The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System
An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for rec...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.627579/full |
| _version_ | 1819169444439523328 |
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| author | Miklós Lipcsey Miklós Lipcsey Barbro Persson Oskar Eriksson Anna M. Blom Karin Fromell Michael Hultström Michael Hultström Markus Huber-Lang Kristina N. Ekdahl Kristina N. Ekdahl Robert Frithiof Bo Nilsson |
| author_facet | Miklós Lipcsey Miklós Lipcsey Barbro Persson Oskar Eriksson Anna M. Blom Karin Fromell Michael Hultström Michael Hultström Markus Huber-Lang Kristina N. Ekdahl Kristina N. Ekdahl Robert Frithiof Bo Nilsson |
| author_sort | Miklós Lipcsey |
| collection | DOAJ |
| description | An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19. |
| first_indexed | 2024-12-22T19:19:36Z |
| format | Article |
| id | doaj.art-88e2b39188194cf78855a73bdfa67f99 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T19:19:36Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-88e2b39188194cf78855a73bdfa67f992022-12-21T18:15:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.627579627579The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin SystemMiklós Lipcsey0Miklós Lipcsey1Barbro Persson2Oskar Eriksson3Anna M. Blom4Karin Fromell5Michael Hultström6Michael Hultström7Markus Huber-Lang8Kristina N. Ekdahl9Kristina N. Ekdahl10Robert Frithiof11Bo Nilsson12Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, SwedenHedenstierna Laboratory, Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Translational Medicine, Lund University, Malmö, SwedenDepartment of Immunology Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, SwedenUnit for Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, SwedenInstitute for Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, GermanyDepartment of Immunology Genetics and Pathology, Uppsala University, Uppsala, SwedenLinnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, SwedenDepartment of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, SwedenDepartment of Immunology Genetics and Pathology, Uppsala University, Uppsala, SwedenAn important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.https://www.frontiersin.org/articles/10.3389/fimmu.2021.627579/fullthromboinflammationkallikrein/kinin systemcomplement systemcoagulation systemfibrinolysis systemCOVID-19 |
| spellingShingle | Miklós Lipcsey Miklós Lipcsey Barbro Persson Oskar Eriksson Anna M. Blom Karin Fromell Michael Hultström Michael Hultström Markus Huber-Lang Kristina N. Ekdahl Kristina N. Ekdahl Robert Frithiof Bo Nilsson The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System Frontiers in Immunology thromboinflammation kallikrein/kinin system complement system coagulation system fibrinolysis system COVID-19 |
| title | The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System |
| title_full | The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System |
| title_fullStr | The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System |
| title_full_unstemmed | The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System |
| title_short | The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System |
| title_sort | outcome of critically ill covid 19 patients is linked to thromboinflammation dominated by the kallikrein kinin system |
| topic | thromboinflammation kallikrein/kinin system complement system coagulation system fibrinolysis system COVID-19 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.627579/full |
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