-
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 -
Trends in Parasitology Feb 2022Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the... (Review)
Review
Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the invertebrate vector. Plasmin, the effector protease of fibrinolysis, maintains homeostasis in the blood vasculature by degrading the fibrin that forms blood clots. Plasmin also degrades proteins from extracellular matrices, the complement system, and immunoglobulins. Here, we review some of the mechanisms by which vector-borne pathogens interact with components of the fibrinolytic system and co-opt its functions to facilitate transmission and infection in the host and the vector. Further, we discuss innovative strategies beyond conventional therapeutics that could be developed to target the interaction of vector-borne pathogens with the fibrinolytic proteins and prevent their transmission.
Topics: Animals; Fibrinolysin; Fibrinolysis; Humans; Malaria; Mammals; Plasminogen; Vector Borne Diseases
PubMed: 34649773
DOI: 10.1016/j.pt.2021.09.008 -
International Journal of Molecular... Mar 2021Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity... (Review)
Review
Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.
Topics: Animals; Antifibrinolytic Agents; Blood Chemical Analysis; Disease; Fibrin; Fibrinolysin; Fibrinolytic Agents; Humans; Plasminogen
PubMed: 33803235
DOI: 10.3390/ijms22052758 -
Journal of Thrombosis and Haemostasis :... Dec 2019Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the... (Review)
Review
Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the decades since their introduction into clinical practice, several limitations of have been identified in terms of both efficacy and bleeding risk associated with these agents. Engineered nanoparticles and microparticles address some of these limitations by improving circulation time, reducing inhibition and degradation in circulation, accelerating recanalization, improving targeting to thrombotic occlusions, and reducing off-target effects; however, many particle-based approaches have only been used in preclinical studies to date. This review covers four advances in coupling fibrinolytic agents with engineered particles: (a) modifications of plasminogen activators with macromolecules, (b) encapsulation of plasminogen activators and plasmin in polymer and liposomal particles, (c) triggered release of encapsulated fibrinolytic agents and mechanical disruption of clots with ultrasound, and (d) enhancing targeting with magnetic particles and magnetic fields. Technical challenges for the translation of these approaches to the clinic are discussed.
Topics: Animals; Drug Carriers; Drug Compounding; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; High-Energy Shock Waves; Humans; Liposomes; Magnetite Nanoparticles; Nanomedicine; Nanoparticles; Plasminogen Activators; Thrombolytic Therapy
PubMed: 31529593
DOI: 10.1111/jth.14637 -
International Journal of Molecular... Oct 2021Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen...
Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior hemostatic safety profile; however, if injected intravenously it becomes rapidly inactivated by anti-plasmin. Nanoformulations have been shown to increase drug stability and half-life and hence could be applied to increase the plasmin therapeutic efficacy. Here in this paper, we report a novel heparin and arginine-based plasmin nanoformulation that exhibits increased plasmin stability and efficacy. In vitro studies revealed significant plasmin stability in the presence of anti-plasmin and efficient fibrinolytic activity. In addition, these particles showed no significant toxicity or oxidative stress effects in human brain microvascular endothelial cells, and no significant blood brain barrier permeability. Further, in a mouse photothrombotic stroke model, plasmin nanoparticles exhibited significant efficacy in reducing stroke volume without overt intracerebral hemorrhage (ICH) compared to free plasmin treatment. The study shows the potential of a plasmin nanoformulation in ischemic stroke therapy.
Topics: Animals; Arginine; Blood-Brain Barrier; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Thrombolytic Therapy
PubMed: 34768908
DOI: 10.3390/ijms222111477 -
International Journal of Molecular... Apr 2020It is widely known that glomerulonephritis (GN) often develops after the curing of an infection, a typical example of which is GN in children following streptococcal... (Review)
Review
Glomerular Deposition of Nephritis-Associated Plasmin Receptor (NAPlr) and Related Plasmin Activity: Key Diagnostic Biomarkers of Bacterial Infection-related Glomerulonephritis.
It is widely known that glomerulonephritis (GN) often develops after the curing of an infection, a typical example of which is GN in children following streptococcal infections (poststreptococcal acute glomerulonephritis; PSAGN). On the other hand, the term "infection-related glomerulonephritis (IRGN)" has recently been proposed, because infections are usually ongoing at the time of GN onset in adult patients, particularly in older patients with comorbidities. However, there has been no specific diagnostic biomarker for IRGN, and diagnosis is based on the collection of several clinical and pathological findings and the exclusion of differential diagnoses. Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A streptococcus as a candidate nephritogenic protein for PSAGN and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase and plasmin receptor. NAPlr deposition and related plasmin activity were observed with a similar distribution pattern in the glomeruli of patients with PSAGN. However, glomerular NAPlr deposition and plasmin activity could be observed not only in patients with PSAGN but also in patients with other glomerular diseases, in whom a preceding streptococcal infection was suggested. Furthermore, such glomerular staining patterns have been demonstrated in patients with IRGN induced by bacteria other than streptococci. This review discusses the recent advances in our understanding of the pathogenesis of bacterial IRGN, which is characterized by NAPlr and plasmin as key biomarkers.
