Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19
Malgorzata Wygrecka
(1)
,
Anna Birnhuber
(2)
,
Benjamin Seeliger
(3)
,
Laura Michalick
(4)
,
Oleg Pak
(1)
,
Astrid-Solveig Schultz
(1)
,
Fabian Schramm
(1)
,
Martin Zacharias
(5)
,
Gregor Gorkiewicz
(5)
,
Sascha David
(6)
,
Tobias Welte
(3)
,
Julius Schmidt
(3)
,
Norbert Weissmann
(1)
,
Ralph Schermuly
(1)
,
Guillermo Barreto
(7, 8)
,
Liliana Schaefer
(9)
,
Philipp Markart
,
Markus Brack
(4)
,
Stefan Hippenstiel
(4)
,
Florian Kurth
(4)
,
Leif Sander
(4)
,
Martin Witzenrath
(4)
,
Wolfgang Kuebler
(4)
,
Grazyna Kwapiszewska
(2)
,
Klaus Preissner
(1)
1
JLU -
Justus-Liebig-Universität Gießen = Justus Liebig University
2 Ludwig Boltzmann Institute for Lung Vascular Research [Graz]
3 MHH - Medizinische Hochschule Hannover = Hannover Medical School
4 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
5 Medical University Graz
6 University hospital of Zurich [Zurich]
7 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
8 CRRET - Croissance cellulaire, réparation et régénération tissulaires
9 Goethe-Universität Frankfurt am Main
2 Ludwig Boltzmann Institute for Lung Vascular Research [Graz]
3 MHH - Medizinische Hochschule Hannover = Hannover Medical School
4 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
5 Medical University Graz
6 University hospital of Zurich [Zurich]
7 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
8 CRRET - Croissance cellulaire, réparation et régénération tissulaires
9 Goethe-Universität Frankfurt am Main
Malgorzata Wygrecka
- Fonction : Auteur
- PersonId : 762581
- ORCID : 0000-0002-3656-2932
Oleg Pak
- Fonction : Auteur
- PersonId : 815366
- ORCID : 0000-0002-9733-3690
Norbert Weissmann
- Fonction : Auteur
- PersonId : 815367
- ORCID : 0000-0003-2675-3871
Guillermo Barreto
- Fonction : Auteur
- PersonId : 749236
- IdHAL : guillermo-barreto
- ORCID : 0000-0002-7777-4712
Liliana Schaefer
- Fonction : Auteur
- PersonId : 808050
- ORCID : 0000-0002-3318-3005
Philipp Markart
- Fonction : Auteur
Florian Kurth
- Fonction : Auteur
- PersonId : 770542
- ORCID : 0000-0002-3807-473X
Wolfgang Kuebler
- Fonction : Auteur
- PersonId : 793952
- ORCID : 0000-0003-4100-2961
Résumé
Abstract The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza. Using confocal and electron microscopy, we show that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, we observed clot lysis in 30% of COVID-19 patients and 84% of ARDS-influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19. Together, our results indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.