Editorial

7 pages, 396 KiB

Open AccessEditorial

The Role of Fibrinolytic System in Health and Disease

by Hau C. Kwaan

Int. J. Mol. Sci. 2022, 23(9), 5262; https://doi.org/10.3390/ijms23095262 - 09 May 2022

Cited by 5 | Viewed by 3466

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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Research

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9 pages, 1914 KiB

Open AccessArticle

Reduced Expression of Urokinase Plasminogen Activator in Brown Adipose Tissue of Obese Mouse Models

by Chung-Ze Wu, Li-Chien Chang, Chao-Wen Cheng, Te-Chao Fang, Yuh-Feng Lin, Dee Pei and Jin-Shuen Chen

Int. J. Mol. Sci. 2021, 22(7), 3407; https://doi.org/10.3390/ijms22073407 - 26 Mar 2021

Viewed by 1579

Abstract

In recent decades, the obesity epidemic has resulted in morbidity and mortality rates increasing globally. In this study, using obese mouse models, we investigated the relationship among urokinase plasminogen activator (uPA), metabolic disorders, glomerular filtration rate, and adipose tissues. Two groups, each comprised [...] Read more.

In recent decades, the obesity epidemic has resulted in morbidity and mortality rates increasing globally. In this study, using obese mouse models, we investigated the relationship among urokinase plasminogen activator (uPA), metabolic disorders, glomerular filtration rate, and adipose tissues. Two groups, each comprised of C57BL/6J and BALB/c male mice, were fed a chow diet (CD) and a high fat diet (HFD), respectively. Within the two HFD groups, half of each group were euthanized at 8 weeks (W8) or 16 weeks (W16). Blood, urine and adipose tissues were collected and harvested for evaluation of the effects of obesity. In both mouse models, triglyceride with insulin resistance and body weight increased with duration when fed a HFD in comparison to those in the groups on a CD. In both C57BL/6J and BALB/c HFD mice, levels of serum uPA initially increased significantly in the W8 group, and then the increment decreased in the W16 group. The glomerular filtration rate declined in both HFD groups. The expression of uPA significantly decreased in brown adipose tissue (BAT), but not in white adipose tissue, when compared with that in the CD group. The results suggest a decline in the expression of uPA in BAT in obese m models as the serum uPA increases. There is possibly an association with BAT fibrosis and dysfunction, which may need further study. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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Review

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12 pages, 979 KiB

Open AccessReview

Fibrinolysis in Platelet Thrombi

by Rahim Kanji, Ying X. Gue, Vassilios Memtsas and Diana A. Gorog

Int. J. Mol. Sci. 2021, 22(10), 5135; https://doi.org/10.3390/ijms22105135 - 12 May 2021

Cited by 5 | Viewed by 5454

Abstract

The extent and duration of occlusive thrombus formation following an arterial atherothrombotic plaque disruption may be determined by the effectiveness of endogenous fibrinolysis. The determinants of endogenous fibrinolysis are the subject of much research, and it is now broadly accepted that clot composition [...] Read more.

The extent and duration of occlusive thrombus formation following an arterial atherothrombotic plaque disruption may be determined by the effectiveness of endogenous fibrinolysis. The determinants of endogenous fibrinolysis are the subject of much research, and it is now broadly accepted that clot composition as well as the environment in which the thrombus was formed play a significant role. Thrombi with a high platelet content demonstrate significant resistance to fibrinolysis, and this may be attributable to an augmented ability for thrombin generation and the release of fibrinolysis inhibitors, resulting in a fibrin-dense, stable thrombus. Additional platelet activators may augment thrombin generation further, and in the case of coronary stenosis, high shear has been shown to strengthen the attachment of the thrombus to the vessel wall. Neutrophil extracellular traps contribute to fibrinolysis resistance. Additionally, platelet-mediated clot retraction, release of Factor XIII and resultant crosslinking with fibrinolysis inhibitors impart structural stability to the thrombus against dislodgment by flow. Further work is needed in this rapidly evolving field, and efforts to mimic the pathophysiological environment in vitro are essential to further elucidate the mechanism of fibrinolysis resistance and in providing models to assess the effects of pharmacotherapy. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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21 pages, 7938 KiB

Open AccessReview

Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

by Manuel Yepes, Yena Woo and Cynthia Martin-Jimenez

Int. J. Mol. Sci. 2021, 22(9), 4380; https://doi.org/10.3390/ijms22094380 - 22 Apr 2021

Cited by 12 | Viewed by 4922

Abstract

The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with [...] Read more.

