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Seminars in Thrombosis and Hemostasis Feb 2021Abuse of anabolic-androgenic steroids (AASs) is suspected to increase the risk of cardiovascular disease (CVD) and cardiovascular mortality in otherwise healthy... (Review)
Review
Abuse of anabolic-androgenic steroids (AASs) is suspected to increase the risk of cardiovascular disease (CVD) and cardiovascular mortality in otherwise healthy individuals. AAS abuse may increase the incidence of CVD by altering the hemostatic balance toward a procoagulant state. Studies on the effect of AAS abuse on the fibrinolytic system, however, have either demonstrated a profibrinolytic effect or no effect of AAS abuse, but the overall effect of AAS on fibrinolysis has not been addressed so far. This cross-sectional study investigated the effect of AAS on fibrin clot lysis, fibrin structure, and the hemostatic proteins, potentially affecting these measures in current and former AAS abusers and healthy age-matched controls. The study population consisted of 37 current and 33 former AAS abusers, along with 30 healthy age-matched controls. Fibrin clot lysis, fibrin structure properties, fibrinogen, coagulation factor XIII (FXIII) plasminogen, plasmin inhibitor, plasminogen activator inhibitor-1 (PAI-1), and thrombin activatable fibrinolysis inhibitor (TAFI) were determined. Fibrin clot lysis was significantly reduced in participants abusing AAS compared with former abusers and controls ( < 0.001). Plasma fibrinogen, plasminogen, and plasmin inhibitor were significantly increased in current abusers ( < 0.05). No significant differences were observed with respect to measures of fibrin structure properties, PAI-1, and TAFI ( > 0.05). In conclusion, AAS abuse depresses fibrin clot lysis. This effect is not associated with alterations in fibrin structure but is rather caused by increased plasma concentrations of fibrinogen, FXIII, and plasmin inhibitor. These findings suggest that AAS abuse may be associated with increased thrombotic disease.
Topics: Blood Coagulation Tests; Case-Control Studies; Cross-Sectional Studies; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Steroids
PubMed: 33017849
DOI: 10.1055/s-0040-1714398 -
International Journal of Molecular... May 2022The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and...
The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), counteracted by their inhibitors, plasminogen activator inhibitor type 1 (PAI-1), plasminogen activator inhibitor type 2 (PAI-2), protein C inhibitor (PCI), thrombin activable fibrinolysis inhibitor (TAFI), protease nexin 1 (PN-1) and neuroserpin. The action of plasmin is counteracted by α2-antiplasmin, α2-macroglobulin, TAFI, and other serine protease inhibitors (antithrombin and α2-antitrypsin) and PN-1 (protease nexin 1). These components are essential regulators of many physiologic processes. They are also involved in the pathogenesis of many disorders. Recent advancements in our understanding of these processes enable the opportunity of drug development in treating many of these disorders.
Topics: Fibrinolysin; Fibrinolysis; Plasminogen; Plasminogen Activator Inhibitor 1; Protease Nexins; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 35563651
DOI: 10.3390/ijms23095262 -
Thrombosis Journal Sep 2023Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue... (Review)
Review
Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue that competes for the lysine binding sites in plasminogen and tissue-type plasminogen activator impairing its interaction with the exposed lysine residues on the fibrin surface. The presence of TXA therefore, impairs the plasminogen and tPA engagement and subsequent plasmin generation on the fibrin surface, protecting fibrin clot from proteolytic degradation. However, critical lysine binding sites for plasmin(ogen) also exist on other proteins and on various cell-surface receptors allowing plasmin to exert potent effects on other targets that are unrelated to classical fibrinolysis, notably in relation to immunity and inflammation. Indeed, TXA was reported to significantly reduce post-surgical infection rates in patients after cardiac surgery unrelated to its haemostatic effects. This has provided an impetus to consider TXA in other indications beyond inhibition of fibrinolysis. While there is extensive literature on the optimal dosage of TXA to reduce bleeding rates and transfusion needs, it remains to be determined if these dosages also apply to blocking the non-canonical effects of plasmin.
