Thromb Haemost 2022; 122(04): 506-516
DOI: 10.1055/a-1530-3980
Coagulation and Fibrinolysis

The Proteolytic Inactivation of Protein Z-Dependent Protease Inhibitor by Neutrophil Elastase Might Promote the Procoagulant Activity of Neutrophil Extracellular Traps in Sepsis

1   HITh, UMR_S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Mahita Razanakolona
1   HITh, UMR_S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Julie Helms
2   Service de Médecine Intensive-Réanimation, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
3   UMR_S1109, Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, Fédération Hospitalo-Universitaire, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
,
Fouzia Zouiti
4   Service d'Hématologie biologique, Hôpital Antoine Béclère, APHP, Université Paris-Saclay, Clamart, France
,
Amélie Couteau-Chardon
5   Service de Médecine Intensive-Réanimation, Hôpital Européen Georges Pompidou, APHP, Paris, France
,
Viviana Marin-Esteban
6   UMR_996, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Chatenay-Malabry, France
,
Luc de Chaisemartin
6   UMR_996, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Chatenay-Malabry, France
7   Laboratoire d'Immunologie, Hôpital Bichat, APHP, Paris, France
,
Allan De-Carvalho
1   HITh, UMR_S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Roselyne Bironien
8   Service de Biologie Clinique, Hôpital Foch, Suresnes, France
,
Sylvie Chollet-Martin
6   UMR_996, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Chatenay-Malabry, France
7   Laboratoire d'Immunologie, Hôpital Bichat, APHP, Paris, France
,
Cécile V. Denis
1   HITh, UMR_S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Jean-Luc Diehl
5   Service de Médecine Intensive-Réanimation, Hôpital Européen Georges Pompidou, APHP, Paris, France
9   UMR_S1140, Institut National de la Santé et de la Recherche Médicale, Université de Paris, Paris, France
,
Marc Vasse
1   HITh, UMR_S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
8   Service de Biologie Clinique, Hôpital Foch, Suresnes, France
,
Ferhat Meziani
2   Service de Médecine Intensive-Réanimation, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
10   UMR_1260, Institut National de la Santé et de la Recherche Médicale, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
,
Delphine Borgel
1   HITh, UMR_S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
11   Laboratoire d'Hématologie Biologique, Hôpital Necker, APHP, Paris, France
› Author Affiliations
Funding This study is funded by the French Intensive Care Society (FICS/SRLF).

Abstract

Septic shock is the archetypal clinical setting in which extensive crosstalk between inflammation and coagulation dysregulates the latter. The main anticoagulant systems are systematically impaired, depleted, and/or downregulated. Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that not only targets coagulation factors Xa and XIa but also acts as an acute phase reactant whose plasma concentration rises in inflammatory settings. The objective of the present study was to assess the plasma ZPI antigen level in a cohort of patients suffering from septic shock with or without overt-disseminated intravascular coagulation (DIC). The plasma ZPI antigen level was approximately 2.5-fold higher in the patient group (n = 100; 38 with DIC and 62 without) than in healthy controls (n = 31). The elevation's magnitude did not appear to depend on the presence/absence of DIC. Furthermore, Western blots revealed the presence of cleaved ZPI in plasma from patients with severe sepsis, independently of the DIC status. In vitro, ZPI was proteolytically inactivated by purified neutrophil elastase (NE) and by NE on the surface of neutrophil extracellular traps (NETs). The electrophoretic pattern of ZPI after NE-catalyzed proteolysis was very similar to that resulting from the clotting process—suggesting that the cleaved ZPI observed in severe sepsis plasma is devoid of anticoagulant activity. Taken as a whole, our results (1) suggest that NE is involved in ZPI inactivation during sepsis, and (2) reveal a novel putative mechanism for the procoagulant activity of NETs in immunothrombosis.

Supplementary Material



Publication History

Received: 21 December 2020

Accepted: 15 June 2021

Accepted Manuscript online:
16 June 2021

Article published online:
28 July 2021

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