist cangrelor.

show abstract

“…Indeed, during the COVID‐19 pandemic, BTK has been shown to be activated in monocytes and intervention with the BTK inhibitor acalabrutinib has been reported to reduce systemic inflammation in patients with severe COVID‐19 (Roschewski et al, 2020 ). Nicolson, Welsh, et al ( 2020 ) provided evidence that BTK inhibitors could be used to reduced thromboinflammation in COVID‐19 patients (Siess et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Bruton's TK regulates myeloid cell recruitment during acute inflammation

Purvis

Aranda-Tavío

Channon

et al. 2022

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose Bruton's TK (BTK) is a non‐receptor kinase best known for its role in B lymphocyte development that is critical for proliferation and survival of leukaemic cells in B‐cell malignancies. However, BTK is expressed in myeloid cells, particularly neutrophils, monocytes and macrophages where its inhibition has been reported to cause anti‐inflammatory properties. Experimental Approach We explored the role of BTK on migration of myeloid cells (neutrophils, monocytes and macrophages), in vitro using chemotaxis assays and in vivo using zymosan‐induced peritonitis as model systems. Key Results Using the zymosan‐induced peritonitis model of sterile inflammation, we demonstrated that acute inhibition of BTK prior to zymosan challenge reduced phosphorylation of BTK in circulating neutrophils and monocytes. Moreover, pharmacological inhibition of BTK with ibrutinib specifically inhibited neutrophil and Ly6Chi monocytes, but not Ly6Clo monocyte recruitment to the peritoneum. X‐linked immunodeficient (XID) mice, which have a point mutation in the Btk gene, had reduced neutrophil and monocyte recruitment to the peritoneum following zymosan challenge. Pharmacological or genetic inhibition of BTK signalling substantially reduced human monocyte and murine macrophage chemotaxis, to a range of clinically relevant chemoattractants (C5a and CCL2). We also demonstrated that inhibition of BTK in tissue resident macrophages significantly decreases chemokine secretion by reducing NF‐κB activity and Akt signalling. Conclusion and Implications Our work has identified a new role of BTK in regulating myeloid cell recruitment via two mechanisms, reducing monocyte/macrophages' ability to undergo chemotaxis and reducing chemokine secretion, via reduced NF‐κB and Akt activity in tissue resident macrophages.

show abstract

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

Cited by 10 publications

References 38 publications

Platelet-Based Biomarkers for Diagnosis and Prognosis in COVID-19 Patients

Platelet-Based Biomarkers for Diagnosis and Prognosis in COVID-19 Patients

Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets

Bruton's TK regulates myeloid cell recruitment during acute inflammation

Contact Info

Product

Resources

About