Topics: Bacterial Infections; Biomarkers; Fibrinolysin; Glomerulonephritis; Humans; Kidney Glomerulus; Receptors, Peptide; Streptococcal Infections
PubMed: 32276523
DOI: 10.3390/ijms21072595 -
The Journal of Experimental Medicine Apr 2020Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has... (Review)
Review
Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has been implicated in the progression of a wide range of diseases with an inflammatory component. In this review, we discuss the functions of plasminogen in inflammatory regulation and how this system plays a role in the pathogenesis of diseases spanning organ systems throughout the body.
Topics: Animals; Disease Progression; Fibrinolysin; Humans; Inflammation; Plasminogen
PubMed: 32159743
DOI: 10.1084/jem.20191865 -
Respiratory Research Nov 2023Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2).
METHODS
In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis.
RESULTS
Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-β upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion.
CONCLUSIONS
These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.
Topics: Mice; Humans; Animals; Leukocytes, Mononuclear; Antibodies, Monoclonal; Endothelial Cells; Fibrinolysin; Lung; Fibrosis; Idiopathic Pulmonary Fibrosis; Pneumonia; Collagen; Bleomycin; Fibroblasts; Phosphopyruvate Hydratase; Mice, Inbred C57BL
PubMed: 37964270
DOI: 10.1186/s12931-023-02583-3 -
Journal of Thrombosis and Haemostasis :... Apr 2023Fibrin-rich clot formation in thrombo-occlusive pathologies is currently treated by systemic administration of plasminogen activators (e.g. tPA), to convert...
BACKGROUND
Fibrin-rich clot formation in thrombo-occlusive pathologies is currently treated by systemic administration of plasminogen activators (e.g. tPA), to convert fibrin-associated plasminogen to plasmin for fibrinolytic action. However, this conversion is not restricted to clot site only but also occurs on circulating plasminogen, causing systemic fibrinogenolysis and bleeding risks. To address this, past research has explored tPA delivery using clot-targeted nanoparticles.
OBJECTIVES
We designed a nanomedicine system that can (1) target clots via binding to activated platelets and fibrin, (2) package plasmin instead of tPA as a direct fibrinolytic agent, and (3) release this plasmin triggered by thrombin for clot-localized action.
METHODS
Clot-targeted thrombin-cleavable nanoparticles (CTNPs) were manufactured using self-assembly of peptide-lipid conjugates. Plasmin loading and its thrombin-triggered release from CTNPs were characterized by UV-visible spectroscopy. CTNP-targeting to clots under flow was studied using microfluidics. Fibrinolytic effect of CTNP-delivered plasmin was studied in vitro using BioFlux imaging and D-dimer analysis and in vivo in a zebrafish thrombosis model.
RESULTS
Plasmin-loaded CTNPs significantly bound to clots under shear flow and showed thrombin-triggered enhanced release of plasmin. BioFlux studies confirmed that thrombin-triggered plasmin released from CTNPs rendered fibrinolysis similar to free plasmin, further corroborated by D-dimer analysis. In the zebrafish model, CTNP-delivered plasmin accelerated time-to-recanalization, or completely prevented occlusion when infused before thrombus formation.
CONCLUSION
Considering that the very short circulation half-life (<1 second) of plasmin prevents its systemic use but also makes it safer without off-target drug effects, clot-targeted delivery of plasmin using CTNPs can enable safer and more efficacious fibrinolytic therapy.
Topics: Animals; Fibrinolysin; Thrombin; Zebrafish; Fibrinolysis; Thrombolytic Therapy; Thrombosis; Fibrin; Plasminogen; Nanoparticles; Tissue Plasminogen Activator
PubMed: 36696210
DOI: 10.1016/j.jtha.2022.11.037 -
Scientific Reports Mar 2020Animal models of hemostasis are often extrapolated to humans; however, only a few studies have compared coagulation and fibrinolysis across species. Simultaneous... (Comparative Study)
Comparative Study
Animal models of hemostasis are often extrapolated to humans; however, only a few studies have compared coagulation and fibrinolysis across species. Simultaneous thrombin (TG) and plasmin (PG) generation is useful to assessing coagulation and fibrinolysis within the same sample. In this study, we performed simultaneous TG and PG analysis in blood plasma samples from humans and 6 species commonly evaluated in pre-clinical research. TG and PG were investigated in male and female donor platelet-poor plasmas (PPP) obtained from 28 healthy humans, 10 baboons, 12 rhesus monkeys, 20 Yorkshire pigs, 20 Sprague-Dawley rats, 10 New Zealand White rabbits and 14 Hartley guinea pigs. The continuous generation of the 7-amino-4-methylcoumarin (AMC) from substrates specific to thrombin or plasmin was monitored. The thrombin and plasmin concentration peak heights (PH) and production rates (PR) were calculated. TG and PG parameters from baboon and rhesus macaque plasma approximated that of humans. The other species differed significantly from both human and non-human primates. For example, swine and rat plasmas demonstrated similar TG, but swine plasmas did not generate plasmin. TG and PG parameters from Guinea pig samples were extremely low, while rabbit plasmas showed variable PG curves demonstrating one or two peaks with low and high PR values, respectively. Correlations between PH and PR values were significant with the exceptions of human PG, baboon TG, rat TG and Guinea pig PG. These findings are informative to pre-clinical animal species selection and optimization of coagulation and fibrinolysis translational research.
Topics: Animals; Female; Fibrinolysin; Humans; Male; Plasma; Species Specificity; Thrombin
PubMed: 32127577
DOI: 10.1038/s41598-020-60436-1