Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy

Author:

Nicolai Leo12ORCID,Leunig Alexander12ORCID,Brambs Sophia1,Kaiser Rainer12,Weinberger Tobias12,Weigand Michael3,Muenchhoff Maximilian45ORCID,Hellmuth Johannes C.67ORCID,Ledderose Stephan8,Schulz Heiko8,Scherer Clemens12ORCID,Rudelius Martina8,Zoller Michael9,Höchter DominikORCID,Keppler Oliver45,Teupser Daniel3,Zwißler Bernhard9,von Bergwelt-Baildon Michael67,Kääb Stefan12ORCID,Massberg Steffen12,Pekayvaz Kami12ORCID,Stark Konstantin12

Affiliation:

1. Medizinische Klinik und Poliklinik I (L.N., A.L., S.B., R.K., T.W., C.S., S.K., S.M., K.P., K.S.), University Hospital Ludwig-Maximilian University Munich, Germany.

2. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (L.N., A.L., R.K., T.W., C.S., S.K., S.M., K.P., K.S.).

3. Institute of Laboratory Medicine (M.W., D.T.), University Hospital Ludwig-Maximilian University Munich, Germany.

4. Virology, Max von Pettenkofer Institute (M.M., O.K.), Ludwig-Maximilian University Munich, Germany.

5. German Center for Infection Research (DZIF), Partner Site Munich (M.M., O.K.).

6. Medizinische Klinik und Poliklinik III (J.C.H., M.v.B.-B.), University Hospital Ludwig-Maximilian University Munich, Germany.

7. German Cancer Consortium (DKTK), Munich (J.C.H., M.v.B.-B.).

8. Institute of Pathology (S.L., H.S., M.R.), Ludwig-Maximilian University Munich, Germany.

9. Department of Anesthesiology (M.Z., B.Z.), University Hospital Ludwig-Maximilian University Munich, Germany.

Abstract

Background: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. Methods: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction–confirmed COVID-19 and n=24 non–COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker–based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. Results: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non–COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. Conclusions: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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