PubMed: 37700271
DOI: 10.1186/s12959-023-00540-0 -
Journal of Thrombosis and Haemostasis :... Oct 2020Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal... (Review)
Review
Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal lysine functions to tether plasminogen to cell surfaces. Overexpression of Plg-R increases cell surface plasminogen binding capacity while genetic deletion of Plg-R decreases plasminogen binding. Plasminogen binding to Plg-R results in promotion of plasminogen activation to the broad spectrum serine protease plasmin. This function is promoted by the physical association of Plg-R with the urokinase receptor (uPAR). Plg-R is broadly expressed in cells and tissues throughout the organism and its sequence is remarkably conserved phylogenetically. Plg-R also is required for lactation and, thus, is necessary for survival of the species. This review provides an overview of established and emerging functions of Plg-R and highlights major roles for Plg-R in both the initiation and resolution of inflammation. While the roles for Plg-R in the inflammatory response are predominantly plasmin(ogen)-dependent, its role in lactation requires both plasminogen-dependent and plasminogen-independent mechanisms. Furthermore, the functions of Plg-R are dependent on sex. In view of the broad tissue distribution of Plg-R , its role in a broad array of physiological and pathological processes should provide a fruitful area for future investigation.
Topics: Cell Membrane; Female; Fibrinolysin; Humans; Inflammation; Plasminogen
PubMed: 32662180
DOI: 10.1111/jth.15014 -
Cellular Signalling Nov 2020A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen... (Review)
Review
A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.
Topics: Animals; Blood Coagulation; COVID-19; Complement Activation; Coronavirus Infections; Cytokine Release Syndrome; Cytokines; Humans; Immune System; Inflammation; Low Density Lipoprotein Receptor-Related Protein-1; NF-kappa B; Pandemics; Plasminogen; Pneumonia, Viral; Tissue Plasminogen Activator
PubMed: 32861744
DOI: 10.1016/j.cellsig.2020.109761 -
Blood Feb 2024
Topics: Humans; Fibrinolysin; Lysine; Angioedemas, Hereditary; Methionine; Kininogens; Edema; Racemethionine
PubMed: 38358851
DOI: 10.1182/blood.2023023292 -
Frontiers in Immunology 2019Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation... (Review)
Review
Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.
Topics: Angioedemas, Hereditary; Animals; Blood Coagulation; Bradykinin; Brain; Complement C1 Inhibitor Protein; Factor XII; Humans; Molecular Targeted Therapy; Plasminogen; Tissue Plasminogen Activator
PubMed: 31507620
DOI: 10.3389/fimmu.2019.02046 -
Journal of Thrombosis and Haemostasis :... Oct 2023The plasminogen/plasmin (Plg/Pla) system, best known for its classical role in thrombolysis, has been recently highlighted as a regulator of other biological processes... (Review)
Review
The plasminogen/plasmin (Plg/Pla) system, best known for its classical role in thrombolysis, has been recently highlighted as a regulator of other biological processes in mammals, including key steps involved in the resolution of inflammation. Inflammation resolution is a complex process coordinated by different cellular effectors, notably leukocytes, and active mediators, and is initiated shortly after the inflammatory response begins. Once the inflammatory insult is eliminated, an effective and timely engagement of proresolution programs prevents persistent inflammation, thereby avoiding excessive tissue damage, fibrosis, and the development of autoimmunity. Interestingly, recent studies demonstrate that Plg/Pla and their receptor, plasminogen receptor (Plg-R), regulate key steps in inflammation resolution. The number of studies investigating the involvement of the Plg/Pla system in these and other aspects of inflammation, including degradation of extracellular matrices, immune cell migration, wound healing, and skeletal growth and maintenance, highlights key roles of the Plg/Pla system during physiological and pathologic conditions. Here, we discuss robust evidence in the literature for the emerging roles of the Plg/Pla system in key steps of inflammation resolution. These findings suggest that dysregulation in Plg production and its activation plays a role in the pathogenesis of inflammatory diseases. Elucidating central mechanisms underlying the role of Plg/Pla in key steps of inflammation resolution either in preclinical models of inflammation or in human inflammatory conditions, can provide a rationale for the development of new pharmacologic interventions to promote resolution of inflammation, and open new pathways for the treatment of thromboinflammatory conditions.
Topics: Animals; Humans; Plasminogen; Fibrinolysin; Macrophages; Inflammation; Fibrinolysis; Mammals
PubMed: 37495082
DOI: 10.1016/j.jtha.2023.07.013 -
Circulation Research Feb 2021Current thrombolytic agents activate plasminogen to plasmin which triggers fibrinolysis to dissolve thrombi. Since plasmin is a nonspecific proteolytic enzyme, all of...
