-
Plasminogen, human-tvmh for the treatment of children and adults with plasminogen deficiency type 1.Haemophilia : the Official Journal of... Nov 2023An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted....
AIM
An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here.
METHODS
The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment.
RESULTS
The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2-5 days for 48 weeks and every 1-7 days for up to 124 weeks was well tolerated.
CONCLUSION
This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www.
CLINICALTRIALS
gov as #NCT02690714.
Topics: Humans; Child; Adult; Plasminogen; Treatment Outcome
PubMed: 37674358
DOI: 10.1111/hae.14849 -
American Journal of Reproductive... Apr 2017Multiparity increased the number of trophoblast cells in decidua of both low and high fetal loss mouse models. However, they differ in fetal survival rate and maternal...
PROBLEM
Multiparity increased the number of trophoblast cells in decidua of both low and high fetal loss mouse models. However, they differ in fetal survival rate and maternal thymocyte subpopulations, suggesting that trophoblast invasiveness is not equivalent. Our aim was to explore the involved mechanism.
METHOD OF STUDY
We studied placentae from primiparous and multiparous females of low and high fetal loss models. We investigated invasiveness in vitro, expression of plasminogen, and its activators: tissue type (tPA)-urokinase type (uPA), and activity and expression of matrix metalloproteinases (MMP)-2 and MMP-9.
RESULTS
Placental invasiveness is upregulated by multiparity, but lesser in the high fetal loss model. Multiparous animals showed elevated expression of plasminogen and uPA. However, the high fetal loss combination showed higher expression of a short and less active fragment of uPA (LMW-uPA). MMP-2, MMP-9, and tPA were unaffected.
CONCLUSION
uPA would participate in the increased multiparity-associated placental invasiveness.
Topics: Animals; Blotting, Western; Female; Immunohistochemistry; Mice; Models, Animal; Parity; Placenta; Placentation; Plasminogen; Pregnancy; Trophoblasts; Up-Regulation; Urokinase-Type Plasminogen Activator
PubMed: 28158911
DOI: 10.1111/aji.12633 -
Preparative Biochemistry & Biotechnology 2022The magnetic particles modified with silicon dioxide (SiO) and amino groups (-NH), as well as the magnetic particles modified with human serum albumin (HSA) were...
The magnetic particles modified with silicon dioxide (SiO) and amino groups (-NH), as well as the magnetic particles modified with human serum albumin (HSA) were synthesized using the approaches we developed before and characterized by physico-chemical methods in this study. Plasminogen was chosen as a model protein since plasminogen plays a major role in the fibrinolytic system and plasminogen level correlates with different pathologies and conditions. For the first time it has been carried out qualitative and quantitative assessment of plasminogen nonspecific binding (noncovalent adsorption) by the particles in buffer and plasma solutions. The fibrinolytic activity of plasminogen on the surface of the particles has been measured by the aid of commercially available kits and appeared to be 28-30% of its initial value. Plasminogen desorption from the surface of particles was studied in phosphate buffer with NaCl and ε-aminocaproic acid. Despite nonspecific plasminogen binding is an undesirable process, the data obtained is valuable for further modification of particles for high-specific proteins extraction from biological fluids or transport of plasminogen by the particles. The perspectives of particles modified with SiO and -NH, and particles modified with HSA for isolation of protein analytes and their quantitative assessment thereafter have been discussed.
Topics: Adsorption; Humans; Magnetic Iron Oxide Nanoparticles; Magnetite Nanoparticles; Nanoparticles; Plasminogen; Proteins; Serum Albumin, Human; Silicon Dioxide
PubMed: 34751636
DOI: 10.1080/10826068.2021.1998110 -
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 -
The Journal of Biological Chemistry Jan 2024Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular...
Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular functions, including roles in calcium homeostasis and protein folding. Recently, several extracellular functions have been identified for CRT, including roles in cancer cell invasion and phagocytosis of apoptotic and cancer cells by macrophages. In the current report, we uncover a novel function for extracellular CRT and report that CRT functions as a plasminogen-binding receptor that regulates the conversion of plasminogen to plasmin. We show that human recombinant or bovine tissue-derived CRT dramatically stimulated the conversion of plasminogen to plasmin by tissue plasminogen activator or urokinase-type plasminogen activator. Surface plasmon resonance analysis revealed that CRT-bound plasminogen (K = 1.8 μM) with moderate affinity. Plasminogen binding and activation by CRT were inhibited by ε-aminocaproic acid, suggesting that an internal lysine residue of CRT interacts with plasminogen. We subsequently show that clinically relevant CRT variants (lacking four or eight lysines in carboxyl-terminal region) exhibited decreased plasminogen activation. Furthermore, CRT-deficient fibroblasts generated 90% less plasmin and CRT-depleted MDA MB 231 cells also demonstrated a significant reduction in plasmin generation. Moreover, treatment of fibroblasts with mitoxantrone dramatically stimulated plasmin generation by WT but not CRT-deficient fibroblasts. Our results suggest that CRT is an important cellular plasminogen regulatory protein. Given that CRT can empower cells with plasmin proteolytic activity, this discovery may provide new mechanistic insight into the established role of CRT in cancer.
