https://orcid.org/0000-0001-5147-989X
Key Points
Neither genetic nor pharmacologic loss of plasmin(ogen) increases venous thrombus formation in mice
Neither plasminogen gene variants nor perturbations in plasminogen levels or activity are associated with venous thromboembolism in humans
Suppression of plasminogen activation and/or plasmin activity (PA) reduces blood loss and decreases hemorrhage-related death. However, whether the endogenous PA system is a biological mechanism to prevent intravascular thrombus formation is debated, and the potential that reduced PA may increase venous thrombosis/thromboembolism (VTE) risk cautions against the use of antifibrinolytic agents. We aimed to determine the contribution of PA to VTE. Type 1 plasminogen-deficient humans enrolled in the HISTORY registry (https://clinical trials.gov; NCT03797495) reported pathologic pseudomembrane formation, but not unprovoked VTE. When subjected to an experimental model of venous thrombosis, compared to Plg+/+ mice, neither partial (Plg+/-) nor complete (Plg-/-) deletion of plasminogen altered thrombus mass or thrombus nucleated cell, platelet, or fibrin(ogen) content at 24 or 6 hours after thrombus induction. Administration of tranexamic acid (TXA) to mouse plasma in vitro or healthy mice in vivo dose-dependently delayed and suppressed plasma plasmin generation for up to 3 hours. However, mice administered TXA did not have significantly altered thrombus mass or thrombus composition at 24 or 6 hours after thrombus induction, despite unexpectedly persistent TXA in plasma. In a genome-wide association study, variants in gene regions encoding PA pathway proteins were not significantly associated with VTE risk. In the UK Biobank repository, plasminogen protein levels were not significantly associated with VTE risk. These data from genetic, pharmacologic, and proteomic analyses of mice and humans indicate that perturbations in PA do not increase VTE risk. Collectively, these results suggest PA is not a molecular regulatory mechanism to protect against VTE.
Comments
Plasminogen deficiency does not lead to thrombosis but to fibrin depositions on mucous epithelia – A puzzle to be solved
Why patients with severe plasminogen deficiency develop fibrin depositions on tissues contacting body fluids, and why these patients do not develop intravascular thrombosis, is unresolved. Available evidence points to the following explanation. Under physiologic conditions, normal human body fluids such as tears and saliva contain highly procoagulant extracellular vesicles that expose complexes of tissue factor (TF) and activated factor VII (FVIIa), so-called extrinsic tenase complexes. These extrinsic tenase complexes trigger fibrin formation. At the same time, body fluids as tears and saliva are also potent fibrinolytics, because they lyse fibrin in a plasmin-dependent manner. In persons with plasminogen deficiency, the formation of fibrin depositions on mucous epithelia reveals that fibrin is constantly generated and deposited on mucous epithelia, where it cannot be degraded due to the absence of plasminogen. Therefore, patients with plasminogen deficiency will suffer from excessive fibrin depositions in their airways, conjunctiva, gingiva, and the vaginal tract.
Under normal, physiological conditions, blood does not contain extrinsic tenase complexes that trigger fibrin formation. Thus, in blood, and this is in marked contrast to other physiological body fluids, no fibrin will be formed, and thus fibrinolysis plays no essential role. Consequently, plasminogen deficiency does not increase the risk of intravascular thrombosis, but fibrin deposition on mucous epithelia.