The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with these observations, a growing body of evidence has linked NVU dysfunction to neurodegeneration. Plasminogen activators catalyze the conversion of the zymogen plasminogen into the two-chain protease plasmin, which in turn triggers a plethora of physiological events including wound healing, angiogenesis, cell migration and inflammation. The last four decades of research have revealed that the two mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are pivotal regulators of NVU function during physiological and pathological conditions. Here, we will review the most relevant data on their expression and function in the NVU and their role in neurovascular and neurodegenerative disorders. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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16 pages, 492 KiB

Open AccessReview

Fibrinolytic System and Cancer: Diagnostic and Therapeutic Applications

by Niaz Mahmood and Shafaat A. Rabbani

Int. J. Mol. Sci. 2021, 22(9), 4358; https://doi.org/10.3390/ijms22094358 - 22 Apr 2021

Cited by 18 | Viewed by 3030

Abstract

Fibrinolysis is a crucial physiological process that helps to maintain a hemostatic balance by counteracting excessive thrombosis. The components of the fibrinolytic system are well established and are associated with a wide array of physiological and pathophysiological processes. The aberrant expression of several [...] Read more.

Fibrinolysis is a crucial physiological process that helps to maintain a hemostatic balance by counteracting excessive thrombosis. The components of the fibrinolytic system are well established and are associated with a wide array of physiological and pathophysiological processes. The aberrant expression of several components, especially urokinase-type plasminogen activator (uPA), its cognate receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), has shown a direct correlation with increased tumor growth, invasiveness, and metastasis. As a result, targeting the fibrinolytic system has been of great interest in the field of cancer biology. Even though there is a plethora of encouraging preclinical evidence on the potential therapeutic benefits of targeting the key oncogenic components of the fibrinolytic system, none of them made it from “bench to bedside” due to a limited number of clinical trials on them. This review summarizes our existing understanding of the various diagnostic and therapeutic strategies targeting the fibrinolytic system during cancer. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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17 pages, 1321 KiB

Open AccessReview

Thrombin Activatable Fibrinolysis Inhibitor (TAFI): An Updated Narrative Review

by Machteld Sillen and Paul J. Declerck

Int. J. Mol. Sci. 2021, 22(7), 3670; https://doi.org/10.3390/ijms22073670 - 01 Apr 2021

Cited by 31 | Viewed by 4040

Abstract

Thrombin activatable fibrinolysis inhibitor (TAFI), a proenzyme, is converted to a potent attenuator of the fibrinolytic system upon activation by thrombin, plasmin, or the thrombin/thrombomodulin complex. Since TAFI forms a molecular link between coagulation and fibrinolysis and plays a potential role in venous [...] Read more.

Thrombin activatable fibrinolysis inhibitor (TAFI), a proenzyme, is converted to a potent attenuator of the fibrinolytic system upon activation by thrombin, plasmin, or the thrombin/thrombomodulin complex. Since TAFI forms a molecular link between coagulation and fibrinolysis and plays a potential role in venous and arterial thrombotic diseases, much interest has been tied to the development of molecules that antagonize its function. This review aims at providing a general overview on the biochemical properties of TAFI, its (patho)physiologic function, and various strategies to stimulate the fibrinolytic system by interfering with (activated) TAFI functionality. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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10 pages, 276 KiB

Open AccessReview

Fibrinolysis: A Primordial System Linked to the Immune Response

by Robert L. Medcalf and Charithani B. Keragala

Int. J. Mol. Sci. 2021, 22(7), 3406; https://doi.org/10.3390/ijms22073406 - 26 Mar 2021

Cited by 15 | Viewed by 3016

Abstract

The fibrinolytic system provides an essential means to remove fibrin deposits and blood clots. The actual protease responsible for this is plasmin, formed from its precursor, plasminogen. Fibrin is heralded as it most renowned substrate but for many years plasmin has been known [...] Read more.

The fibrinolytic system provides an essential means to remove fibrin deposits and blood clots. The actual protease responsible for this is plasmin, formed from its precursor, plasminogen. Fibrin is heralded as it most renowned substrate but for many years plasmin has been known to cleave many other substrates, and to also activate other proteolytic systems. Recent clinical studies have shown that the promotion of plasmin can lead to an immunosuppressed phenotype, in part via its ability to modulate cytokine expression. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allows plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, a multitude of pathogens can also express their own plasminogen activators, or contain surface proteins that provide binding sites host plasminogen. Plasmin formed under these circumstances also empowers these pathogens to modulate host immune defense mechanisms. Phylogenetic studies have revealed that the plasminogen activating system predates the appearance of fibrin, indicating that plasmin did not evolve as a fibrinolytic protease but perhaps has its roots as an immune modifying protease. While its fibrin removing capacity became apparent in lower vertebrates these primitive under-appreciated immune modifying functions still remain and are now becoming more recognised. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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Graphical abstract

18 pages, 2320 KiB

Open AccessReview

Coagulation and Fibrinolysis in Obstructive Sleep Apnoea

by Andras Bikov, Martina Meszaros and Esther Irene Schwarz

Int. J. Mol. Sci. 2021, 22(6), 2834; https://doi.org/10.3390/ijms22062834 - 11 Mar 2021

Cited by 17 | Viewed by 3872

Abstract

Obstructive sleep apnoea (OSA) is a common disease which is characterised by repetitive collapse of the upper airways during sleep resulting in chronic intermittent hypoxaemia and frequent microarousals, consequently leading to sympathetic overflow, enhanced oxidative stress, systemic inflammation, and metabolic disturbances. OSA is [...] Read more.

