AbstractSevere 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.