Activation of the Carboxypeptidase U (CPU, TAFIa, CPB2) System in Patients with SARS-CoV-2 Infection Could Contribute to COVID-19 Hypofibrinolytic State and Disease Severity Prognosis

Claesen, Karen; Sim, Yani; Bracke, An; bruyn, Michelle De; Hert, Emilie De; Vliegen, Gwendolyn; Hotterbeekx, An; Vujkovic, Alexandra; Petersen, Lida van; Winter, Fien H. R. De; Brosius, Isabel; Theunissen, Caroline; Ierssel, Sabrina H. van; Frankenhuijsen, Maartje Van; Vlieghe, Erika; Vercauteren, Koen; Kumar‐Singh, Samir; Meester, Ingrid De; Hendriks, Dirk

doi:10.3390/jcm11061494

Cited by 2 publications

(2 citation statements)

References 33 publications

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“…Fibrinolysis is also modulated by TAFI, a carboxypeptidase that cleaves terminal lysine in fibrin, preventing t-PA-mediated plasminogen activation. We did not detect consumption of TAFI/TAFIa, in contrast to variable or increased levels reported in critically ill/ICU patients [14,17,20,52], suggesting that TAFIa also functions as a negative modulator of fibrinolysis in advanced conditions.…”

Section: Post-mortem Studiescontrasting

confidence: 92%

SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

Toomer

Gerber

Zhang

et al. 2023

eJHaem

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D‐dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus disease 2019 (COVID‐19) coagulopathy, 64 adult patients with SARS‐CoV‐2 infection (36 moderate and 28 severe) and 16 controls were studied. We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin‐like) targeting the fibrinolytic system: Plasminogen Activator Inhibitor‐1 (PAI‐1), Tissue Plasminogen Activator/Plasminogen Activator Inhibitor‐1 complex (t‐PA/PAI‐1), α‐2‐Antiplasmin, Plasmin‐α2‐Antiplasmin Complex, Thrombin‐activatable Fibrinolysis Inhibitor (TAFI)/TAFIa, Protease Nexin‐1 (PN‐1), and Neuroserpin (the main t‐PA inhibitor of the central nervous system). Inhibitors of the common (Antithrombin, Thrombin‐antithrombin complex, Protein Z [PZ]/PZ inhibitor, Heparin Cofactor II, and α2‐Macroglobulin), Protein C ([PC], Protein C inhibitor, and Protein S), contact (Kallistatin, Protease Nexin‐2/Amyloid Beta Precursor Protein, and α‐1‐Antitrypsin), and complement (C1‐Inhibitor) pathways, in addition to Factor XIII, Histidine‐rich glycoprotein (HRG) and Vaspin were also investigated by enzyme‐linked immunosorbent assay. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI‐1 and Neuroserpin in the lungs from eight post‐mortem cases was assessed by immunohistochemistry. Results show that six patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI‐1, Neuroserpin, PN‐1, PAP, and t‐PA/PAI‐1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI‐1 in epithelial cells, macrophages, and endothelial cells of fatal COVID‐19, while Neuroserpin was found in intraalveolar macrophages only. These results imply that the lungs in SARS‐CoV‐2 infection provide anti‐fibrinolytic activity resulting in a shift toward a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated disseminated intravascular coagulation.

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Section: Post-mortem Studiescontrasting

confidence: 92%

SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

Toomer

Gerber

Zhang

et al. 2023

eJHaem

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“… 21 Levels of PAI‐1 are low in the circulation, but it is released from the endothelium, circulating platelets and adipocytes following stimulation. 22 Studies have indicated that the balance of fibrinolytic activators and inhibitors are altered in COVID‐19, however there is inadequate consensus on the drivers of the hypofibrinolytic state, with the suggestion that elevated fibrinogen, 23 , 24 TAFI, 24 , 25 tPA 26 , 27 and PAI‐1 24 , 28 , 29 or decreased plasminogen 28 , 30 are responsible.…”

Section: Introductionmentioning

confidence: 99%

The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

Whyte

Simpson

Morrow

et al. 2022

Journal of Thrombosis and Haemostasis

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Background Severe COVID‐19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID‐19 disease arise due to dysregulation of the fibrinolytic system. Methods This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID‐19 disease with 24 patients with non‐COVID‐19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor‐1 (PAI‐1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. Results PAI‐1 and its cofactor, vitronectin, are significantly elevated in patients with COVID‐19 disease compared with those with non‐COVID‐19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID‐19 disease relative to healthy controls. PAI‐1 and tissue plasminogen activator (tPA) were associated with more severe COVID‐19 disease severity. Clots formed from COVID‐19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID‐19 disease, while PAI‐1 activity was elevated. Clot lysis time significantly correlated with PAI‐1 levels. Stratification of COVID‐19 samples according to PAI‐1 levels reveals significantly faster lysis when using the PAI‐1 resistant (tPA) variant, tenecteplase, over alteplase lysis. Conclusion This study shows that the suboptimal fibrinolytic response in COVID‐19 disease is directly attributable to elevated levels of PAI‐1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI‐1 and the possibility of using pre‐existing drugs, such as tenecteplase, to treat COVID‐19 disease and potentially other respiratory diseases.

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Activation of the Carboxypeptidase U (CPU, TAFIa, CPB2) System in Patients with SARS-CoV-2 Infection Could Contribute to COVID-19 Hypofibrinolytic State and Disease Severity Prognosis

Cited by 2 publications

References 33 publications

SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

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