The Kallikrein-kinin System in Bronchoalveolar Lavage Fluid from Patients with COVID-19

C.P. Martens^1,2, P. Van Mol^3,4, J. Wauters^5,6, E. Wauters⁷, T. Gangnus⁸, B. Noppen⁹, L. Liesenborghs^1,10, E. Heylen¹⁰, S. Jansen¹⁰, L.C. Velásquez Pereira¹, M.M Engelen^1,2, A. Van Herck⁷, R. Vos^7,4, C. Vandenbriele^1,2, K. Martinod¹, B.B Burckhardt⁸, M. Vanhove⁹, P. Verhamme^1,2, J. Neyts¹⁰, T. Vanassche^1,2

¹Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium, ²Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium, ³Laboratory of Translational Genetics, VIB – KU Leuven, Leuven, Belgium, ⁴Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium, ⁵Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium, ⁶Laboratory for Clinical Infectious and Inflammatory Diseases, Department of Microbiology and Immunity, KU Leuven, Leuven, Belgium, ⁷Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium, ⁸Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Düsseldorf, Germany, ⁹Oxurion NV, Leuven, Belgium, ¹⁰Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium

Abstract Number: PB0167

Meeting: ISTH 2021 Congress

Theme: COVID and Coagulation » COVID and Coagulation, Clinical

Background: Markers of both inflammation and coagulation are linked to clinical outcome in coronavirus disease 2019 (COVID-19). Binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the angiotensin-converting enzyme 2 receptor, which is involved in kinin breakdown, interferes with the kallikrein-kinin pathway. This could result in increased vascular permeability, fluid excess in the lungs and pulmonary edema. Furthermore, the kallikrein-kinin pathway links coagulation and inflammation through its interactions with the contact activation pathway of coagulation via factor XII and with neutrophil extracellular traps (NETs). These insights could help to explain the clinical presentation of COVID-19 pneumonia with pulmonary coagulopathy and the high incidence of thromboembolic complications in COVID-19.

Aims: Given the lack of clinical evidence to support this hypothesis, we studied the kallikrein-kinin system in bronchoalveolar lavage (BAL) fluid.

Methods: In BAL fluid samples from patients with or without COVID-19, we performed in-depth analyses of kinin peptides (bradykinin, Lys-bradykinin, Lys-bradykinin-(1-8), bradykinin-(1-8), bradykinin-(1-7), and bradykinin-(1-5)) using a liquid chromatography with tandem mass spectrometry assay, along with measurements of plasma and tissue kallikrein hydrolytic activity and myeloperoxidase (MPO)-DNA complexes as a biomarker for NETs. Informed consent and ethical approval were obtained.

Results: We observed higher levels of the most downstream kinin peptide bradykinin-(1-5) (Figure 1), higher tissue kallikrein activity (Figure 2), and higher levels of MPO-DNA complexes (699.0 ng/mL [66.0-142621.0], median [range], n = 21 vs 70.5 [9.9-960.0], n = 19; p < 0.001) in BAL fluid from patients with COVID-19 compared to those in BAL fluid from patients without COVID-19.

Levels of kinin peptides in bronchoalveolar lavage fluid samples from patients with COVID-19 compared to patients without COVID-19. Graphs show individual dots representing patient data and bar representing median of each patient group. Pairwise comparisons were made between patients with COVID-19 (n = 21) and patients without COVID-19 (n = 19). Median [min-max] and p-value are shown.

Kallikrein hydrolytic activity in bronchoalveolar lavage fluid samples from patients with COVID-19 compared to patients without COVID-19. Graphs show individual dots representing patient data and bar representing median of each patient group. Pairwise comparisons were made between patients with COVID-19 (n = 9) and patients without COVID-19 (n = 11). Median [min-max] and p-value are shown.

Conclusions: Our data support the hypothesis that SARS-CoV-2 induces dysregulation of the kallikrein-kinin system, which contributes to thromboinflammation in COVID-19. These findings encourage the investigation of drugs that target the kallikrein-kinin system as a potential treatment option for patients with COVID-19.
Funding: Research Foundation-Flanders (G0G4720N, 1843418N), KU Leuven COVID research fund.

To cite this abstract in AMA style:

Martens CP, Van Mol P, Wauters J, Wauters E, Gangnus T, Noppen B, Liesenborghs L, Heylen E, Jansen S, Velásquez Pereira LC, M Engelen M, Van Herck A, Vos R, Vandenbriele C, Martinod K, B Burckhardt B, Vanhove M, Verhamme P, Neyts J, Vanassche T. The Kallikrein-kinin System in Bronchoalveolar Lavage Fluid from Patients with COVID-19 [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-kallikrein-kinin-system-in-bronchoalveolar-lavage-fluid-from-patients-with-covid-19/. Accessed December 11, 2023.

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