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Transfusion Aug 2022Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients.... (Review)
Review
Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis.
Topics: Antifibrinolytic Agents; Blood Coagulation Disorders; Fibrinolysin; Fibrinolysis; Hemorrhage; Humans; Tranexamic Acid
PubMed: 35834488
DOI: 10.1111/trf.16976 -
Science (New York, N.Y.) Dec 2021Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at...
Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota trigger extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the αβ integrin receptor and activates effector functions, including the production of reactive oxygen species and neutrophil extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis in mice and humans. Concordantly, genetic polymorphisms in , encoding plasminogen, are associated with common forms of periodontal disease. Thus, fibrin is a critical regulator of neutrophil effector function, and fibrin-neutrophil engagement may be a pathogenic instigator for a prevalent mucosal disease.
Topics: Alveolar Bone Loss; Animals; Extracellular Traps; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Gastrointestinal Microbiome; Gingiva; Humans; Immunity, Mucosal; Macrophage-1 Antigen; Male; Mice; Mouth Mucosa; Neutrophil Activation; Neutrophils; Periodontitis; Plasminogen; Polymorphism, Single Nucleotide; RNA-Seq; Reactive Oxygen Species
PubMed: 34941394
DOI: 10.1126/science.abl5450 -
Journal of Thrombosis and Haemostasis :... Dec 2023Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is... (Review)
Review
Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is formed from its circulating precursor, plasminogen. Fibrin is by far the most legendary substrate, but plasmin is notoriously prolific and is known to cleave many other proteins and participate in the activation of other proteolytic systems. Fibrinolysis is often overshadowed by the coagulation system and viewed as a simplistic poorer relation. However, the primordial plasminogen activators evolved alongside the complement system, approximately 70 million years before coagulation saw the light of day. It is highly likely that the plasminogen activation system evolved with its roots in primordial immunity. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allow plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, numerous pathogens express their own plasminogen activators or contain surface proteins that provide binding sites for host plasminogen. The fibrinolytic system has been harnessed for clinical medicine for many decades with the development of thrombolytic drugs and antifibrinolytic agents. Our refined understanding and appreciation of the fibrinolytic system and its alliance with infection and immunity and beyond are paving the way for new developments and interest in novel therapeutics and applications. One must ponder as to whether the nomenclature of the system hampered our understanding, by focusing on fibrin, rather than the complex myriad of interactions and substrates of the plasminogen activation system.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen Activators; Plasminogen; Fibrin; Serine Proteases
PubMed: 38000850
DOI: 10.1016/j.jtha.2023.09.012 -
Advanced Science (Weinheim,... Aug 2023The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here,...
The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-β into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-β signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
Topics: Mice; Humans; Animals; Transforming Growth Factor beta; Tissue Plasminogen Activator; Fibrinolysin; Plasminogen Activator Inhibitor 1; Liver Neoplasms; Muscles; Brain; Tumor Microenvironment
PubMed: 37330661
DOI: 10.1002/advs.202301505 -
Journal of Dental Research Aug 2023The hemostatic and inflammatory systems work hand in hand to maintain homeostasis at mucosal barrier sites. Among the factors of the hemostatic system, fibrin is well... (Review)
Review
The hemostatic and inflammatory systems work hand in hand to maintain homeostasis at mucosal barrier sites. Among the factors of the hemostatic system, fibrin is well recognized for its role in mucosal homeostasis, wound healing, and inflammation. Here, we present a basic overview of the fibrinolytic system, discuss fibrin as an innate immune regulator, and provide recent work uncovering the role of fibrin-neutrophil activation as a regulator of mucosal/periodontal homeostasis. We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis. Consistent with plasminogen deficiency being a risk factor for periodontitis, recent genomics studies uncover genetic polymorphisms in , encoding plasminogen, being significantly associated with periodontal disease, and suggesting variants as candidate risk indicators for common forms of periodontitis.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen; Fibrin; Periodontitis; Hemostatics
PubMed: 37506226
DOI: 10.1177/00220345231171837 -
Frontiers in Immunology 2024Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. species are... (Review)
Review
Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.
Topics: Humans; Streptococcal Infections; Rheumatic Fever; Streptococcus pyogenes; Pharyngitis; Autoimmune Diseases
PubMed: 38464518
DOI: 10.3389/fimmu.2024.1361123 -
Journal of Clinical Medicine May 2021SSI are a universal economic burden and increase individual patient morbidity and mortality. While antibiotic prophylaxis is the primary preventative intervention, these... (Review)
Review
SSI are a universal economic burden and increase individual patient morbidity and mortality. While antibiotic prophylaxis is the primary preventative intervention, these agents are not themselves benign and may be less effective in the context of emerging antibiotic resistant organisms. Exploration of novel therapies as an adjunct to antimicrobials is warranted. Plasmin and the plasminogen activating system has a complex role in immune function. The immunothrombotic role of plasmin is densely interwoven with the coagulation system and has a multitude of effects on the immune system constituents, which may not always be beneficial. Tranexamic acid is an antifibrinolytic agent which inhibits the conversion of plasminogen to plasmin. Clinical trials have demonstrated a reduction in surgical site infection in TXA exposed patients, however the mechanism and magnitude of this benefit is incompletely understood. This effect may be through the reduction of local wound haematoma, decreased allogenic blood transfusion or a direct immunomodulatory effect. Large scale randomised clinical trial are currently being undertaken to better explain this association. Importantly, TXA is a safe and widely available pharmacological agent which may have a role in the reduction of SSI.
PubMed: 34065949
DOI: 10.3390/jcm10102070 -
Blood May 2021Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential... (Review)
Review
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.
Topics: Animals; Antifibrinolytic Agents; Brain; Conjunctivitis; Enzyme Activation; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity; Infections; Inflammation; Mice; Plasminogen; Radiodermatitis; Receptors, Cell Surface; Skin Diseases, Genetic; Thrombosis; Tranexamic Acid; Wound Healing; Wounds and Injuries
PubMed: 33735914
DOI: 10.1182/blood.2020008951 -
Neural Regeneration Research Dec 2020Plasmin is generally known as a promotor of inflammation. Recent advancement suggests that it has a complex role as immunity modulator. Pharmacological inhibition of... (Review)
Review
Plasmin is generally known as a promotor of inflammation. Recent advancement suggests that it has a complex role as immunity modulator. Pharmacological inhibition of plasmin production and activity has been proven to improve neurological outcomes in traumatic brain injury and subarachnoid hemorrhage, most probably by preventing re-bleeding. The immune-modulatory properties of antifibrinolytics, however, suggest that they probably have effects unrelated to fibrinolysis inhibition, which are currently not adequately harnessed. The present work aims to give an account of the existing data regarding antifibrinolytics as agents influencing neuroinflammation. Preclinical and clinical studies on the possible influence of antifibrinolytics on neuroinflammation are scarce. However, the emerging evidence suggests that inhibition of plasmin(ogen) activity can ameliorate neuroinflammation to some extent. This data demonstrate that plasmin(ogen) is not exclusively involved in fibrinolysis, but also has other substrates and can precipitate in inflammatory processes. Investigation on the role of plasmin as the factor for the development of neuroinflammation shows the significant potential of antifibrinolytics as pharmacotherapy of neuroinflammationm, which is worthy of further exploration.
PubMed: 32594031
DOI: 10.4103/1673-5374.284979