RATIONALE
Current thrombolytic agents activate plasminogen to plasmin which triggers fibrinolysis to dissolve thrombi. Since plasmin is a nonspecific proteolytic enzyme, all of the current plasmin-dependent thrombolytics lead to serious hemorrhagic complications, demanding a new class of fibrinolytic enzymes independent from plasmin activation and undesirable side effects. We speculated that the mammalian version of bacterial heat-shock proteins could selectively degrade intravascular thrombi, a typical example of a highly aggregated protein mixture.
OBJECTIVE
The objective of this study is to identify enzymes that can dissolve intravascular thrombi specifically without affecting fibrinogen and fibronectin so that the wound healing processes remain uninterrupted and tissues are not damaged. In this study, HtrA (high-temperature requirement A) proteins were tested for its specific proteolytic activity on intravascular thrombi independently from plasmin activation.
METHODS AND RESULTS
HtrA1 and HtrA2/Omi proteins, collectively called as HtrAs, lysed ex vivo blood thrombi by degrading fibrin polymers. The thrombolysis by HtrAs was plasmin-independent and specific to vascular thrombi without causing the systemic activation of plasminogen and preventing nonspecific proteolysis of other proteins including fibrinogen and fibronectin. As expected, HtrAs did not disturb clotting and wound healing of excised wounds from mouse skin. It was further confirmed in a tail bleeding and a rebleeding assay that HtrAs allowed normal clotting and maintenance of clot stability in wounds, unlike other thrombolytics. Most importantly, HtrAs completely dissolved blood thrombi in tail thrombosis mice, and the intravenous injection of HtrAs to mice with pulmonary embolism completely dissolved intravascular thrombi and thus rescued thromboembolism.
CONCLUSIONS
Here, we identified HtrA1 and HtrA2/Omi as plasmin-independent and highly specific thrombolytics that can dissolve intravascular thrombi specifically without bleeding risk. This work is the first report of a plasmin-independent thrombolytic pathway, providing HtrA1 and HtrA2/Omi as ideal therapeutic candidates for various thrombotic diseases without hemorrhagic complications.
Topics: Animals; Disease Models, Animal; Female; Fibrin; Fibrinolysis; Fibrinolytic Agents; Hemorrhage; High-Temperature Requirement A Serine Peptidase 1; High-Temperature Requirement A Serine Peptidase 2; Humans; Kinetics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pulmonary Embolism; Recombinant Proteins; Thrombosis; Wound Healing
PubMed: 33292062
DOI: 10.1161/CIRCRESAHA.120.317245 -
Clinical and Applied... 2023Sepsis-induced coagulopathy (SIC) is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. The diagnostic criteria of SIC... (Review)
Review
Sepsis-induced coagulopathy (SIC) is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. The diagnostic criteria of SIC consist of three items, including Sequential Organ Failure Assessment (SOFA) score, platelet count, and prothrombin time (PT)-international normalized ratio (INR). SIC has a high prevalence and it can lead to a higher mortality rate and longer length of hospital and ICU stay. Thus, the early detection of SIC is extremely important. It is unfortunate that there is still no precise biomarker for early diagnosis and assessment of the prognosis of SIC. We reviewed the current literature and discovered that some potential biomarkers, such as soluble thrombomodulin (sTM), thrombin-antithrombin complex (TAT), tissue plasminogen activator-inhibitor complex (t-PAIC), α2-plasmin inhibitor-plasmin complex (PIC), C-type lectin-like receptor 2 (CLEC-2), neutrophil extracellular traps (NETs), prothrombin fragment 1.2 (F1.2), Angiopoietin-2 (Ang-2), plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be useful for early diagnosis, evaluation, and prognosis of SIC. Early initiation of treatment without missing any therapeutic opportunities may improve SIC patients' prognosis. Further large-scale clinical studies are still needed to confirm the role of these biomarkers in the diagnosis and prognosis assessment of SIC.
Topics: Humans; Tissue Plasminogen Activator; Tissue Inhibitor of Metalloproteinase-1; Blood Coagulation Disorders; Prognosis; Biomarkers; Early Diagnosis; Sepsis; Disseminated Intravascular Coagulation
PubMed: 37605466
DOI: 10.1177/10760296231195089