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Frontiers in Immunology 2020
Topics: Female; Fibrinolysis; Humans; Immunity, Innate; Male
PubMed: 32296445
DOI: 10.3389/fimmu.2020.00582 -
JCI Insight Apr 2023Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high....
Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.
Topics: Mice; Animals; Fibrinolysin; Plasminogen; Extracellular Traps; Interleukin-6; Inflammation; Sepsis; Fibrin
PubMed: 36917195
DOI: 10.1172/jci.insight.166044 -
Journal of Tissue Engineering and... May 2022Segmental recanalization of chronically occluded arteries was observed in patients with chronic limb-threatening ischemia (CLTI) treated with Filgrastim, a granulocyte...
Segmental recanalization of chronically occluded arteries was observed in patients with chronic limb-threatening ischemia (CLTI) treated with Filgrastim, a granulocyte colony stimulating factor, every 72 h for up to a month, and an infra-geniculate programmed compression pump (PCP) for 3 h daily. Molecular evidence for fibrinolysis and neovascularization was sought. CLTI patients were treated with PCP alone (N = 19), or with Filgrastim and PCP (N = 8 and N = 6, at two institutions). Enzyme-Linked Immunosorbent Assay was used to measure the plasma concentration of plasmin and of fibrin degradation products (FDP), and the serum concentration of proteins associated with neovascularization. In the PCP-alone group, blood was sampled on Day 1 (baseline) and after 30 days of daily PCP. In the Filgrastim and PCP group, blood was drawn on Day 1, and 1 day after the 5th and the 10th Filgrastim doses. Each blood draw occurred before and after 2 h of supervised PCP. Significant (p < 0.01) PCP independent increases in the plasma concentration of plasmin (>10-fold) and FDP (>5-fold) were observed 1 day after both the 5th and the 10th Filgrastim doses, compared to Day 1. Significant (p < 0.05) increases in the concentration of pro-angiogenic proteins (e.g., HGF, MMP-9, VEGF A) were also observed. Filgrastim at this novel dosimetry induced fibrinolysis without causing acute hemorrhage, in addition to inducing a pro-angiogenic milieu conducive to NV. Further clinical testing is warranted at this novel dosimetry in CLTI, as well as in other chronically ischemic tissue beds. Trial registration. https://clinicaltrials.gov/ct2/show/NCT02802852.
Topics: Blood Group Antigens; Fibrinolysin; Fibrinolysis; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neovascularization, Pathologic; Recombinant Proteins
PubMed: 35175691
DOI: 10.1002/term.3284 -
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 -
Frontiers in Physiology 2020The emerging novel coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 presents with high infectivity, morbidity and mortality. It presenting a need for... (Review)
Review
The emerging novel coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 presents with high infectivity, morbidity and mortality. It presenting a need for immediate understanding of its pathogenicity. Inflammation and coagulation systems are over-activated in COVID-19. SARS-CoV-2 damages endothelial cell and pneumocyte, resulting in hemostatic disorder and ARDS. An influential biomarkers of poor outcome in COVID-19 are high circulating cytokines and D-dimer level. This latter is due to hyper-fibrinolysis and hyper-coagulation. Plasmin is a key player in fibrinolysis and is involved in the cleavage of many viruses envelop proteins, including SARS-CoV. This function is similar to that of TMPRSS2, which underpins the entry of viruses into the host cell. In addition, plasmin is involved in the pathophysiology of ARDS in SARS and promotes secretion of cytokine, such as IL-6 and TNF, from activated macrophages. Here, we suggest an out-of-the-box treatment for alleviating fibrinolysis and the ARDS of COVID-19 patients. This proposed treatment is concomitant administration of an anti-fibrinolytic drug and the anticoagulant.
PubMed: 33391014
DOI: 10.3389/fphys.2020.596057 -
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 -
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 -
Seminars in Thrombosis and Hemostasis Jun 2023The relationship between depression and reduced fibrinolytic activity reflects the role of tissue plasminogen activator and plasmin in brain remodeling underlying...