Topics: Animals; Cattle; Humans; Calreticulin; Fibrinolysin; Plasminogen; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Protein Domains; Mutation; Recombinant Proteins; Gene Knockout Techniques; Cell Line, Tumor; Neoplasms
PubMed: 37979915
DOI: 10.1016/j.jbc.2023.105465 -
Doklady. Biochemistry and Biophysics Nov 2021Plasminogen is a zymogenic form of plasmin, an enzyme that plays a fundamental role in the dissolution of fibrin clots as well as in many other physiological processes....
Plasminogen is a zymogenic form of plasmin, an enzyme that plays a fundamental role in the dissolution of fibrin clots as well as in many other physiological processes. For the first time, by the method of gas chromatography-mass spectrometry, post-translational modifications in the primary structure of plasminogen treated with physiologically relevant amounts of hydrogen peroxide were identified. It was found that methionine and tryptophan residues located in different structural regions of plasminogen served as targets of the oxidant. Plasminogen oxidation caused a dose-dependent effect in decreasing the fibrinogenolytic activity of plasmin evidenced by the formation of fibrinogen degradation products. The possible antioxidant role of methionines in the oxidative modification of plasminogen is discussed.
Topics: Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Oxidants; Peroxides; Plasminogen
PubMed: 34966964
DOI: 10.1134/S1607672921060053 -
International Journal of Molecular... Jan 2019Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral... (Review)
Review
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc.
Topics: Angiostatins; Apoptosis; Endothelium; Fibrinolysin; Fibrinolytic Agents; Humans; Plasminogen; Plasminogen Activator Inhibitor 1; Receptors, Urokinase Plasminogen Activator; Scleroderma, Systemic; Signal Transduction; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 30709025
DOI: 10.3390/ijms20030619 -
Endocrine, Metabolic & Immune Disorders... 2023Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome, coronavirus type 2 (SARS-CoV-2), leading to acute tissue injury and an overstated... (Review)
Review
Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome, coronavirus type 2 (SARS-CoV-2), leading to acute tissue injury and an overstated immune response. In COVID-19, there are noteworthy changes in the fibrinolytic system with the development of coagulopathy. Therefore, modulation of the fibrinolytic system may affect the course of COVID-19. Tranexamic acid (TXA) is an anti-fibrinolytic drug that reduces the conversion of plasminogen to plasmin, which is necessary for SARS-CoV-2 infectivity. In addition, TXA has anti-inflammatory, anti-platelet, and anti-thrombotic effects, which may attenuate the COVID-19 severity. Thus, in this narrative review, we try to find the beneficial and harmful effects of TXA in COVID-19.
Topics: Humans; Fibrinolysin; Plasminogen; Tranexamic Acid; COVID-19; SARS-CoV-2
PubMed: 35927893
DOI: 10.2174/1871530322666220801102402 -
Journal of Thrombosis and Haemostasis :... Jan 2017The cell surface orchestrates plasminogen activation through the concomitant binding of plasminogen and plasminogen activators to specific receptors. In this issue,...
The cell surface orchestrates plasminogen activation through the concomitant binding of plasminogen and plasminogen activators to specific receptors. In this issue, Miles and colleagues describe their detailed phenotypic characterization of mice deficient in Plg-R, a key plasminogen receptor expressed in numerous tissues, but highly expressed by proinflammatory macrophages. The analysis provides critical and surprising new insights into the biology of this receptor.
Topics: Amino Acid Sequence; Enzyme Activation; Humans; Plasminogen; Plasminogen Activators; Protein Processing, Post-Translational; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 27740735
DOI: 10.1111/jth.13541 -
International Journal of Molecular... Dec 2021Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological... (Review)
Review
Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator-plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization.
Topics: Animals; Humans; Models, Biological; Neovascularization, Pathologic; Neovascularization, Physiologic; Plasminogen; Serine Proteases; Tissue Plasminogen Activator
PubMed: 35008762
DOI: 10.3390/ijms23010337