Obstructive sleep apnoea (OSA) is a common disease which is characterised by repetitive collapse of the upper airways during sleep resulting in chronic intermittent hypoxaemia and frequent microarousals, consequently leading to sympathetic overflow, enhanced oxidative stress, systemic inflammation, and metabolic disturbances. OSA is associated with increased risk for cardiovascular morbidity and mortality, and accelerated coagulation, platelet activation, and impaired fibrinolysis serve the link between OSA and cardiovascular disease. In this article we briefly describe physiological coagulation and fibrinolysis focusing on processes which could be altered in OSA. Then, we discuss how OSA-associated disturbances, such as hypoxaemia, sympathetic system activation, and systemic inflammation, affect these processes. Finally, we critically review the literature on OSA-related changes in markers of coagulation and fibrinolysis, discuss potential reasons for discrepancies, and comment on the clinical implications and future research needs. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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16 pages, 1084 KiB

Open AccessReview

A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?

by Machteld Sillen and Paul J. Declerck

Int. J. Mol. Sci. 2021, 22(5), 2721; https://doi.org/10.3390/ijms22052721 - 08 Mar 2021

Cited by 67 | Viewed by 6112

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction [...] Read more.

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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14 pages, 1356 KiB

Open AccessReview

The Contribution of the Urokinase Plasminogen Activator and the Urokinase Receptor to Pleural and Parenchymal Lung Injury and Repair: A Narrative Review

by Torry A. Tucker and Steven Idell

Int. J. Mol. Sci. 2021, 22(3), 1437; https://doi.org/10.3390/ijms22031437 - 01 Feb 2021

Cited by 9 | Viewed by 3495

Abstract

Pleural and parenchymal lung injury have long been characterized by acute inflammation and pathologic tissue reorganization, when severe. Although transitional matrix deposition is a normal part of the injury response, unresolved fibrin deposition can lead to pleural loculation and scarification of affected areas. [...] Read more.

Pleural and parenchymal lung injury have long been characterized by acute inflammation and pathologic tissue reorganization, when severe. Although transitional matrix deposition is a normal part of the injury response, unresolved fibrin deposition can lead to pleural loculation and scarification of affected areas. Within this review, we present a brief discussion of the fibrinolytic pathway, its components, and their contribution to injury progression. We review how local derangements of fibrinolysis, resulting from increased coagulation and reduced plasminogen activator activity, promote extravascular fibrin deposition. Further, we describe how pleural mesothelial cells contribute to lung scarring via the acquisition of a profibrotic phenotype. We also discuss soluble uPAR, a recently identified biomarker of pleural injury, and its diagnostic value in the grading of pleural effusions. Finally, we provide an in-depth discussion on the clinical importance of single-chain urokinase plasminogen activator (uPA) for the treatment of loculated pleural collections. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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15 pages, 2597 KiB

Open AccessReview

The Central Role of Fibrinolytic Response in COVID-19—A Hematologist’s Perspective

by Hau C. Kwaan and Paul F. Lindholm

Int. J. Mol. Sci. 2021, 22(3), 1283; https://doi.org/10.3390/ijms22031283 - 28 Jan 2021

Cited by 33 | Viewed by 5766

Abstract

The novel coronavirus disease (COVID-19) has many characteristics common to those in two other coronavirus acute respiratory diseases, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). They are all highly contagious and have severe pulmonary complications. Clinically, patients with COVID-19 [...] Read more.

The novel coronavirus disease (COVID-19) has many characteristics common to those in two other coronavirus acute respiratory diseases, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). They are all highly contagious and have severe pulmonary complications. Clinically, patients with COVID-19 run a rapidly progressive course of an acute respiratory tract infection with fever, sore throat, cough, headache and fatigue, complicated by severe pneumonia often leading to acute respiratory distress syndrome (ARDS). The infection also involves other organs throughout the body. In all three viral illnesses, the fibrinolytic system plays an active role in each phase of the pathogenesis. During transmission, the renin-aldosterone-angiotensin-system (RAAS) is involved with the spike protein of SARS-CoV-2, attaching to its natural receptor angiotensin-converting enzyme 2 (ACE 2) in host cells. Both tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) are closely linked to the RAAS. In lesions in the lung, kidney and other organs, the two plasminogen activators urokinase-type plasminogen activator (uPA) and tissue plasminogen activator (tPA), along with their inhibitor, plasminogen activator 1 (PAI-1), are involved. The altered fibrinolytic balance enables the development of a hypercoagulable state. In this article, evidence for the central role of fibrinolysis is reviewed, and the possible drug targets at multiple sites in the fibrinolytic pathways are discussed. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease)

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