The relationship between depression and reduced fibrinolytic activity reflects the role of tissue plasminogen activator and plasmin in brain remodeling underlying resilience, depression remission, and reward processing, rather than the dissolution of fibrin clots. Individuals who experience depression demonstrate hippocampal and prefrontal cortex atrophy, as well as impaired neuronal connectivity. Brain-derived neurotrophic factor (BDNF), synthesized as a precursor that is activated through cleavage by tissue plasminogen activator and plasmin, influences adult neurogenesis and neuronal plasticity in the hippocampus and prefrontal cortex. Depression is associated with decreased brain levels of BDNF, due to reduced activity of tissue plasminogen activator and plasmin. Tissue plasminogen activator and plasmin also mediate the release of dopamine, a neurotransmitter implicated in motivation and reward. Peripartum depression defines a depressive episode that occurs during pregnancy or in the first month after delivery, reinforcing the concept that postpartum depression may be a continuum of antenatal depression. This article describes the fibrinolytic status in the healthy brain, in stress and depression, emphasizing the links between biological markers of depression and defective fibrinolysis. It also discusses the association between hypofibrinolysis and risk factors for perinatal depression, including polycystic ovary syndrome, early miscarriage, preeclampsia, stressful life events, sedentariness, eating habits, gestational and type 2 diabetes, and antithyroid peroxidase antibodies. In addition, it reviews the evidence that antidepressant medications and interventions as diverse as placebo, psychotherapy, massage, video game playing, regular exercise, dietary modifications, omega 3 fatty acid supplementation, neurohormones, and cigarette smoking may reduce depression by restoring the fibrinolytic activity. Last, it suggests new directions for research.
Topics: Female; Humans; Pregnancy; Tissue Plasminogen Activator; Fibrinolysin; Brain-Derived Neurotrophic Factor; Diabetes Mellitus, Type 2; Depression; Peripartum Period; Fibrinolysis
PubMed: 36113504
DOI: 10.1055/s-0042-1756194 -
Microbiology Spectrum Jun 2023parasites are the etiological agents of malaria, a disease responsible for over half a million deaths annually. Successful completion of the parasite's life cycle in...
parasites are the etiological agents of malaria, a disease responsible for over half a million deaths annually. Successful completion of the parasite's life cycle in the vertebrate host and transmission to a mosquito vector is contingent upon the ability of the parasite to evade the host's defenses. The extracellular stages of the parasite, including gametes and sporozoites, must evade complement attack in both the mammalian host and in the blood ingested by the mosquito vector. Here, we show that Plasmodium falciparum gametes and sporozoites acquire mammalian plasminogen and activate it into the serine protease plasmin to evade complement attack by degrading C3b. Complement-mediated permeabilization of gametes and sporozoites was higher in plasminogen-depleted plasma, suggesting that plasminogen is important for complement evasion. Plasmin also facilitates gamete exflagellation through complement evasion. Furthermore, supplementing serum with plasmin significantly increased parasite infectivity to mosquitoes and lowered the transmission-blocking activity of antibodies to Pfs230, a potent vaccine candidate currently in clinical trials. Finally, we show that human factor H, previously shown to facilitate complement evasion by gametes, also facilitates complement evasion by sporozoites. Plasmin and factor H simultaneously cooperate to enhance complement evasion by gametes and sporozoites. Taken together, our data show that Plasmodium falciparum gametes and sporozoites hijack the mammalian serine protease plasmin to evade complement attack by degrading C3b. Understanding of the mechanisms of complement evasion by the parasite is key to the development of novel effective therapeutics. Current approaches to control malaria are complicated by the development of antimalarial-resistant parasites and insecticide-resistant vectors. Vaccines that block transmission to mosquitoes and humans are a plausible alternative to overcome these setbacks. To inform the development of efficacious vaccines, it is imperative to understand how the parasite interacts with the host immune response. In this report, we show that the parasite can co-opt host plasmin, a mammalian fibrinolytic protein to evade host complement attack. Our results highlight a potential mechanism that may reduce efficacy of potent vaccine candidates. Taken together, our results will inform future studies in developing novel antimalarial therapeutics.
Topics: Animals; Humans; Plasmodium falciparum; Complement Factor H; Sporozoites; Fibrinolysin; Antimalarials; Complement System Proteins; Malaria; Culicidae; Germ Cells; Plasminogen; Mammals
PubMed: 37191558
DOI: 10.1128/spectrum.04493-22 -
Journal of Thrombosis and Haemostasis :... Dec 2023Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized...
BACKGROUND
Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia.
OBJECTIVES
To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.
METHODS
Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-αantiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen.
RESULTS
VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.
CONCLUSION
VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.
Topics: Humans; Fibrinolysis; Purpura, Thrombocytopenic, Idiopathic; Fibrinolysin; Disseminated Intravascular Coagulation; COVID-19 Vaccines; Thrombocytopenia; Thrombosis; Vaccines; Fibrinogen
PubMed: 37734715
DOI: 10.1016/j.jtha.2023.09.007